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A Novel Polymeric Absorption Enhancer for the Oral Delivery of Macromolecules ⁎ M Journal of Controlled Release 117 (2007) 171–178 www.elsevier.com/locate/jconrel N-sulfonato-N,O-carboxymethylchitosan: A novel polymeric absorption enhancer for the oral delivery of macromolecules ⁎ M. Thanou a, , S. Henderson b, A. Kydonieus b, C. Elson c a Genetic Therapies Centre, Chemistry, Imperial College London, SW72AZ, London, United Kingdom b Kytogenics Pharmaceuticals, One Research Drive, Dartmouth, Canada NS B2Y 4M9 c Department of Chemistry, Saint Mary's University, Halifax, Nova Scotia, Canada Received 4 May 2006; accepted 7 November 2006 Available online 11 November 2006 Abstract Chitosan has been shown to act on the mucosal epithelial barriers mainly when protonated at acidic pH values in which it is soluble. Soluble chitosan is able to improve the permeation and absorption of neutral to cationic macromolecules only, as it forms polyelectrolyte complexes with anionic macromolecules. LMWH (Low Molecular Weight Heparin) is an anionic polysaccharide finding clinical application as an improved antithrombotic agent compared to Unfractionated Heparin (UFH). In this study we have employed N-sulfonato-N,O-carboxymethylchitosan (SNOCC) as a potential intestinal absorption enhancer of LMWH, Reviparin. SNOCC was prepared at 3 different viscosity grades 20, 40 and 60 cps and identified as SNOCC-20, SNOCC-40 and SNOCC-60, respectively. SNOCC materials were tested in vitro for their ability to decrease the Trans Epithelial Electrical Resistance (TEER) of Caco-2 cell monolayers. They were further tested as transport enhancers of hydrophilic compounds such as 14C-mannitol, FITC-Dextran (MW 4400 Da) and Reviparin (LMWH). Solutions of Reviparin, with or without SNOCC, were administered intraduodenally in vivo in rats and the absorption of the drug was assessed by measuring the Anti-Xa levels in rat plasma. In vitro studies showed that SNOCC materials were able to induce a concentration dependent decrease in the TEER of the Caco-2 monolayers. SNOCC- 40 and -60 were shown to decrease resistance more readily compared to the low viscosity SNOCC-20. 14C-mannitol permeation data across intestinal epithelia were in agreement with the observed decrease in TEER; the higher viscosity SNOCC-60 was the most effective demonstrating a 51-fold enhancement of the permeation of the radiolabeled marker. Studies with both FITC-Dextran and Reviparin demonstrated significantly increased permeation across Caco-2 cell monolayers when they were co-incubated at the apical side of the monolayer. Intestinal absorption of Reviparin in rats was increased when it was co-administered with SNOCC-40 and -60, in agreement with in vitro data. Anti-Xa levels were elevated to and above the antithrombotic levels and were sustained for at least 6 h, giving an 18.5-fold increase in the AUC of LMWH in rats. In conclusion, SNOCC-40 and -60 have been shown to enhance both permeation and absorption of Reviparin across intestinal epithelia proving their potential as polymeric absorption enhancers. © 2006 Elsevier B.V. All rights reserved. Keywords: SNOCC; Reviparin; LMWH; Chitosan; Oral delivery 1. Introduction [4]. It is postulated that the transient and reversible opening of the tight junctions should increase the permeation and intestinal Oral administration of macromolecules is restricted by the absorption of therapeutic macromolecules [1,5]. intestinal epithelial barrier [1,2] which results in greatly reduced Oral administration of the anticoagulant heparin and LMWH bioavailability and unpredictable pharmacokinetics and phar- would be beneficial for the prevention of deep vein thrombosis macodynamics [3]. Hydrophilic macromolecules are not (DVT) [6]. A number of strategies have been suggested for the absorbed by the enterocytes unless their transport is carrier- development of an “oral heparin” the most successful of which mediated. The paracellular route appears to be the preferred is the co-administration with small carriers [named SNACs; pathway, however, this route is restricted by the tight junctions sodium N-(8-[7] amino) caprylate)] that are able to interact with macromolecules such as heparins to allow for a more absorbable ⁎ Corresponding author. conformation [5,8]. SNAC has delivered UFH (Unfractionated E-mail address: [email protected] (M. Thanou). Heparin) efficiently and safely to patients undergoing elective 0168-3659/$ - see front matter © 2006 Elsevier B.V. All rights reserved. doi:10.1016/j.jconrel.2006.11.002 172 M. Thanou et al. / Journal of Controlled Release 117 (2007) 171–178 total hip arthroplasty in clinical trials [9]. In these trials, Anti-Xa Reviparin (reviparin sodium) is a low molecular weight levels peaked at 40–60 min after oral absorption and returned heparin (LMWH; 3900 Da) that catalyses the inactivation of to baseline by 4 h [9]. SNAC was tested with LMWH and was factors Xa and IIa by binding to antithrombin which ultimately shown to decrease caval thrombosis in a porcine model of deep leads to the inhibition of the clotting cascade. It is administered vein thrombosis and to increase plasma levels of antifactor Xa subcutaneously for the treatment and/or prevention of DVT. [10,11]. Reviparin in dosages of 7000 to 12,600 Anti-Xa IU/day was It has been suggested that molecules of the SNAC-type affect found to be as effective as intravenous UFH in preventing the the transcellular rather than the paracellular transport of heparin clinical recurrence of acute DVTand/or pulmonary embolism [7]. across the intestinal epithelia. Using a series of fluorescent In general, LMWHs are considered to be improved antic- probes and Caco-2 cells, it was shown by microscopy that oagulants and are preferred clinically for the prevention and heparin transport in the presence of SNAC was selective and did treatment of DVT [6]. It has been recognized that LMWHs not involve permeabilization of the plasma membrane or tight provide a more predictable anticoagulant response but their use junction disruption [12]. is limited by the need for subcutaneous administration [24]. LMW heparin conjugates with deoxycholate have been In this study, we investigated the use of polymeric absorption developed as a prodrug approach to permeation enhancement enhancers for the oral delivery of LMWH. Reviparin was used [13]. The conjugates were administered in mice in 10% DMSO as the LMWH to be administered orally and N-sulfonato-N,O- and produced an increased oral bioavailability [14]. Assessment carboxymethylchitosan (SNOCC), a novel chitosan derivative, of the conjugate's mechanism of absorption showed increased was employed as the absorption enhancer. SNOCCs of different particulate absorption by the ileum without damage or lesions viscosity grades were investigated for their effect on the TEER [15]. In this latter study, the conjugate was co-administered with and permeability of Caco-2 cells using a series of paracellular deoxycholate and it was suggested that free deoxycholic acid markers. Then, the most effective formulations of SNOCC were induced a decrease in particle size and a concomitant increase in tested for their ability to affect the intestinal absorption of absorption [15]. LMWH after intraduodenal administration in rats. In the cases of SNAC-Heparin complex and the Deoxycho- late-LMWH conjugate, the absorption is achieved through 2. Materials and methods increased transcytosis of either molecular assemblies or nanoparticles, respectively. With this type of absorption, the 2.1. Materials enhancer is absorbed by enterocytes as well as the drug, and though claimed to be metabolically inactive and safe, the LMWH, Reviparin (108 Anti-Xa U/mg, MW 3900 Da) was enhancer follows its own pharmacokinetics. obtained from Knoll, Germany. Caco-2 cells were obtained Sodium caprate, a known paracellular permeation enhancer, from the ATCC. Trypsin, EDTA, FITC-Dextran, Dulbecco's has been tested as a permeation enhancer of heparin with Caco-2 Modified Eagle's Medium (DMEM), Hank's Balanced Salt cells and rats. A 2-fold increase in drug transport was observed Solution-w/o phenol red, (HBSS), n-(2-hydroxyethyl) pipera- with Caco-2 cells; whereas, when administered in rats, it pro- zine-N-(2-ethanosulfonic acid) (HEPES), benzyl-penicillin G vided a 27% oral bioavailability relative to subcutaneous ad- and streptomycin sulfate and SO3-pyridine were all obtained ministration [16]. Sodium caprate acts on the tight junctions and, from Sigma. Fetal calf serum was from Hyclone, The Nether- therefore, alters the paracellular permeability of epithelia [17]. lands. 14C-Mannitol (MW 182.2; specific radioactivity 57 mCi/ An alternative approach that precludes the permeation mmol) was obtained from Amersham-Pharmacia, The Nether- enhancer from being absorbed is the use of polymers as lands. Scintillation cocktail Ultima Gold, was obtained from permeability enhancers. Polymers of high molecular weight can Packard, The Netherlands. Chromostrate heparin Anti-Xa assay alter the permeability of intestinal epithelia [17–19]. Different kits were purchased from Organon Teknika, The Netherlands. structural polymers have been found to increase the absorption of LMWH: mucoadhesive Carbopol 934P or thiolated chitosans 2.2. Preparation of N-sulfonato-N,O-carboxymethylchitosan and polycarbophil, known as thiomers, have shown increased SNOCC polymers absorption of LMWH to anticoagulant levels [18,20–22]. Mono-N-Carboxymethylchitosan (MCC), a polyampholyte Derivatives of NOCC, N,O-carboxymethylchitosan, contain- − + chitosan derivative, has been shown to increase the paracellular ing sulfonate
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