Thiomer

Thiolated polymers or designated thiomers were first described by Andreas Bernkop-Schnürch et al.^[1] in 1999. One year later the same research group introduced the name thiomers.^[2] They are mucoadhesive polymers which display thiol group bearing side chains. In brief, low molecular mass thiol group bearing compounds are covalently bound to a polymeric backbone. This backbone consists of well-established and safe polymers such as chitosan or poly(acrylic acid). It has been demonstrated in various studies, that thiomers exhibit mucoadhesive, permeation enhancing, controlled release as well as enzyme and efflux pump inhibitory properties. These features make the thiomer technology highly interesting for non-invasive delivery routes, including in first instance the oral but also the nasal, buccal and vaginal route. Thiomers can be directly compressed to tablets or given as solutions. Furthermore thiomer based micro- and nanoparticles have already been developed. In 2012 a second generation of thiomers – so called preactivated or S-protected thiomers – were introduced. ^[3] In contrast to thiomers of the first generation preactivated thiomers are stable towards oxidation and display comparatively higher mucoadhesive and permeation enhancing properties. ^[4]

Numerous original research and review articles as well as book contributions have been published in recent years:

Review articles

Bernkop-Schnürch A. Chitosan and its derivatives: potential excipients for peroral peptide delivery systems. Int J Pharm 2000;194(1):1-13.
Bernkop-Schnürch A. Thiomers: A new generation of mucoadhesive polymers. Adv Drug Deliv Rev 2004;57(11):1569-82.
Albrecht K. and Bernkop-Schnürch A. Thiomers: forms, functions and applications to nanomedicine. Nanomedicine. 2007 Feb;2(1):41-50.
Bernkop-Schnürch A., Krauland A.H., Leitner V.M., Palmberger T. Thiomers: potential excipients for non-invasive peptide delivery systems. Eur J Pharm Biopharm. 2004 Sep;58(2):253-63.
Bonengel S, Bernkop-Schnürch A. Thiomers—from bench to market. J Control Release. 2014 Dec 10;195:120-9.
Ijaz M, Bernkop-Schnürch A. Preactivated thiomers: their role in drug delivery. Expert Opin Drug Deliv. 2015 Aug;12(8):1269-81.

Original research articles

Mucoadhesion

Thiomers are capable of forming disulfide bonds with cysteine substructures of the mucus gel layer covering mucosal membranes. Because of this property they exhibit up to 100-fold higher mucoadhesive properties in comparison to the corresponding unthiolated polymers.

Grabovac V, Guggi D, Bernkop-Schnurch A. Comparison of the mucoadhesive properties of various polymers. Adv Drug Deliv Rev. 2005 Nov 3;57(11):1713-23
Bernkop-Schnürch A, Kast CE, Richter MF. Improvement in the mucoadhesive properties of alginate by the covalent attachment of cysteine. J Control Release 2001;71:277-85.

Permeation enhancement

Thiomers are able to reversibly open tight junctions. Due to thiolation the permeation enhancing effect of polymers such as polyacrylic acid or chitosan can be up to 10-fold ımproved.

Bernkop-Schnürch A, Kast CE, Guggi D. Permeation enhancing polymers in oral delivery of hydrophilic macromolecules: thiomer/GSH systems. J Control Release 2003;93(2):95-103.
Langoth N, Kalbe J, Bernkop-Schnurch A. Development of a mucoadhesive and permeation enhancing buccal delivery system for PACAP (pituitary adenylate cyclase-activating polypeptide). Int J Pharm. 2005 May 30;296(1-2):103-11.

Efflux pump inhibition

Thiomers are able to reversibly inhıbit efflux pumps. Because of this property the mucosal uptake of various efflux pump substrates such as anticancer drugs, antimycotic drugs and antiinflammatory drugs can be tremendously ımproved.

Werle M, Hoffer M. Glutathione and thiolated chitosan inhibit multidrug resistance P-glycoprotein activity in excised small intestine. J Control Release 2006;111(1-2):41-6.
Föger F, Hoyer H, Kafedjiiski K, Thaurer M, Bernkop-Schnürch A. In vivo comparison of various polymeric and low molecular mass inhibitors of intestinal P-glycoprotein. Biomaterials 2006;27(34):5855-60.

Enzyme inhibition

Due to the binding of metal ions, which are needed by various enzymes to maintain their enzymatic activity, thiomers are potent reversible inhibitors of various enzymes.

Valenta C, Marschutz M, Egyed C, Bernkop-Schnürch A. Evaluation of the inhibition effect of thiolated poly(acrylates) on vaginal membrane bound aminopeptidase N and release of the model drug LH-RH. J Pharm Pharmacol 2002;54(5):603-10.
Bernkop-Schnürch A, Walker G, Zarti H. Thiolation of polycarbophil enhances its inhibition of intestinal brush border membrane bound aminopeptidase N. J Pharm Sci 2001;90(11):1907-14.

References

↑ Bernkop-Schnürch, Andreas; Schwarz, Veronika; Steininger, Sonja (1999). "Polymers with Thiol Groups: A New Generation of Mucoadhesive Polymers". Pharm. Res. 16: 876–881.
↑ Bernkop-Schnürch, Andreas; Steininger, Sonja (2000). "Synthesis and characterisation of mucoadhesive thiolated polymers". Int. J. Pharm. 194: 239–247.
↑ Iqbal, J; Shahnaz, G; Dünnhaupt, S; Müller, C; Hintzen, F; Bernkop-Schnürch, A (2012). "Preactivated thiomers as mucoadhesive polymers for drug delivery". Biomaterials. 33 (5): 1528–1535. doi:10.1016/j.biomaterials.2011.10.021.
↑ Ijaz, M; Bernkop-Schnürch, A (2015). "Preactivated thiomers: their role in drug delivery". Expert Opin Drug Deliv. 12 (8): 1269–1281. doi:10.1517/17425247.2015.1005598.

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