Penetration enhancer

Penetration enhancers (also called chemical penetration enhancers, absorption enhancers or sorption promotors) are chemical compounds that can facilitate the penetration of active pharmaceutical ingredients (API) into or through the poorly permeable biological membranes. These compounds are used in some pharmaceutical formulations to enhance the penetration of APIs in transdermal drug delivery and transmucosal drug delivery (for example, ocular, nasal, oral and buccal).[1] They typically penetrate into the biological membranes and reversibly decrease their barrier properties.

Transdermal drug delivery

Human skin is a very impermeable membrane that protects the body from ingress of harmful substances and prevents water loss from underlying organs. However, this seriously limits the use of skin as a site for drug administration. One of the approaches to facilitate transdermal drug delivery is the use of penetration enhancers. Many different compounds have been explored as potential penetration enhancers to facilitate transdermal drug delivery. These include dimethylsulphoxide, azones (such as laurocapram), pyrrolidones (for example 2-pyrrolidone), alcohols (ethanol and decanol), glycols (for example propylene glycol), surfactants, urea, various hydrocarbons and terpenes.[2][3][4] Different potential skin site and modes of action were identified for penetration enhancement through the skin. In some cases, penetration enhancers may disrupt the packing motif of the intercellular lipid matrix or keratin domains. In other cases, drug penetration to the skin is facilitated because the penetration enhancer saturates the tissue and becomes a better system to dissolve the molecules of API.

Ocular drug delivery

Topical administration to the eye is usually characterised by very poor drug bioavailability due to several natural defence mechanisms, including nasolacrymal drainage, blinking, and poor permeability of the cornea. Enhancement of the corneal permeability to drug molecules is one of the strategies to improve the efficiency of topical drug delivery to the eye. Several classes of compounds have been researched as potential penetration enhancers through ocular membranes. These include chelating agents, cyclodextrins, surfactants, bile acids and salts, and crown ethers.[5] There are also reports on the use of cell penetrating peptides and chitosan as penetration enhancers in ocular drug delivery.[6] The most commonly used penetration enhancers in ocular formulations are benzalkonium chloride and ethylenediamine tetraacetate (EDTA). Benzalkonium chloride is often used as an antimicrobial preservative in eye drops[7] and EDTA is used as a chelating agent.

Nasal drug delivery

Cyclodextrins, chitosan, some surfactants, bile acids and salts, sodium tauro-24,25-dihydro-fusidate, and phospholipids were reported as penetration enhancers in nasal drug delivery both for humans and equines.[8] Chitosan is one of the most widely researched penetration enhancers in nasal drug delivery and it enhances the penetration of drugs by opening the tight junctions in the cell membranes.[9]

Oral drug delivery

Penetration enhancers have been applied to improve the absorption of poorly permeable, hydrophilic drugs or macromolecules.[10] Permeation enhancers that have been used successfully for oral drug development include medium-chain fatty acids like caprylic acid[11] or caprate, or its amino acid ester like Salcaprozate sodium (SNAC).[12] The above-mentioned permeation/penetration enhancers have a surfactant-like activity where they perturb the intestinal epithelium, promoting transcellular or paracellular absorption.[13]

References
  1. Maher, Sam; Casettari, Luca; Illum, Lisbeth (July 2019). "Transmucosal Absorption Enhancers in the Drug Delivery Field". Pharmaceutics. 11 (7): 339. doi:10.3390/pharmaceutics11070339. ISSN 1999-4923. PMC 6680553. PMID 31311173.
  2. Williams, Adrian C; Barry, Brian W (2004-03-27). "Penetration enhancers". Advanced Drug Delivery Reviews. Breaking the Skin Barrier. 56 (5): 603–618. doi:10.1016/j.addr.2003.10.025. ISSN 0169-409X. PMID 15019749.
  3. Ita, Kevin (2020-01-01), Ita, Kevin (ed.), "Chapter 5 - Chemical permeation enhancers", Transdermal Drug Delivery, Academic Press, pp. 63–96, ISBN 978-0-12-822550-9, retrieved 2022-11-15
  4. Lane, Majella E. (2013-04-15). "Skin penetration enhancers". International Journal of Pharmaceutics. 447 (1): 12–21. doi:10.1016/j.ijpharm.2013.02.040. ISSN 0378-5173. PMID 23462366.
  5. Moiseev, Roman V.; Morrison, Peter W. J.; Steele, Fraser; Khutoryanskiy, Vitaliy V. (July 2019). "Penetration Enhancers in Ocular Drug Delivery". Pharmaceutics. 11 (7): 321. doi:10.3390/pharmaceutics11070321. ISSN 1999-4923. PMC 6681039. PMID 31324063.
  6. Thareja, Abhinav; Hughes, Helen; Alvarez-Lorenzo, Carmen; Hakkarainen, Jenni J.; Ahmed, Zubair (February 2021). "Penetration Enhancers for Topical Drug Delivery to the Ocular Posterior Segment—A Systematic Review". Pharmaceutics. 13 (2): 276. doi:10.3390/pharmaceutics13020276. ISSN 1999-4923. PMC 7922526. PMID 33670762.
  7. Datta, Sandipan; Baudouin, Christophe; Brignole-Baudouin, Francoise; Denoyer, Alexandre; Cortopassi, Gino A. (April 2017). "The Eye Drop Preservative Benzalkonium Chloride Potently Induces Mitochondrial Dysfunction and Preferentially Affects LHON Mutant Cells". Investigative Ophthalmology & Visual Science. 58 (4): 2406–2412. doi:10.1167/iovs.16-20903. ISSN 0146-0404. PMC 5407244. PMID 28444329.
  8. Velloso, María Inés; Landoni, Fabiana (2022-03-28). "Penetration Enhancers for the Development of Intranasal Formulations for Use in Equines". International Journal of Equine Science. 1 (1): 16–32–16–32. ISSN 2805-3117.
  9. Rassu, Giovanna; Ferraro, Luca; Pavan, Barbara; Giunchedi, Paolo; Gavini, Elisabetta; Dalpiaz, Alessandro (December 2018). "The Role of Combined Penetration Enhancers in Nasal Microspheres on In Vivo Drug Bioavailability". Pharmaceutics. 10 (4): 206. doi:10.3390/pharmaceutics10040206. ISSN 1999-4923. PMC 6321492. PMID 30373187.
  10. Walsh, Edwin G; Adamczyk, Bozena E; Chalasani, Kishore B; Maher, Sam; O’Toole, Edel B; Fox, John S; Leonard, Thomas W; Brayden, David J (December 2011). "Oral delivery of macromolecules: rationale underpinning Gastrointestinal Permeation Enhancement Technology (GIPET®)". Therapeutic Delivery. 2 (12): 1595–1610. doi:10.4155/tde.11.132. ISSN 2041-5990. PMID 22833984.
  11. Tuvia, Shmuel; Pelled, Dori; Marom, Karen; Salama, Paul; Levin-Arama, Maya; Karmeli, Irina; Idelson, Gregory H.; Landau, Isaac; Mamluk, Roni (2014-08-01). "A Novel Suspension Formulation Enhances Intestinal Absorption of Macromolecules Via Transient and Reversible Transport Mechanisms". Pharmaceutical Research. 31 (8): 2010–2021. doi:10.1007/s11095-014-1303-9. ISSN 1573-904X. PMC 4153969. PMID 24558008.
  12. Buckley, Stephen T.; Bækdal, Tine A.; Vegge, Andreas; Maarbjerg, Stine J.; Pyke, Charles; Ahnfelt-Rønne, Jonas; Madsen, Kim G.; Schéele, Susanne G.; Alanentalo, Tomas; Kirk, Rikke K.; Pedersen, Betty L.; Skyggebjerg, Rikke B.; Benie, Andrew J.; Strauss, Holger M.; Wahlund, Per-Olof (2018-11-14). "Transcellular stomach absorption of a derivatized glucagon-like peptide-1 receptor agonist". Science Translational Medicine. 10 (467). doi:10.1126/scitranslmed.aar7047. ISSN 1946-6234. PMID 30429357. S2CID 53434572.
  13. Maher, Sam; Mrsny, Randall J.; Brayden, David J. (2016-11-15). "Intestinal permeation enhancers for oral peptide delivery". Advanced Drug Delivery Reviews. Oral delivery of peptides. 106: 277–319. doi:10.1016/j.addr.2016.06.005. hdl:10197/7800. ISSN 0169-409X. PMID 27320643.
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