{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,26]],"date-time":"2026-08-26T20:14:29Z","timestamp":1787775269012,"version":"build-2784847793"},"reference-count":59,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2021,5,4]],"date-time":"2021-05-04T00:00:00Z","timestamp":1620086400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceutics"],"abstract":"<jats:p>Ocular drug absorption after eye drop instillation has been widely studied, but partitioning phenomena and spatial drug distribution are poorly understood. We investigated partitioning of seven beta-blocking drugs in corneal epithelium, corneal stroma, including endothelium and conjunctiva, using isolated porcine tissues and cultured human corneal epithelial cells. The chosen beta-blocking drugs had a wide range (\u22121.76\u20130.79) of n-octanol\/buffer solution distribution coefficients at pH 7.4 (Log D7.4). In addition, the ocular surface distribution of three beta-blocking drugs was determined by matrix-assisted laser desorption\/ionization imaging mass spectrometry (MALDI-IMS) after their simultaneous application in an eye drop to the rabbits in vivo. Studies with isolated porcine corneas revealed that the distribution coefficient (Kp) between the corneal epithelium and donor solution showed a positive relationship and good correlation with Log D7.4 and about a 50-fold range of Kp values (0.1\u20135). On the contrary, Kp between corneal stroma and epithelium showed an inverse (negative) relationship and correlation with Log D7.4 based on a seven-fold range of Kp values. In vitro corneal cell uptake showed a high correlation with the ex vivo corneal epithelium\/donor Kp values. Partitioning of the drugs into the porcine conjunctiva also showed a positive relationship with lipophilicity, but the range of Kp values was less than with the corneal epithelium. MALDI-IMS allowed simultaneous detection of three compounds in the cornea, showed data in line with other experiments, and revealed uneven spatial drug distribution in the cornea. Our data indicate the importance of lipophilicity in defining the corneal pharmacokinetics and the Kp values are a useful building block in the kinetic simulation models for topical ocular drug administration.<\/jats:p>","DOI":"10.3390\/pharmaceutics13050658","type":"journal-article","created":{"date-parts":[[2021,5,5]],"date-time":"2021-05-05T22:51:42Z","timestamp":1620255102000},"page":"658","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":22,"title":["Partitioning and Spatial Distribution of Drugs in Ocular Surface Tissues"],"prefix":"10.3390","volume":"13","author":[{"given":"Anusha","family":"Balla","sequence":"first","affiliation":[{"name":"School of Pharmacy, University of Eastern Finland, Yliopistonranta 1, 70211 Kuopio, Finland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Seppo","family":"Auriola","sequence":"additional","affiliation":[{"name":"School of Pharmacy, University of Eastern Finland, Yliopistonranta 1, 70211 Kuopio, Finland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1540-1080","authenticated-orcid":false,"given":"Angus C.","family":"Grey","sequence":"additional","affiliation":[{"name":"School of Medical Sciences, University of Auckland, Auckland 1142, New Zealand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicholas J.","family":"Demarais","sequence":"additional","affiliation":[{"name":"School of Biological Sciences, University of Auckland, Auckland 1142, New Zealand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9905-8709","authenticated-orcid":false,"given":"Annika","family":"Valtari","sequence":"additional","affiliation":[{"name":"School of Pharmacy, University of Eastern Finland, Yliopistonranta 1, 70211 Kuopio, Finland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emma M.","family":"Heikkinen","sequence":"additional","affiliation":[{"name":"School of Pharmacy, University of Eastern Finland, Yliopistonranta 1, 70211 Kuopio, Finland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elisa","family":"Toropainen","sequence":"additional","affiliation":[{"name":"School of Pharmacy, University of Eastern Finland, Yliopistonranta 1, 70211 Kuopio, Finland"},{"name":"Institute of Clinical Medicine, University of Eastern Finland, Yliopistonranta 1, 70211 Kuopio, Finland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arto","family":"Urtti","sequence":"additional","affiliation":[{"name":"School of Pharmacy, University of Eastern Finland, Yliopistonranta 1, 70211 Kuopio, Finland"},{"name":"Faculty of Pharmacy, University of Helsinki, Viikinkaari, 00014 Helsinki, Finland"},{"name":"Institute of Chemistry, Saint Petersburg State University, 26 Universitetskii Prospect, 198504 Saint Petersburg, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kati-Sisko","family":"Vellonen","sequence":"additional","affiliation":[{"name":"School of Pharmacy, University of Eastern Finland, Yliopistonranta 1, 70211 Kuopio, Finland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marika","family":"Ruponen","sequence":"additional","affiliation":[{"name":"School of Pharmacy, University of Eastern Finland, Yliopistonranta 1, 70211 Kuopio, Finland"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,5,4]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"47","DOI":"10.5497\/wjp.v2.i2.47","article-title":"Ocular drug delivery systems: An overview","volume":"2","author":"Patel","year":"2013","journal-title":"World J. Pharmacol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1131","DOI":"10.1016\/j.addr.2006.07.027","article-title":"Challenges and obstacles of ocular pharmacokinetics and drug delivery","volume":"58","author":"Urtti","year":"2006","journal-title":"Adv. Drug Deliv. Rev."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"105553","DOI":"10.1016\/j.ejps.2020.105553","article-title":"Topical ocular pharmacokinetics and bioavailability for a cocktail of timolol, betaxolol and atenolol in rabbits","volume":"155","author":"Fayyaz","year":"2020","journal-title":"Eur. J. Pharm. Sci."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"529","DOI":"10.1016\/j.xphs.2020.09.051","article-title":"Comprehensive Ocular and Systemic Pharmacokinetics of Brinzolamide in Rabbits After Intracameral, Topical, and Intravenous Administration","volume":"110","author":"Naageshwaran","year":"2021","journal-title":"J. Pharm. Sci."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"673","DOI":"10.1002\/jps.2600680606","article-title":"Mechanistic and quantitative evaluation of precorneal pilocarpine disposition in albino rabbits","volume":"68","author":"Lee","year":"1979","journal-title":"J. Pharm. Sci."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"463","DOI":"10.1111\/j.2042-7158.1986.tb04611.x","article-title":"A comparison of the effect of viscosity on the precorneal residence of solutions in rabbit and man","volume":"38","author":"Zaki","year":"1986","journal-title":"J. Pharm. Pharmacol."},{"key":"ref_7","first-page":"1032","article-title":"A novel method to evaluate residence time in humans using a nonpenetrating fluorescent tracer","volume":"43","author":"Meadows","year":"2002","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1007\/978-3-642-69222-2_2","article-title":"Ocular Pharmacokinetics","volume":"Volume 69","author":"Maurice","year":"1984","journal-title":"Handbook of Experimental Pharmacology"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1016\/0169-409X(95)00010-5","article-title":"Ocular absorption following topical delivery","volume":"16","author":"Urtti","year":"1995","journal-title":"Adv. Drug Deliv. Rev."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"83","DOI":"10.1016\/j.ejps.2018.03.034","article-title":"Corneal and conjunctival drug permeability: Systematic comparison and pharmacokinetic impact in the eye","volume":"119","author":"Ramsay","year":"2018","journal-title":"Eur. J. Pharm. Sci."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"147","DOI":"10.1016\/0378-5173(85)90005-5","article-title":"Systemic absorption of ocular pilocarpine is modified by polymer matrices","volume":"23","author":"Urtti","year":"1985","journal-title":"Int. J. Pharm."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"159","DOI":"10.1089\/jop.1987.3.159","article-title":"Nasal and Conjunctival Contributions to the Systemic Absorption of Topical Timolol in the Pigmented Rabbit: Implications in the Design of Strategies to Maximize the Ratio of Ocular to Systemic Absorption","volume":"3","author":"Chang","year":"1987","journal-title":"J. Ocul. Pharmacol."},{"key":"ref_13","first-page":"1827","article-title":"Improved ocular: Systemic absorption ratio of timolol by viscous vehicle and phenylephrine","volume":"31","author":"Kyyronen","year":"1990","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"435","DOI":"10.1016\/0039-6257(93)90141-S","article-title":"Minimizing systemic absorption of topically administered ophthalmic drugs","volume":"37","author":"Urtti","year":"1993","journal-title":"Surv. Ophthalmol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"363","DOI":"10.1016\/0039-6257(79)90229-7","article-title":"Experimental studies on the mechanism of action of timolol","volume":"23","author":"Neufeld","year":"1979","journal-title":"Surv. Ophthalmol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"337","DOI":"10.3109\/02713689409167297","article-title":"Local efficacy of cyclosporine in corneal transplant therapy","volume":"13","author":"Oh","year":"1994","journal-title":"Curr. Eye Res."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"105","DOI":"10.1097\/01.iio.0000212135.77675.6a","article-title":"Topical cyclosporine for treatment of ocular surface disease","volume":"46","author":"Foulks","year":"2006","journal-title":"Int. Ophthalmol. Clin."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"631","DOI":"10.1016\/S0161-6420(99)00176-1","article-title":"Two multicenter randomized studies of the efficacy and safety of cyclosporine ophthalmic emulsion in moderate to severe dry eye disease","volume":"107","author":"Sall","year":"2000","journal-title":"Ophthalmology"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1790","DOI":"10.1016\/j.ophtha.2005.05.013","article-title":"Phase III safety evaluation of cyclosporine 0.1% ophthalmic emulsion administered twice daily to dry eye disease patients for up to 3 years","volume":"112","author":"Barber","year":"2005","journal-title":"Ophthalmology"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"E371","DOI":"10.1208\/aapsj0903044","article-title":"Preparation and ocular pharmacokinetics of ganciclovir liposomes","volume":"9","author":"Shen","year":"2007","journal-title":"AAPS J."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1266","DOI":"10.1002\/jps.2600721108","article-title":"Corneal penetration behavior of \u03b2-blocking agents I: Physicochemical factors","volume":"72","author":"Schoenwald","year":"1983","journal-title":"J. Pharm. Sci."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1699","DOI":"10.1016\/0002-9394(67)93652-5","article-title":"Gentamicin in the treatment of bacterial conjunctivitis","volume":"63","author":"Halasa","year":"1967","journal-title":"Am. J. Ophthalmol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"282","DOI":"10.1016\/j.ajo.2005.08.081","article-title":"Comparison of topical gatifloxacin 0.3% and ciprofloxacin 0.3% for the treatment of bacterial keratitis","volume":"141","author":"Parmar","year":"2006","journal-title":"Am. J. Ophthalmol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"786","DOI":"10.1002\/jps.2600670614","article-title":"Relationship between steroid permeability across excised rabbit cornea and octanol-water partition coefficients","volume":"67","author":"Schoenwald","year":"1978","journal-title":"J. Pharm. Sci."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"97","DOI":"10.1016\/S0168-3659(97)00078-3","article-title":"Estimation of pore size and pore density of biomembranes from permeability measurements of polyethylene glycols using an effusion-like approach","volume":"49","author":"Kontturi","year":"1997","journal-title":"J. Control. Release"},{"key":"ref_26","first-page":"238","article-title":"Ocular drug delivery; Impact of in vitro cell culture models","volume":"4","author":"Barar","year":"2014","journal-title":"J. Ophthalmic Vis. Res."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"583","DOI":"10.1002\/jps.2600760802","article-title":"Physicochemical Determinants of Drug Diffusion across the Conjunctiva, Sclera, and Cornea","volume":"76","author":"Ahmed","year":"1987","journal-title":"J. Pharm. Sci."},{"key":"ref_28","first-page":"684","article-title":"Paracellular permeability of corneal and conjunctival epithelia","volume":"30","author":"Huang","year":"1989","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"329","DOI":"10.1089\/jop.1990.6.329","article-title":"Rate Limiting Barrier to the Penetration of Ocular Hypotensive Beta Blockers Across the Corneal Epithelium in the Pigmented Rabbit","volume":"6","author":"Shih","year":"1990","journal-title":"J. Ocul. Pharmacol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"571","DOI":"10.3109\/02713689109001766","article-title":"Lipophilicity influence on conjunctival drug penetration in the pigmented rabbit: A comparison with corneal penetration","volume":"10","author":"Wang","year":"1991","journal-title":"Curr. Eye Res."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"131","DOI":"10.1016\/j.ejps.2012.05.007","article-title":"Determination of permeability coefficients of ophthalmic drugs through different layers of porcine, rabbit and bovine eyes","volume":"47","author":"Loch","year":"2012","journal-title":"Eur. J. Pharm. Sci."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1222","DOI":"10.1002\/jps.2600660905","article-title":"Vehicle effects on ocular drug bioavailability II: Evaluation of pilocarpine","volume":"66","author":"Sieg","year":"1977","journal-title":"J. Pharm. Sci."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1002\/jps.2600770104","article-title":"Mechanisms of corneal drug penetration II: Ultrastructural analysis of potential pathways for drug movement","volume":"77","author":"Grass","year":"1988","journal-title":"J. Pharm. Sci."},{"key":"ref_34","first-page":"2581","article-title":"pH and drug ionization affects ocular pressure lowering of topical carbonic anhydrase inhibitors","volume":"34","author":"Brechue","year":"1993","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1398","DOI":"10.1007\/s11095-010-0132-8","article-title":"Prediction of the corneal permeability of drug-like compounds","volume":"27","author":"Kidron","year":"2010","journal-title":"Pharm. Res."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"296","DOI":"10.1002\/(SICI)1097-0029(19960301)33:4<296::AID-JEMT2>3.0.CO;2-O","article-title":"Conjunctiva","volume":"33","author":"Nichols","year":"1996","journal-title":"Microsc. Res. Tech."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"555","DOI":"10.1016\/S1350-9462(02)00038-1","article-title":"Regulation of mucin and fluid secretion by conjunctival epithelial cells","volume":"21","author":"Dartt","year":"2002","journal-title":"Prog. Retin. Eye Res."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"2463","DOI":"10.1016\/j.xphs.2017.04.061","article-title":"Impact of Chemical Structure on Conjunctival Drug Permeability: Adopting Porcine Conjunctiva and Cassette Dosing for Construction of In Silico Model","volume":"106","author":"Ramsay","year":"2017","journal-title":"J. Pharm. Sci."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"483","DOI":"10.3109\/02713688809031801","article-title":"Comparison of conjunctival and corneal surface areas in rabbit and human","volume":"7","author":"Watsky","year":"1988","journal-title":"Curr. Eye Res."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"215","DOI":"10.1016\/0378-5173(84)90164-9","article-title":"Effect of pH and buffer on the precorneal disposition and ocular penetration of pilocarpine in rabbits","volume":"19","author":"Ahmed","year":"1984","journal-title":"Int. J. Pharm."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1479","DOI":"10.1021\/js9802594","article-title":"Permeability of cornea, sciera, and conjunctiva: A literature analysis for drug delivery to the eye","volume":"87","author":"Prausnitz","year":"1998","journal-title":"J. Pharm. Sci."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"1409","DOI":"10.1023\/A:1025754026449","article-title":"Ocular pharmacokinetic modeling using corneal absorption and desorption rates from in vitro permeation experiments with cultured corneal epithelial cells","volume":"20","author":"Ranta","year":"2003","journal-title":"Pharm. Res."},{"key":"ref_43","doi-asserted-by":"crossref","unstructured":"Patton, T.F., and Robinson, J.R. (1976). Quantitative Precorneal Disposition of Topically Applied Pilocarpine Nitrate in Rabbit Eyes. J. Pharm. Sci., 65.","DOI":"10.1002\/jps.2600650909"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"98","DOI":"10.1002\/j.2055-2335.2007.tb00027.x","article-title":"Lipophilicity of beta-adrenocepter antagonists: A new classification scheme for clinical use","volume":"37","author":"Northfield","year":"2007","journal-title":"J. Pharm. Pract. Res."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"18","DOI":"10.1016\/j.ejpb.2019.08.008","article-title":"Role of retinal pigment epithelium permeability in drug transfer between posterior eye segment and systemic blood circulation","volume":"143","author":"Ramsay","year":"2019","journal-title":"Eur. J. Pharm. Biopharm."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"123","DOI":"10.1679\/aohc.66.123","article-title":"Use of a new adhesive film for the preparation of multi-purpose fresh-frozen sections from hard tissues, whole-animals, insects and plants","volume":"66","author":"Kawamoto","year":"2003","journal-title":"Arch. Histol. Cytol."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"e4460","DOI":"10.1002\/jms.4460","article-title":"Detection of small molecule concentration gradients in ocular tissues and humours","volume":"55","author":"Boughton","year":"2020","journal-title":"J. Mass Spectrom."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"99","DOI":"10.1016\/S0928-0987(03)00173-8","article-title":"Paracellular and passive transcellular permeability in immortalized human corneal epithelial cell culture model","volume":"20","author":"Toropainen","year":"2003","journal-title":"Eur. J. Pharm. Sci."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"1026","DOI":"10.1002\/jps.2600700915","article-title":"Mechanistic studies on transcorneal permeation of fluorometholone","volume":"70","author":"Sieg","year":"1981","journal-title":"J. Pharm. Sci."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"435","DOI":"10.1002\/jps.2600680411","article-title":"Pharmacokinetics of Topically Applied Pilocarpine in the Albino Rabbit Eye","volume":"68","author":"Makoid","year":"1979","journal-title":"J. Pharm. Sci."},{"key":"ref_51","first-page":"584","article-title":"Importance of the noncorneal absorption route in topical ophthalmic drug delivery","volume":"26","author":"Ahmed","year":"1985","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"e238","DOI":"10.1111\/aos.13889","article-title":"The penetration and distribution of topical atropine in animal ocular tissues","volume":"97","author":"Wang","year":"2019","journal-title":"Acta Ophthalmol."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1371\/journal.pone.0211376","article-title":"MALDI imaging mass spectrometry revealed atropine distribution in the ocular tissues and its transit from anterior to posterior regions in the whole-eye of rabbit after topical administration","volume":"14","author":"Mori","year":"2019","journal-title":"PLoS ONE"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"1239","DOI":"10.1177\/2472555217724780","article-title":"Application of Imaging Mass Spectrometry to Assess Ocular Drug Transit","volume":"22","author":"Grove","year":"2017","journal-title":"SLAS Discov."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"3968","DOI":"10.1021\/acs.molpharmaceut.9b00585","article-title":"Distribution of small molecular weight drugs into the porcine lens: studies on imaging mass spectrometry, partition coefficients, and implications in ocular pharmacokinetics","volume":"16","author":"Heikkinen","year":"2019","journal-title":"Mol. Pharm."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"335","DOI":"10.1089\/jop.1988.4.335","article-title":"Application Site Dependent Ocular Absorption of Timolol","volume":"4","author":"Urtti","year":"1988","journal-title":"J. Ocul. Pharmacol. Ther."},{"key":"ref_57","first-page":"296","article-title":"Central and Peripheral Corneal Thickness Measurement in Normal and Keratoconic Eyes Using Three Corneal Pachymeters","volume":"9","author":"Feizi","year":"2014","journal-title":"J. Ophthalmic Vis. Res."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"26","DOI":"10.1136\/bjo.28.1.26","article-title":"A Study of Epithelial Regeneration in the living EYE","volume":"28","author":"Mann","year":"1941","journal-title":"Br. J. Ophthalmol."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"560","DOI":"10.1038\/229560a0","article-title":"Role of the Pericorneal Papillary Structure in Renewal of Corneal Epithelium","volume":"229","author":"Davanger","year":"1971","journal-title":"Nature"}],"container-title":["Pharmaceutics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1999-4923\/13\/5\/658\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T05:57:10Z","timestamp":1760162230000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1999-4923\/13\/5\/658"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,5,4]]},"references-count":59,"journal-issue":{"issue":"5","published-online":{"date-parts":[[2021,5]]}},"alternative-id":["pharmaceutics13050658"],"URL":"https:\/\/doi.org\/10.3390\/pharmaceutics13050658","relation":{},"ISSN":["1999-4923"],"issn-type":[{"value":"1999-4923","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,5,4]]}}}