{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,10]],"date-time":"2026-08-10T12:28:55Z","timestamp":1786364935026,"version":"build-2736575974"},"reference-count":52,"publisher":"MDPI AG","issue":"16","license":[{"start":{"date-parts":[[2026,8,10]],"date-time":"2026-08-10T00:00:00Z","timestamp":1786320000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"DuNing Incorporated"},{"name":"NCKU Research and Development Foundation","award":["107S238"],"award-info":[{"award-number":["107S238"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>Glaucoma is an ocular disease caused by the improper management of elevated intraocular pressure (IOP). IOP-lowering via topical administration is the first choice to prevent further progression. However, patients may forget to administer their medication, compromising IOP control. To address this problem, a prolonged active pharmaceutical ingredient (API) release system is proposed. A new prodrug (latanoprost acid\u2013brimonidine conjugate, LBJ) was designed and expected to achieve potential long-lasting release of APIs. LBJ was synthesized by two methods. First, Steglich esterification without protecting the hydroxyl group led to a yield of 34.24%. However, the integral ratio between LPA and BM obtained from NMR was 1.25:1, indicating a potential side product resulting from further coupling through the unprotected hydroxyl group in LBJ. As an alternative route, Steglich esterification with a protecting agent, tert-butyldimethylchlorosilane (TBDMSCl), resulted in a yield of 39.35%, and the integral ratio between LPA and BM obtained from NMR was 1:1. The hydrolysis time of LBJ was investigated and compared with that of latanoprost (LP). In the presence of esterase (0.4 U\/mL), the hydrolysis times of LP and LBJ were 4 h and 28 days, respectively. The prolonged hydrolysis time results in sustained APIs release, which is beneficial for the development of a sustained drug release system.<\/jats:p>","DOI":"10.3390\/molecules31162780","type":"journal-article","created":{"date-parts":[[2026,8,10]],"date-time":"2026-08-10T11:38:09Z","timestamp":1786361889000},"page":"2780","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Latanoprost Acid\u2013Brimonidine, a New Amide Prodrug for Glaucoma Management Based on the Concept of Sustained Release"],"prefix":"10.3390","volume":"31","author":[{"ORCID":"https:\/\/orcid.org\/0009-0002-3303-4824","authenticated-orcid":false,"given":"Hong-Jia","family":"Lin","sequence":"first","affiliation":[{"name":"Department of Chemical Engineering, National Cheng Kung University, Tainan 701, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shih-Horng","family":"Su","sequence":"additional","affiliation":[{"name":"DuNing Incorporated, Tustin, CA 92780, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wen-Chung","family":"Wu","sequence":"additional","affiliation":[{"name":"Department of Chemical Engineering, National Cheng Kung University, Tainan 701, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,8,10]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"902","DOI":"10.1016\/j.ophtha.2024.02.008","article-title":"Relationship between Intraocular Pressure Fluctuation and Visual Field Progression Rates in the United Kingdom Glaucoma Treatment Study","volume":"131","author":"Rabiolo","year":"2024","journal-title":"Ophthalmology"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"101303","DOI":"10.1016\/j.preteyeres.2024.101303","article-title":"The relationship between intraocular pressure and glaucoma: An evolving concept","volume":"103","author":"Asrani","year":"2024","journal-title":"Prog. Retin. Eye Res."},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Patton, G.N., and Lee, H.J. (2024). Chemical Insights into Topical Agents in Intraocular Pressure Management: From Glaucoma Etiopathology to Therapeutic Approaches. Pharmaceutics, 16.","DOI":"10.3390\/pharmaceutics16020274"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"618","DOI":"10.1016\/j.mayocpiqo.2022.09.007","article-title":"Updates on the Diagnosis and Management of Glaucoma","volume":"6","author":"Wagner","year":"2022","journal-title":"Mayo Clin. Proc. Innov. Qual. Outcomes"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"735","DOI":"10.1007\/s13346-016-0339-2","article-title":"A comprehensive insight on ocular pharmacokinetics","volume":"6","author":"Agrahari","year":"2016","journal-title":"Drug Deliv. Transl. Res."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"507","DOI":"10.2174\/1389200043335342","article-title":"Role of Metabolism in Ocular Drug Delivery","volume":"5","author":"Duvvuri","year":"2004","journal-title":"Curr. Drug Metab."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"4231","DOI":"10.1021\/pr300358k","article-title":"Human cornea proteome: Identification and quantitation of the proteins of the three main layers including epithelium, stroma, and endothelium","volume":"11","author":"Dyrlund","year":"2012","journal-title":"J. Proteome Res."},{"key":"ref_8","first-page":"175","article-title":"Ocular prodrugs: Attributes and challenges","volume":"16","author":"Kour","year":"2021","journal-title":"Asian J. Pharm. Sci."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1080\/17425247.2016.1208649","article-title":"Advances in the use of prodrugs for drug delivery to the eye","volume":"14","author":"Taskar","year":"2017","journal-title":"Expert. Opin. Drug Deliv."},{"key":"ref_10","first-page":"232","article-title":"Prodrug Design: An Overview","volume":"5","author":"Shirke","year":"2015","journal-title":"Int. J. Pharm. Chem. Biol. Sci. IJPCBS"},{"key":"ref_11","first-page":"1134","article-title":"From PGF2a-Isopropyl Ester to Latanoprost, a reviwew of the development of xalatan","volume":"425","author":"Stjernschantz","year":"2001","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_12","first-page":"1967","article-title":"Latanoprost in the treatment of glaucoma","volume":"8","author":"Alm","year":"2014","journal-title":"Clin. Ophthalmol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"205","DOI":"10.3109\/02713688109001850","article-title":"Reduction of intraocular pressure in normal and glaucomatous primate (Aotus trivirgatus) eyes by topically applied prostaglandin F2\u03b1","volume":"1","author":"Camras","year":"1981","journal-title":"Curr. Eye Res."},{"key":"ref_14","first-page":"1987","article-title":"Prostaglandin F2\u03b1 Formation from Prostaglandin H2 by Prostaglandin F Synthase (PGFS): Crystal Structure of PGFS Containing Bimatoprost","volume":"45","author":"Komoto","year":"2006","journal-title":"Am. Chem. Soc."},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Yamada, H., Yoneda, M., Gosho, M., Kato, T., and Zako, M. (2016). Bimatoprost, latanoprost, and tafluprost induce differential expression of matrix metalloproteinases and tissue inhibitor of metalloproteinases. BMC Ophthalmol., 16.","DOI":"10.1186\/s12886-016-0202-8"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"3887","DOI":"10.1167\/iovs.06-0036","article-title":"Effect of latanoprost on the expression of matrix metalloproteinases and their tissue inhibitors in human trabecular meshwork cells","volume":"47","author":"Oh","year":"2006","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_17","first-page":"1308","article-title":"Metalloproteinases as mediators of inflammation and the eyes: Molecular genetic underpinnings governing ocular pathophysiology","volume":"10","author":"Singh","year":"2017","journal-title":"Int. J. Ophthalmol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"208","DOI":"10.1089\/jop.2019.0146","article-title":"Matrix Metalloproteinases and Glaucoma Treatment","volume":"36","author":"Weinreb","year":"2020","journal-title":"J. Ocul. Pharmacol. Ther."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"108","DOI":"10.3109\/13816810.2016.1164193","article-title":"Prostaglandins in the eye: Function, expression, and roles in glaucoma","volume":"38","author":"Doucette","year":"2017","journal-title":"Ophthalmic Genet."},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Zhou, L., Zhan, W., and Wei, X. (2022). Clinical pharmacology and pharmacogenetics of PGA in glaucoma. Frontier, 13.","DOI":"10.3389\/fphar.2022.1015338"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"S107","DOI":"10.1016\/j.survophthal.2008.08.010","article-title":"Update on the mechanism of action of topical prostaglandins for intraocular pressure reduction","volume":"53","author":"Toris","year":"2008","journal-title":"Surv. Ophthalmol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"337","DOI":"10.2147\/tcrm.2006.2.4.337","article-title":"Brimonidine in the treatment of glaucoma and ocular hypertension","volume":"2","author":"Cantor","year":"2006","journal-title":"Ther. Clin. Risk Manag."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"115","DOI":"10.1080\/14656566.2018.1544241","article-title":"Brimonidine tartrate for the treatment of glaucoma","volume":"20","author":"Oh","year":"2019","journal-title":"Expert. Opin. Pharmacother."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"380","DOI":"10.4103\/ijo.IJO_1158_21","article-title":"Neuroprotection in glaucoma","volume":"70","author":"Vishwaraj","year":"2022","journal-title":"Indian. J. Ophthalmol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"220","DOI":"10.1097\/00061198-200106000-00014","article-title":"Effectiveness and Safety of Brimonidine as Adjunctive Therapy for Patients with Elevated Intraocular Pressure in a Large, Open-label Community Trial","volume":"10","author":"Lee","year":"2001","journal-title":"J. Glaucoma"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"473","DOI":"10.1016\/S0021-5155(03)00106-0","article-title":"A short-term study of the additive effect of latanoprost 0.005% and brimonidine 0.2%","volume":"47","author":"Erdogan","year":"2003","journal-title":"Jpn. J. Ophthalmol."},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Munawar, S., Zahoor, A.F., Hussain, S.M., Ahmad, S., Mansha, A., Parveen, B., Ali, K.G., and Irfan, A. (2024). Steglich esterification: A versatile synthetic approach toward the synthesis of natural products, their analogues\/derivatives. Heliyon, 10.","DOI":"10.1016\/j.heliyon.2023.e23416"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"3799","DOI":"10.1139\/v73-569","article-title":"The tert-Butyldimethylsilyl Group as a Protecting Group in Deoxynucleosides","volume":"51","author":"Ogilvi","year":"1973","journal-title":"Can. J. Chem."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"723","DOI":"10.1021\/ol063113h","article-title":"An Operationally Simple and Efficient Work-up Procedure for TBAF-mediated Desilylation; Application to Halichondrin Synthesis","volume":"9","author":"Kaburagi","year":"2007","journal-title":"Org. Lett."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"401","DOI":"10.1089\/10807680260362687","article-title":"Causes of Non-Compliance with Drug Regimens in Glaucoma Patients: A Qualitative Study","volume":"18","author":"Taylor","year":"2002","journal-title":"J. Ocul. Pharmacol. Ther."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"393","DOI":"10.1097\/00061198-200310000-00001","article-title":"Compliance Barriers in Glaucoma: A Systematic Classification","volume":"12","author":"Tsai","year":"2003","journal-title":"J. Glaucoma"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"924","DOI":"10.1038\/eye.2008.103","article-title":"Barriers to adherence with glaucoma medications: A qualitative research study","volume":"23","author":"Lacey","year":"2009","journal-title":"Eye"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"441","DOI":"10.2147\/PPA.S23780","article-title":"Objective assessment of compliance and persistence among patients treated for glaucoma and ocular hypertension: A systematic review","volume":"5","author":"Reardon","year":"2011","journal-title":"Patient Prefer. Adherence"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"2863","DOI":"10.1007\/s40123-023-00797-8","article-title":"Factors Affecting Glaucoma Medication Adherence and Interventions to Improve Adherence: A Narrative Review","volume":"12","author":"Moore","year":"2023","journal-title":"Ophthalmol. Ther."},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Zaharia, A.C., Dumitrescu, O.M., Radu, M., and Rogoz, R.E. (2022). Adherence to Therapy in Glaucoma Treatment-A Review. J. Pers. Med., 12.","DOI":"10.3390\/jpm12040514"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1","DOI":"10.20935\/AcadMed6126","article-title":"Improving compliance and evaluating physician\u2013patient concerns in glaucoma: A pilot study","volume":"1","author":"Albdour","year":"2023","journal-title":"Acad. Med."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"2653","DOI":"10.1007\/s40123-025-01241-9","article-title":"Clinical Benefits of Preservative-Free Treatment for Glaucoma with a Focus on Preservative-Free Latanoprost","volume":"14","author":"Dhaliwal","year":"2025","journal-title":"Ophthalmol. Ther."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"738","DOI":"10.1016\/j.ophtha.2014.11.022","article-title":"Impact of the introduction of generic latanoprost on glaucoma medication adherence","volume":"122","author":"Stein","year":"2015","journal-title":"Ophthalmology"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"2575","DOI":"10.1007\/s10792-023-02637-x","article-title":"Implantable sustained-release drug delivery systems: A revolution for ocular therapeutics","volume":"43","author":"Cong","year":"2023","journal-title":"Int. Ophthalmol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"658","DOI":"10.1038\/s41433-024-03134-w","article-title":"Sustained-release drug delivery systems","volume":"39","author":"Williams","year":"2025","journal-title":"Eye"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"343","DOI":"10.1080\/07853890.2021.1955146","article-title":"Sustained release glaucoma therapies: Novel modalities for overcoming key treatment barriers associated with topical medications","volume":"54","author":"Belamkar","year":"2022","journal-title":"Ann. Med."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"S6","DOI":"10.1016\/S0039-6257(02)00302-8","article-title":"Ocular and Systemic Pharmacokinetics of Latanoprost in Humans","volume":"47","author":"Stjernschantz","year":"2002","journal-title":"Surv. Ophthalmol."},{"key":"ref_43","doi-asserted-by":"crossref","unstructured":"Zhou, Q., Yan, B., Sun, W., Chen, Q., Xiao, Q., Xiao, Y., Wang, X., and Shi, D. (2021). Pig Liver Esterases Hydrolyze Endocannabinoids and Promote Inflammatory Response. Front. Immunol., 12.","DOI":"10.3389\/fimmu.2021.670427"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"1483","DOI":"10.1124\/dmd.122.000993","article-title":"Activity and Expression of Carboxylesterases and Arylacetamide Deacetylase in Human Ocular Tissues","volume":"50","author":"Hammid","year":"2022","journal-title":"Drug Metab. Dispos."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"1305","DOI":"10.1021\/acs.molpharmaceut.0c01154","article-title":"Carboxylesterase Activities and Protein Expression in Rabbit and Pig Ocular Tissues","volume":"18","author":"Hammid","year":"2021","journal-title":"Mol. Pharm."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"100145","DOI":"10.1016\/j.dmd.2025.100145","article-title":"Characterization of hydrolase activity in ocular tissues of humans and preclinical species","volume":"53","author":"Li","year":"2025","journal-title":"Drug Metab. Dispos."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"15564","DOI":"10.1038\/s41598-019-51580-4","article-title":"Pig liver esterases PLE1 and PLE6: Heterologous expression, hydrolysis of common antibiotics and pharmacological consequences","volume":"9","author":"Zhou","year":"2019","journal-title":"Sci. Rep."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"457","DOI":"10.1007\/s40266-020-00769-8","article-title":"Bimatoprost Implant: First Approval","volume":"37","author":"Shirley","year":"2020","journal-title":"Drugs Aging"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"703","DOI":"10.2147\/DDDT.S506520","article-title":"Bimatoprost Intracameral Implant (Durysta\u00ae): A New Era in Glaucoma Management Through Sustained-Release Innovation","volume":"19","author":"Vagiakis","year":"2025","journal-title":"Drug Des. Devel. Ther."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"160","DOI":"10.4103\/JAPAJ.JAPAJ_49_25","article-title":"Revolutionizing Glaucoma Treatment: The FDA-approved iDose\u2122 Travoprost Intracameral Implant","volume":"3","author":"Dalabeh","year":"2025","journal-title":"JAPA Acad. J."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"211","DOI":"10.1186\/s12951-026-04141-7","article-title":"Mucoadhesive and corneal permeable nano eye drops for improved anti-glaucoma therapy","volume":"24","author":"Zhang","year":"2026","journal-title":"J. Nanobiotechnol."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"355","DOI":"10.1016\/j.ijbiomac.2016.10.035","article-title":"Bioadhesive chitosan-loaded liposomes: A more efficient and higher permeable ocular delivery platform for timolol maleate","volume":"94","author":"Tan","year":"2017","journal-title":"Int. J. Biol. Macromol."}],"container-title":["Molecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1420-3049\/31\/16\/2780\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,10]],"date-time":"2026-08-10T11:38:19Z","timestamp":1786361899000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1420-3049\/31\/16\/2780"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,8,10]]},"references-count":52,"journal-issue":{"issue":"16","published-online":{"date-parts":[[2026,8]]}},"alternative-id":["molecules31162780"],"URL":"https:\/\/doi.org\/10.3390\/molecules31162780","relation":{},"ISSN":["1420-3049"],"issn-type":[{"value":"1420-3049","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,8,10]]}}}