{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,25]],"date-time":"2026-10-25T02:45:14Z","timestamp":1792896314631,"version":"4.5.0"},"reference-count":176,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2025,8,20]],"date-time":"2025-08-20T00:00:00Z","timestamp":1755648000000},"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>In this review, our intention was to shed some light on the history of sublingual and buccal delivery over the past 75 years. By searching the query sublingual and buccal, we noticed four steady growth periods in the number of publications between 1950 and 2025. The early phase of sublingual and buccal drug delivery (1950\u20131982) saw limited attempts to explore this delivery route. The exploratory growth phase (1983\u20131993) was marked by the use of nitroglycerin to treat angina, calcium channel blockers to treat hypertension, ACE inhibitors to treat heart conditions, the use of opioids in pain management therapy, and peptide and hormonal therapy. The diversification and discovery phase (1994\u20132009) was marked by the introduction of small molecules for the treatment of opioid use disorder and analgesia, the use of animal models to enhance the pharmacokinetic understanding of the sublingual and buccal route, the use of penetration enhancers, peptide and hormonal therapy, and few marked FDA drug approvals in this area. The innovation and integration phase (2010\u20132025) was marked by the use of nanoparticles, multilayered mucoadhesive systems, pediatric formulations (fast-dissolving films and tablets), immunotherapy and vaccine delivery, and a broad spectrum of therapeutic agents, such as steroids, antifungals, cannabinoids, antidepressants, antipsychotics, and narcotics (e.g., buprenorphine and apomorphine), novel formulations of fentanyl and diazepam for pain and seizure control, and the introduction of buccal vitamin D3 sprays. Understanding the history of sublingual and buccal delivery demonstrates a growing area of research focused on enhancing mucosal drug delivery for achieving local and systemic therapeutic benefits.<\/jats:p>","DOI":"10.3390\/pharmaceutics17081073","type":"journal-article","created":{"date-parts":[[2025,8,20]],"date-time":"2025-08-20T07:50:46Z","timestamp":1755676246000},"page":"1073","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":38,"title":["Sublingual and Buccal Delivery: A Historical and Scientific Prescriptive"],"prefix":"10.3390","volume":"17","author":[{"given":"Sina","family":"Bahraminejad","sequence":"first","affiliation":[{"name":"Department of Pharmaceutical Sciences, University of Tennessee Health Science Center, 881 Madison Ave, Rm 661, Memphis, TN 38018, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8059-1637","authenticated-orcid":false,"given":"Hassan","family":"Almoazen","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences, University of Tennessee Health Science Center, 881 Madison Ave, Rm 661, Memphis, TN 38018, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,8,20]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"661","DOI":"10.2165\/00003088-200241090-00003","article-title":"Oral Mucosal Drug Delivery: Clinical Pharmacokinetics and Therapeutic Applications","volume":"41","author":"Zhang","year":"2002","journal-title":"Clin. 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