Oral Transmucosal Drug Delivery Research Articles

New insights into nanomedicines for oral delivery of glucagon-like peptide-1 analogs.

Type 2 diabetes mellitus (T2DM) is a metabolic disorder that arises when the body cannot respond fully to insulin, leading to impaired glucose tolerance. Currently, the treatment embraces non-pharmacological actions (e.g., diet and exercise) co-associated with the administration of antidiabetic drugs. Metformin is the first-line treatment for T2DM; nevertheless, alternative therapeutic strategies involving glucagon-like peptide-1 (GLP-1) analogs have been explored for managing the disease. GLP-1 analogs trigger insulin secretion and suppress glucagon release in a glucose-dependent manner thereby, reducing the risk of hyperglycemia. Additionally, GLP-1 analogs have an extended plasma half-life compared to the endogenous peptide due to their high resistance to degradation by dipeptidyl peptidase-4. However, GLP-1 analogs are mainly administered via subcutaneous route, which can be inconvenient for the patients. Even considering an oral delivery approach, GLP-1 analogs are exposed to the harsh conditions of the gastrointestinal tract (GIT) and the intestinal barriers (mucus and epithelium). Hereupon, there is an unmet need to develop non-invasive oral transmucosal drug delivery strategies, such as the incorporation of GLP-1 analogs into nanoplatforms, to overcome the GIT barriers. Nanotechnology has the potential to shield antidiabetic peptides against the acidic pH and enzymatic activity of the stomach. In addition, the nanoparticles can be coated and/or surface-conjugated with mucodiffusive polymers and target intestinal ligands to improve their transport through the intestinal mucus and epithelium. This review focuses on the main hurdles associated with the oral administration of GLP-1 and GLP-1 analogs, and the nanosystems developed to improve the oral bioavailability of the antidiabetic peptides. This article is categorized under: Therapeutic Approaches and Drug Discovery > Nanomedicine for Infectious Disease Nanotechnology Approaches to Biology > Nanoscale Systems in Biology.

Composite dissolvable microneedle patch for therapy of oral mucosal diseases.

A composite microneedle patch (MN patch) is developed for oral transmucosal administration. To improve the oral transmucosal drug delivery efficiency, the composite MN patch is designed to consist of an array of 100 dissolvable microneedles (MNs) with drug-loaded tips and a backing layer. The MNs are composed of two parts, the hyaluronic acid (HA) tip part and the polyvinylpyrrolidone (PVP) base part. Due to the small size and sufficient mechanical strength, the HA-PVP MNs can painlessly penetrate the oral mucosa barrier and deliver drugs directly to the basal layer or submucosa. Betamethasone sodium phosphate (BSP), as the model drug, is concentrated in the HA tip parts to avoid the drug waste caused by mucosa elasticity. Considering the special moist environment and saliva flow in the mouth, a double-layer backing layer composed of a poly(vinyl alcohol) (PVA) adhesive layer and an ethyl cellulose (EC) waterproof layer is designed and constructed, which could reduce the saliva flow effects. The in vitro and in vivo results demonstrate that the MN patch could achieve rapid and efficient BSP release in oral mucosa due to the rapid dissolution of HA. The proposed MN patch provides a novel strategy for the therapy of oral mucosal diseases.

Mucoadhesive Nanocarriers as a Promising Strategy to Enhance Intracellular Delivery against Oral Cavity Carcinoma.

Oral cancer, particularly squamous cell carcinoma (SCC), has posed a grave challenge to global health due to its high incidence, metastasis, and mortality rates. Despite numerous studies and favorable improvements in the therapeutic strategies over the past few decades, the prognosis of this disease remains dismal. Moreover, several drawbacks are associated with the conventional treatment; including permanent disfigurement and physical impairment that are attributed to surgical intervention, and systemic toxicity that results from aggressive radio- or chemotherapies, which impacts patients’ prognosis and post-treatment quality of life. The highly vascularized, non-keratinized oral mucosa appears as a potential route for cytotoxic drug administration in treating oral cancer. It acts as a non-invasive portal for drug entry targeting the local oral lesions of the early stages of cancer and the systemic metastasis sites of advanced cancer. The absorption of the poorly aqueous-soluble anti-cancer drugs can be enhanced due to the increased permeability of the ulcerous mucosa lining in the disease state and by bypassing the hepatic first-pass metabolism. However, some challenges in oral transmucosal drug delivery include the drugs’ taste, the limited surface area of the membrane lining the oral cavity, and flushing and enzymatic degradation by saliva. Therefore, mucoadhesive nanocarriers have emerged as promising platforms for controlled, targeted drug delivery in the oral cavity. The surface functionalization of nanocarriers with various moieties allows for drug targeting, bioavailability enhancement, and biodistribution at the site of action, while the mucoadhesive feature prolongs the drug’s residence time for preferential accumulation to optimize the therapeutic effect and reduce systemic toxicity. This review has been focused to highlight the potential of various nanocarriers (e.g., nanoparticles, nanoemulsions, nanocapsules, and liposomes) in conferring targeting, solubility and bioavailability enhancement of actives and mucoadhesive properties as novel tumor-targeted drug delivery approaches in oral cancer treatment.

A novel versatile flow-donor chamber as biorelevant ex-vivo test assessing oral mucoadhesive formulations

Oral transmucosal drug delivery is a non-invasive administration route for rapid therapeutic onset and greater bioavailability avoiding the first-pass metabolism. Mucoadhesive formulations are advantageous as they may retain the drug at the administration site. Proper equipment to assess mucoadhesive properties and corresponding drug absorption is fundamental for the development of novel drug delivery systems. Here we developed a new flow-through donor chamber for well-established diffusion cells, and we tested the effects on drug and formulation retention in situ of adding mucoadhesive polymers or mesoporous silica particles to a reference formulation. Mesoporous silica particles are of particular interest as they may be used to encapsulate and retain drug molecules. Compared to other ex-vivo methods described in literature for assessing mucoadhesive performance and transmucosal drug delivery, this new donor chamber provides several advantages: i) it reflects physiological conditions better as a realistic saliva flow can be provided over the administration site, ii) it is versatile since it can be mounted on any kind of vertical diffusion cell allowing simultaneous detection of drug retention at the administration site and drug permeation through the tissue, and iii) it enables optical quantification of formulations residence time aided by image processing. This new flow-through donor diffusion cell set-up proved sensitive to differentiate a reference formulation from one where 20 %(w/w) Carbomer was added (to further improve the mucoadhesive properties), with respect to both drug and formulation residence times. We also found that mesoporous silica particles, investigated as particles only and mixed together with the reference formulation, gave very similar drug and formulation retention to what we observed with the mucoadhesive Carbomer. However, after some time (>30 min) it became obvious that the tablet excipients in the reference formulation promote particle retention on the mucosa. This work provides a new simple and versatile biorelevant test for the evaluation of oral mucoadhesive formulations and paves the way for further studies on mesoporous silica particles as valuable excipients for enhancing oral mucoadhesion.

Prevention of diabetes-associated fibrosis: Strategies in FcRn-targeted nanosystems for oral drug delivery.

Diabetes mellitus is a chronic disease with an elevated risk of micro- and macrovascular complications, such as fibrosis. To prevent diabetes-associated fibrosis, the symptomatology of diabetes must be controlled, which is commonly done by subcutaneous injection of antidiabetic peptides. To minimize the pain and distress associated with such injections, there is an urgent need for non-invasive oral transmucosal drug delivery strategies. However, orally administered peptide-based drugs are exposed to harsh conditions in the gastrointestinal tract and poorly cross the selective intestinal epithelium. Thus, targeting of drugs to receptors expressed in epithelial cells, such as the neonatal Fc receptor (FcRn), may therefore enhance uptake and transport through mucosal barriers. This review compiles how in-depth studies of FcRn biology and engineering of receptor-binding molecules may pave the way for design of new classes of FcRn-targeted nanosystems. Tailored strategies may open new avenues for oral drug delivery and provide better treatment options for diabetes and, consequently, fibrosis prevention.

BUCCAL DRUG DELIVERY SYSTEM : HISTORY AND RECENT DEVELOPMENTS

Abstract Of the various routes of drug delivery, the oral route is most ancient as well as preferred by the patient being convenient to take. However, peroral administration of drugs has short comings such as hepatic first-pass metabolism and enzymatic degradation within the GI-tract which comprehend a hindrance to the absorption of peptides and protein group of drug. The drug absorption takesplace faster as it is in contact with the absorption surface. The drug delivery system helps the drug to remain at the same place of application longer for once or twice daily dosing. For some drugs alternate way of administration results in novel methods of action as opposed to the above said procedure. The characteristics of the oral mucosa as well as physicochemical properties of the drug poses as a hindrance to the oral mucosal administration of some drugs. Commercial availability of drug is restricted, although most of the drugs are qualitatively assessed for oral transmucosal delivery. The clinical benefit produced by an oral transmucosal dosage form is good eventhough the production of this dosage form is expensive. Transmucosal products are the recent drug delivery strategies. Delivery through transmucosal benefits the absorption four times than that of skin. Considering the availability of products, only some drugs are used for oral transmucosal delivery. So new drugs have to be processed and developed inorder to meet the limited transmucosal drug delivery. Present paper intends to emphasis the importance of oral transmucosal drug delivery and also highlights on the latest advancement in the field.

A SMART ORO-SOFT PALATE MUCOSAL DRUG DELIVERY: CREDENTIALS AND FUTURE TRENDS

Over the last few decades pharmaceutical scientists throughout the world are trying to explore transdermal and transmucosal routes as an alternative to injections. The main impediment for the oral delivery of the drugs as potential therapeutic agents is their extensive pre-systemic metabolism, instability in acidic environment associated with inadequate and erratic oral absorption. The parenteral route is the only established route that overcomes all the drawbacks related with the orally inefficient drugs. However the parenteral formulations are expensive, need frequent administration, with less patient compliance and other harmful effects. Since ancient times oral transmucosal drug delivery has received intensive interest for the systemic delivery of drugs proved to have better systemic bioavailability achieved by oromucosal route. Oral mucosal drug delivery provides an alternative method of systemic drug delivery which offers many advantages for both parenterals and oral methods. The oral mucosa is highly vascularised, hence drugs which are absorbed through the oral mucosa directly enter into the systemic circulation, bypassing the enzymes present in the gastrointestinal tract and first-pass metabolism in the liver. The various transmucosal sites available are sublingual and buccal, but also the soft-palatal mucosa was found to be the most convenient and easily accessible novel site for the delivery of therapeutic agents for systemic delivery as retentive dosage forms. It has adequate blood supply, rapid cellular recovery time after exposure to stress, flexible, smooth surface, devoid of mechanical irritation, local discomfort and non-invasive route. Recently soft palate route explore more attention towards the scientist as an alternative to buccal route for administering drugs using mucoadhesive drug delivery dosage forms. This review focuses the more recent advances in novel soft palate route and formulation strategies to design dosage forms to administer drug through this novel soft palate route.

Oral Strip Technology: A review

Over the recent past, many of the research groups are focusing their research on this technology. Amongst Oral drug delivery system Oral Strip Technology (OST) is gaining much attention. The advantages of OST are the administration to pediatric and geriatric patient population where the difficulty of swallowing larger oral dosage forms is eliminated. This technology has been used for local action, rapid release products and for buccoadhesive systems that are retained in the oral cavity to release drug in controlled fashion. OST offers an alternate platform for molecules that undergo first pass metabolism and for delivery of peptides. An ideal OST should have the following properties: high stability, transportability, ease of handling and administration, no special packaging material and/or processing requirements, no water necessary for application, and a pleasant taste. All these requirement are fulfilled by the oral films. The OST is a good tool for product life cycle management for increasing the patent life of existing molecules or products. Compared to some of the complicated and expensive process (like lyophilization) used to manufacture ODTs(Orally Disintegrating Tablets), the OST is relatively easy to fabricate,thus reducing the overall cost of the therapy. One of the reasons is that the buccal mucosa is less permeable and is thus not able to elicit a rapid onset of absorption and hence better suited for formulations that are intended for sustained release action. Further, the buccal mucosa being relatively immobile mucosa and readily accessible, it makes it more advantageous for retentive systems used for oral trans mucosal drug delivery. The primary disadvantage associated with buccal delivery route is the low flux that in turn results in low drug bioavailability. To overcome this hurdle, various buccal penetration enhancers have been studied which improve the absorption pattern of the molecules. The article shows OST encompassing materials used in OST, method of preparation, evaluation, applications, commercial technologies and future Business prospects of this technology.

Oral transmucosal drug delivery--current status and future prospects.

Oral transmucosal drug delivery (OTDD) dosage forms have been available since the 1980s. In contrast to the number of actives currently delivered locally to the oral cavity, the number delivered as buccal or sublingual formulations remains relatively low. This is surprising in view of the advantages associated with OTDD, compared with conventional oral drug delivery. This review examines a number of aspects related to OTDD including the anatomy of the oral cavity, models currently used to study OTDD, as well as commercially available formulations and emerging technologies. The limitations of current methodologies to study OTDD are considered as well as recent publications and new approaches which have advanced our understanding of this route of drug delivery.

Mucoadhesive Polymers for Oral Transmucosal Drug Delivery: A Review

The oral mucosa offers an interesting site for the application of dosage forms that release drugs within/throughout the oral mucosa, by assuring a high drug bioavailability for topic and systemic effects. However, the relative permeability of the oral mucosa and the washing effect related to the oral fluids and mechanical stresses must be considered in the formulation of oral dosage forms. Since a sustained drug release can be guaranteed only if dosage forms remain in contact with the oral site of absorption/application for a prolonged time, the development of mucoadhesive dosage forms is mandatory. The mucoadhesion is a complex phenomenon and the mucoadhesive bond consists of two different parts, the mucoadhesive polymers and the mucous substrate. In addition to factors related to the oral mucosa and oral environment features, the physical-chemical characteristics of mucoadhesive polymers must be also considered as factors influencing the mucoadhesive bonds. While it is not possible to modify the mucosal features or it is possible to modify or inhibit only in part certain mucosal processes, the knowledge of polymer properties influencing mucoadhesive bonds allows to modify or to control these properties in developing increasingly effective mucoadhesive systems. The aims of this review are to discuss the several mechanisms and factors behind the phenomenon of mucoadhesion with particular reference to the features of the oral environment, oral mucosa, and polymeric compounds influencing mucoadhesion process. Finally, a brief mention to the main mucoadhesive dosage forms designed for oral transmucosal drug delivery is made.

Creating systemic oral transmucosal drug delivery strategies: Case study of APL-130277

This article addresses the strategic application of systemic oral transmucosal* (i.e., sublingual and buccal) drug delivery. Circumvention of first-pass hepatic metabolism in the gut, rapid onset of action, easy access via the oral cavity, easy administration for patients with dysphagia and a high level of patient acceptance are the principal advantages of the oral transmucosal route. Key clinical and commercial strategies driving the development of oral transmucosal formulations are addressed. A case study of Cynapsus Therapeutics' APL-130277, a sublingual apomorphine formulation in clinical development for Parkinson's disease exemplifies the scientific, clinical and commercial considerations for systemic oral transmucosal drug delivery. *Note: In this article, oral transmucosal delivery refers to systemic drug delivery through the sublingual or buccal mucosa. Local delivery to the oral mucosa is not included.

Transport mechanisms in oral transmucosal drug delivery: Implications for pain management

The mechanism for the oral transmucosal delivery of fentanyl citrate (OTFC) was investigated in this work. A developed mathematical model included the following transport characteristics: dissolution of the fentanyl citrate lozenge, diffusion through the saliva and oral mucosal membrane and equilibrium between adjacent layers. An orthogonal-collocation-based solution procedure was adopted to discretize the governing equations and boundary conditions. The Mathematica® built-in function, NDSolve, was applied to integrate the equations with respect to time. Simulations were conducted with a 200 μg-dosage. A novel fabrication method, aimed at maintaining a high flux for a prolonged period of time, was proposed based on the calculated delivery rate and cumulative amount of medicament absorbed into the systemic circulation. The model allows drug manufacturers to decide when to replace the unit based on estimated drug concentrations in the saliva and the mucosal membrane. Both the model and solution strategies were validated using serum fentanyl citrate concentration collected from adult subjects. The predicted profiles, based on parameters obtained from the literature, agree well with the experimental data.

Absorption and tolerability of BEMA (BioErodible MucoAdhesive) fentanyl in cancer subjects with grade 1 mucositis

20559 Background: Oral transmucosal delivery of fentanyl is a rapid and proven route of administration for the management of breakthrough pain in cancer patients. The BEMA drug delivery system was designed for rapid oral transmucosal drug delivery with dose to dose reliability of plasma concentrations and ease of patient use. BEMA fentanyl consists of a small, dissolvable, polymer disc formulated with the opioid narcotic fentanyl for application to the buccal membranes. In subjects with normal intact oral mucosa, fentanyl is rapidly absorbed from BEMA fentanyl. This study was designed to determine if the absorption of fentanyl is more rapid or extensive in the presence of grade 1 mucositis and if the disc causes irritation to the mucosa membrane. Methods: Seven cancer subjects with grade 1 mucositis and seven age- and gender-matched control cancer subjects without mucositis received a single open-label dose of BEMA fentanyl 200 μg applied to the buccal mucosa. Serial blood samples for analysis of fentanyl plasma concentrations were collected immediately prior to application of BEMA fentanyl and for 4 hours post-dosing. All subjects were monitored for safety throughout the study and were serially questioned regarding irritation at the application site. Results: Overall fentanyl exposure following the 200 μg BEMA fentanyl dose was not higher in subjects with mucositis than those without, as assessed by the mean 4-hour AUC (1.14 vs. 1.29 hr*ng/mL, respectively) and mean Cmax values (0.47 vs. 0.69 ng/mL, respectively). All seven subjects with mucositis became mucositis pain-free at one or more time points following BEMA fentanyl application. The only observed adverse event was mild somnolence reported by two subjects with mucositis. There was no evidence of respiratory depression or significant changes in blood pressure. Conclusions: Application of BEMA fentanyl to an area of grade 1 mucositis does not expose cancer patients to a risk of increased fentanyl plasma concentrations compared to cancer patients without mucositis. BEMA fentanyl is well tolerated at a 200 μg dose in subjects with and without mucositis and does not cause local irritation on application to an area of grade 1 mucositis. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration BioDelivery Sciences International BioDelivery Sciences International BioDelivery Sciences International BioDelivery Sciences International

Adverse events affecting the mouth in two clinical trials of BEMA (BioErodible MucoAdhesive) Fentanyl

20648 Background: The BEMA drug delivery system was designed for rapid oral transmucosal drug delivery with dose to dose reliability of plasma concentrations and ease of patient use. BEMA Fentanyl consists of a small, dissolvable, polymer disc formulated with the opioid narcotic fentanyl for application to the buccal (inner lining of cheek) membranes. The mucoadhesive polymers adhere and rapidly deliver fentanyl across the capillary-rich mucosa. Methods: Subjects with cancer-related breakthrough pain who were receiving concomitant chronic opioid therapy were enrolled in two studies: a double-blind, randomized, placebo-controlled, multiple crossover study (FEN-201) and an open-label study (FEN-202). In FEN-201, subjects entered a titration period followed by a double-blind period during which they received 6 doses of BEMA Fentanyl and 3 doses of placebo in random sequence. In FEN-202, subjects successfully completing FEN-201 and a second group of subjects meeting the same entry criteria as for FEN-201 were enrolled. Subjects in both studies were titrated to an effective dose (starting at 200 μg) and then continued with dosage adjustment as required. Results: In FEN-201, 5 of 151 subjects (3.3%) reported oral mucosa-associated adverse events (AEs), including 2 subjects with mucosal inflammation (mucositis) and 3 subjects with oral candidiasis (thrush). None of these events were considered to be related to BEMA Fentanyl, and none were severe in intensity. In FEN-202, adverse oral symptoms were seen in 11 of 220 subjects (5.0%). In 4 subjects, the symptoms were considered to be related to local cancer or infection. In the 7 remaining subjects, the oral events were considered to be potentially attributable to BEMA Fentanyl (3.2%). The events were mild in 6 subjects and moderate in 1 subject. None of the subjects discontinued use of BEMA Fentanyl in either FEN-201 or FEN-202 as a result of BEMA Fentanyl related adverse oral symptoms. Conclusions: In these studies, BEMA Fentanyl exhibited an excellent safety profile with respect to oral AEs, which is of particular importance in a population of cancer patients. Each of the events is typical of the background condition and treatments of the study population. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration BioDelivery Sciences International BioDelivery Sciences International BioDelivery Sciences International BioDelivery Sciences International

The safety of BEMA (BioErodible MucoAdhesive) Fentanyl for breakthrough pain (BTP) in cancer patients

20586 Background: The BEMA drug delivery system was designed for rapid oral transmucosal drug delivery with dose to dose reliability of plasma concentrations and ease of patient use. BEMA Fentanyl consists of a small, dissolvable, polymer disc formulated with the opioid narcotic fentanyl for application to the buccal membranes. The mucoadhesive polymers adhere and rapidly deliver fentanyl into the bloodstream. Methods: Subjects with cancer-related breakthrough pain (BTP) who were receiving concomitant chronic opioid therapy were enrolled in two studies: a double-blind, randomized, placebo-controlled, multiple crossover study (FEN-201) and an open-label study (FEN-202). In FEN-201, subjects entered a titration period followed by a double-blind period and received BEMA Fentanyl or placebo in random order. In FEN-202, subjects successfully completing FEN-201 and a second group of subjects meeting the same entry criteria as for FEN-201 were enrolled to receive open-label BEMA Fentanyl. Subjects in both studies were titrated to an effective dose (starting at 200μg and increasing to 1200μg in FEN-201 and 2400μg in FEN-202) and then continued with dosage adjustment as required. Results: In FEN-201, 141 subjects received an average of 14 doses of study medication over the course of the study. In FEN-202, a total of 220 subjects (70 from FEN-201 and 150 additional subjects) entered the study and received an average of 2.9 doses/day for 111.9 days (maximum duration of 531 days) in the open-label period. The most commonly reported treatment-related adverse events (AEs) during the titration and double-blind periods of FEN-201 were somnolence (6.0%), nausea (5.3%), dizziness (4.6%), and vomiting (4.0%). In the long-term safety study (FEN-202), these 4 events and constipation were the most commonly reported treatment-related AEs. There were no reports of treatment-related respiratory depression or death in either study. No unexpected findings or adverse trends were noted in vital signs or physical examination findings. Conclusions: BEMA Fentanyl administered in doses of 200 to 2400μg was shown to be safe and well-tolerated with no unexpected safety concerns. The AE profile of BEMA Fentanyl was consistent with the use of an opioid in patients with cancer and chronic pain. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration BioDelivery Sciences International BioDelivery Sciences International BioDelivery Sciences International BioDelivery Sciences International

Uptake pharmacokinetics of the Fentanyl Oralet in children scheduled for central venous access removal: implications for the timing of initiating painful procedures.

The Fentanyl Oralet (Abbott Laboratories, Abbott Park, IL, USA) is an oral transmucosal drug delivery system. We previously examined pharmacokinetic parameters of children who had completed consumption of the Fentanyl Oralet. The present study was designed to clarify pharmacokinetic parameters during the consumption phase to determine if there is an optimal administration time before painful procedures. Patients, aged 3-10 years, who were scheduled for elective removal of central venous access devices under general anaesthesia, received a Fentanyl Oralet (fentanyl 10-15 microg x kg(-1)). Plasma fentanyl concentrations were measured by radioimmunoassay. Data from blood samples obtained during and after consumption of the Fentanyl Oralet from 17 patients in the present study were combined with data from our previous study to better characterize both the consumption and postconsumption concentration versus time profiles. Estimated fentanyl bioavailability (mean +/- SD) was low (36.1 +/- 0.4%), as were peak plasma concentrations (1.03 +/- 0.31 ng.ml-1), suggesting that many children swallowed a large fraction of the dose. This led to a relatively late and variable peak concentration time of 53 +/- 40 min. In addition, because of the apparently large degree of gastrointestinal absorption, concentration versus time curves were wide and flat. The wide and flat concentration versus time profile may allow flexibility in the timing of a painful procedure following Fentanyl Oralet administration. However, the variability of the time to peak concentration makes it difficult to suggest a minimum interval between Fentanyl Oralet consumption and the start of a painful procedure.

Transmucosal, Oral Controlled-Release, and Transdermal Drug Administration in Human Subjects: A Crossover Study with Melatonin

□ The effect of oral controlled-release (CR), oral transmucosal (buccal; TMD) and transdermal (TDD) drug delivery systems on plasma concentrations of melatonin (MT) and its principal metabolite in human subjects using a crossover, single dose design was evaluated. Twelve adult male volunteers participated in the study and received all three dosage forms on three separate occasions. All patch dosage forms were removed after 10 h of wear. Plasma concentrations of the parent drug and its metabolite, 6-sulfatoxymelatonin (MT6s) were measured by radioimmunoassay. Between-subject plasma concentrations of MT were very variable following both oral CR and TDD. Use of the oral CR system gave plasma MT profiles in some subjects that were initially similar to physiological levels, but then differed substantially from physiological in the rate of MT offset; in a few subjects, plasma MT levels remained consistently much below normal nocturnal physiological levels. Also, the ratio of metabolite to parent drug by the oral CR route was many times greater than physiological. TDD resulted in a significant delay in systemic drug levels and a gradual decline in drug delivery after patch removal, possibly due to deposition of melatonin in the skin. TDD failed to simulate the physiological plasma profile of MT (rapid achievement of steady-state blood levels and rapid decline after removal of the patch; i.e., so-called “square-wave” profile). TMD provided prompt systemic drug levels with less variability than oral CR or TDD delivery. Also, plasma MT levels fell promptly and rapidly after removal of the patch. No indication of mucosal deposition was observed. TMD was able to mimic the physiological plasma profiles of both MT and its principal metabolite.