索马鲁肽舌下口溶膜

Administration of drugs via the oromucosal route, especially using oral thin films, improves patient adherence compared to conventional oral and injectable methods. However, existing production techniques for oral thin films face considerable challenges in incorporating peptide and protein drugs. This study presents electrospun nanofiber‐based oral thin film as a viable platform for the sublingual delivery of semaglutide. This platform was tested in Göttingen minipigs, which showed a greater response to attenuation of weight gain.

This study aims to compare the single-dose pharmacokinetic profiles of semaglutide administered via sublingual, oral, and injectable routes in Sprague-Dawley rats. Semaglutide was delivered sublingually in a proprietary anhydrous suspension vehicle. Rats were randomized into five groups and received the following treatments: subcutaneous injection (0.011 mg/kg), sublingual suspension (1 mg/kg, prepared from either commercial tablets or peptide powder), and oral tablets (1 mg/kg and 20 mg/kg). Semaglutide was detectable in plasma within 2 minutes post-dosing in all groups except the oral 1 mg/kg group. Sublingual administration demonstrated lower variability in plasma concentrations compared to oral dosing. At 1 mg/kg, the sublingual route achieved a significantly higher area under the curve (AUC) than oral (82.53 vs.15.08 ng*h/ml, p=0.004), indicating improved bioavailability. The maximum plasma concentration (Cmax) was reached within 30 minutes for oral and sublingual routes, and at 8 hours for subcutaneous injection. The relative bioavailability was 0.06% for oral 1 mg/kg, 0.16% for oral 20 mg/kg, and 0.34% and 0.29% for sublingual 1 mg/kg using tablets or powder, respectively. No significant difference in AUC was observed between sublingual semaglutide prepared from oral tablets versus powder. These results highlight the potential of sublingual delivery of semaglutide and suggest this route may improve absorption while reducing variability. This proof-of-concept study supports further development of sublingual semaglutide formulations and pharmacokinetics research in humans.

Background: Clozapine (CLZ) is a potent antipsychotic drug that suppresses the symptoms of schizophrenia and mania. Clozapine falls into Class II (BCS); its poor bioavailability is attributed to low water solubility and an extensive first-pass effect. Objective: To prepare CLZ as a nanosuspension (NS) to improve its low water solubility and load it into a sublingual film to enhance oral bioavailability. Methods: CLZ nanosuspensions are prepared by the “solvent anti-solvent precipitation” method using Soluplus as a stabilizing agent. We evaluated the polydispersity index (PDI) and the particle size of the CLZ nanosuspension formulations. The optimized formula of CLZ nanosuspension is loaded directly onto a sublingual thin film, eliminating the need for freeze-drying for solidification by the solvent casting approach. The sublingual films were characterized by thickness, surface pH, folding endurance, disintegration time, and in vitro dissolution rate. Results: We selected the formula F1 sublingual film as the best, as it demonstrated a uniform thickness of 0.087mm, good flexibility, and a surface pH of 6.7. It disintegrated quickly in 13 seconds and had a faster in vitro dissolution rate (3 min) compared to the CLZ ordinary films. Conclusions: The results confirmed the success of CLZ NS as a sublingual thin film for dissolution rate enhancement, which may improve oral bioavailability.

The present research work aim was to formulate a fast-dissolving sublingual film containing Aripiprazole, which is used in the treatment of schizophrenia and bipolar disorder. Fast Dissolving Sublingual Film Containing Aripiprazole prepared by using the solvent casting method. Aripiprazole is a BCS IV drug with poor solubility and poor permeability causing poor systemic absorption. Fast dissolving sublingual film prepared by using Design-Expert® version13 software with 32 full factorial designs in which Film-forming polymer HPMC K4M and plasticizers like PEG 400, and PVA are used in different concentrations. The formulated batches was evaluated for mechanical properties, surface pH, folding endurance, drug content, swelling property, SEM analysis, and in vitro % drug release. The characterization of the film shows satisfactory results following mechanical properties of a film like weight variation and thickness. The formulation (F4, F12) containing the highest concentration of plasticizer shows a high folding endurance ranges from 90-100%. FTIR and DCS studies reveal that there are no interactions means drugs and excipients are compatible with each other. Formulation F4 is optimized batch passes evaluation parameters and maximum % drug release i.e. 98.79 % ±0.36 within 1.5 min. Therefore, the sublingual film is an effective approach for BCS IV and III class drugs by avoiding first-pass metabolism with rapid onset of action and better patient compliance in psychotic disorders.

Fast-dissolving films (FDFs) are innovative dosage forms offering advantages such as improved patient compliance, rapid onset of action, precise dosing, and favorable taste. Particularly beneficial for patients unable to swallow or require immediate drug absorption, FDFs dissolve rapidly in the mouth, releasing medication directly into the oral cavity. The sublingual application enhances drug delivery due to the high permeability of the sublingual mucosa, bypassing hepatic first-pass metabolism. This route is advantageous for drugs like losartan potassium (LP) and hydrochlorothiazide (HCZ), which benefit from enhanced bioavailability and faster onset of action. Preformulation studies included UV spectroscopy for λmax determination (LP: 282 nm, HCZ: 250 nm), DSC for thermal analysis (LP: 289.11°C, HCZ: 104.76°C), and solubility studies confirming LP’s solubility in acidic pH and HCZ’s increased solubility in pH 6.7 buffer. Compatibility studies using FTIR and DSC validated stability with excipients. Formulation optimization with HPMC E15 resulted in films with characteristics like film weight (145.66–167.0 mg), thickness (0.246–0.326 mm), folding endurance (898.0–1274.0), pH (6.0–6.70), disintegration time (77.66–174.6 s), tensile strength (77.04–141.90 g/cm²), and drug release profiles (LP: 68.78–96.22%, HCZ: 59.49–95.43% at 21 minutes). In summary, this study successfully developed LP and HCZ FDFs with optimized characteristics, demonstrating their potential in hypertension management and improving therapeutic outcomes.

Fast-dissolving pullulan films were developed as a final dosage form for the sublingual administration of nanocapsules containing nifedipine (NIFE). Eudragit® RS100 nanocapsule suspensions presenting 1 mg/mL of NIFE, 150 nm in size, and positive zeta potential were converted into films using pullulan through the solvent-casting method. The films retained the nanometric size profile of the original suspension and NIFE homogeneity content. The conversion of the nanocapsule suspension into films improved the stability of NIFE. SEM analysis identified smooth, uniform surfaces, while AFM revealed increased surface roughness in films containing nanocapsules. All films exhibited high deformability and flexibility, ensuring comfortable sublingual administration. The contact angle of the films was less than 90º, indicating a hydrophilic surface, corroborating the high swelling index (> 200%). Moreover, the films disintegrated and dispersed quickly, with values less than 3 min and 30 s, respectively, confirming their fast-dissolving nature. The in vitro release showed NIFE maintained its controlled release, reaching 66.95 ± 4.18% in 24 h. The porcine mucosa study demonstrated NIFE's ability to permeate sublingual tissue in 3.12 ± 0.89%.cm2 at the end of 6 h. This allows NIFE to reach the bloodstream and exert its effect. Besides, none of the samples induced irritation in the HET-CAM assay. The films showed strong adhesion to the sublingual mucosa of pigs, indicating their mucoadhesive nature, promising a longer retention time of NIFE in the sublingual route. The study has developed a NIFE-loaded nanocomposite sublingual film with promising performance across multiple in vitro and ex vivo critical endpoints.

No abstract available

Abstract Zolmitriptan (ZLT), a 5-HT1B/1D serotonin receptor agonist, is commonly used in the treatment of migraine. However, ZLT suffers from low oral bioavailability due to extensive hepatic metabolism, being a BCS class III drug (highly soluble, low permeability), and having a short biological half-life. To address these limitations, there is increasing interest in alternative routes and delivery systems to enhance ZLT’s therapeutic efficacy. This study aimed to develop a ZLT-loaded electrospun poly(vinyl alcohol) (PVA) nanofiber oral film to improve its biopharmaceutical properties. The film was prepared using the ESPIN-NANO electrospinning device, incorporating PVA, PEG 400, citric acid, methyl paraben and sucrose, with optimization based on a 24 full factorial design. The optimized film exhibited a smooth surface, cylindrical shape and a non-beaded, non-porous structure with an average diameter of 258±30 nm and an entrapment efficiency of 97.25%. Differential scanning calorimetry (DSC) and X-ray diffraction (XRD) studies confirmed the amorphization of ZLT. Attenuated total reflection Fourier-transform infrared (ATR-FTIR) spectroscopy indicated no chemical interactions between ZLT and the polymer. Ex-vivo permeability studies on palatal goat mucosa using a Franz diffusion cell demonstrated 100% permeability of the ZLT-loaded nanofiber film within 300 seconds. In-vitro cytotoxicity testing on human oral epithelial cells (TR146 cells) using the MTT assay showed no significant cytotoxicity. This innovative approach offers a potentially effective and beneficial method for delivering ZLT in migraine therapy. GRAPHICAL ABSTRACT

Orodispersible films (ODFs), easy to administer, flexible in dosage, and free of choking and aspiration risks, have drawn widespread attention as pediatric formulations. However, it is a great challenge to endow ODFs with sustained release due to their fast disintegration. Herein, we designed a novel orodispersible film load with dual-coated sustained-release microparticles (SRMPs) for children using topiramate as a model drug. SRMPs with a particle size of 98.32 ± 0.22 µm, fabricated with a pellet core, a drug layer, and a coating layer, were prepared by two microparticle coating steps. The sustained-release orodispersible films (SRODFs) with uniform distribution of SRMPs and favorable disintegration time showed good formability, mechanical properties, and palatability. The factors affecting drug release of the SRMPs and the SRODFs were further explored. More importantly, pharmacokinetics study in human demonstrated that, although the SRODFs had a longer mean retention time, they were bioequivalence compared with the commercially available extended-release products (Qudexy® XR). A strong in vivo-in vitro correlation of the SRODFs was established. Notably, the SRODFs can be loaded with other drugs other than topiramate, offering a promising formulation option for pediatric patients with different diseases.

Fixed-dose combination (FDC) of antihypertensive drugs improve efficacy, safety, and patient adherence over monotherapy. However, a FDC of telmisartan (TEL) and indapamide (IND), both poorly soluble BCS Class II drugs, has not been available yet. This study aimed to develop an orodispersible film (ODF) containing TEL and IND cyclodextrin (CD) inclusion complexes (ICs) to enhance solubility and offer a patient adherence dosage form. In the first phase of the study, phase-solubility analysis was performed with β-CD then the ICs were prepared via kneading and assessed for solubility enhancement and entrapment efficiency. In the second phase, ICs were incorporated into hydroxypropyl-methylcellulose (HPMC) based ODFs using solvent casting. The films were characterized for thickness, mass and content uniformity, surface pH, water content, folding endurance, Young’s modulus, FTIR, in vitro disintegration and dissolution. AL-type phase-solubility plots confirmed 1:1 complexation and enhanced solubility by 1.7–4.1 fold, with entrapment efficiency >95%. ICs-loaded ODFs were thin (0.138 mm), uniform in mass (236.39 mg) and content (TEL 97.22%, IND 102.09%), nearly neutral pH, and low in water (2.68%). Mechanical testing showed adequate flexibility and stiffness (100 N.mm⁻² modulus). Disintegration occurred in

This research work aimed to develop and evaluate an orodispersible film formulation of Naproxen using natural superdisintegrants. Naproxen is a non-selective nonsteroidal anti-inflammatory drug used to reduce pain, fever, and inflammation. Orodispersible films are thin polymeric strips that dissolve rapidly in the mouth without water requirement, offering quick drug delivery and improved patient compliance. The films were prepared by the solvent casting method using hydroxypropyl methylcellulose (HPMC) as the film-forming polymer, natural superdisintegrants for rapid disintegration, and polyethylene glycol as the plasticizer. A total of 10 formulation batches (F1-F10) were prepared with different polymer concentrations and plasticizer ratios. All formulations were evaluated for physical appearance, pH, thickness, weight variation, folding endurance, swelling property, transparency, drug content uniformity, in-vitro disintegration time, in-vitro dissolution studies, and drug release kinetics. The results showed that Naproxen films possessed uniform characteristics with thickness ranging from 0.7 -1.5 mm, good folding endurance, and rapid disintegration within 16-31 seconds. Drug content was uniform with relative standard deviation values below 6%. In-vitro dissolution studies demonstrated more than 90% drug release within 15 minutes for most formulations. The drug release followed zero-order, first-order, Higuchi, and Korsmeyer-Peppas models. These findings suggest that orodispersible Naproxen films represent a promising patient-friendly, fast-acting dosage form that can improve therapeutic effectiveness and patient compliance. Keywords: Orodispersible film, Naproxen, Natural superdisintegrants, Solvent casting, Drug release kinetics.

ABSTRACT. Lamotrigine (LTG), classified as BCS class II, is dissolved in cosolvent ethanol (EtOH) or ethyl acetate (EA) to enhance solubility. The objectives of this study are to identify the appropriate formulation of LTG orodispersible film (OF) based on hydroxypropyl methylcellulose Pharmacoat® 603 and polyvinyl alcohol (HPMC P.603/PVA) polymer with EtOH or EA solvency using Central Composite Design in Response Surface Methodology (CCD-RSM). An experimental approach was utilized to investigate the effect of cosolvent amount and HPMC P.603/PVA ratios on the film disintegration time (DT) and folding endurance (FE). The optimized OF-EA composition was 0.46 HPMC P.603/PVA ratio and 3.66% EA with a desirability of 0.817. In comparison, the optimal OF-EtOH composition was 0.87 HPMC P.603/PVA ratio and 6.19% EtOH with a desirability of 0.843. The characteristic data for the optimal formulas include: OF-EtOH: weight variation 92.05±4.81 mg, thickness 0.15±0.01 mm, DT 36.11±1.48 sec, and FE 310.33±5.03; and OF-EA: weight variation 93.72±1.50 mg, thickness 0.16±0.00 mm, DT 26.73±3.32 sec, and FE 470.6±37.44. Based on the OF-EtOH FE, the HPMC P.603/PVA ratio had a greater effect compared to the amount of EtOH (p<0.05). The analysis of variance (ANOVA) demonstrated that the amount of EA had a greater impact compared to the HPMC P.603/PVA ratio, with statistical significance (p<0.05). The EtOH cosolvent was preferable to EA based on the LTG solubility and OF dissolution profile. LTG OF had favorable physicochemical properties and showed promise as a rapid-dissolving formulation for therapeutic purposes.   Keywords: Central composite design, cosolvency, disintegration time, folding endurance, oral film.  

Tuberculosis (TB) is a major global health challenge, with high mortality rates. Conventional anti-TB dosage forms, such as tablets are often unsuitable for patients who struggle with swallowing, leading to poorcompliance. Therefore, this study aimed to develop orodispersible film (ODF) containing rifampicin, a widely used anti-TB drug. Rifampicin’s low aqueous solubility poses challenges for its incorporation into ODF andaffects its therapeutic effectiveness. To address these issues, rifampicin was first prepared as nanosuspension and subsequently dried before being formulated into ODF. Nanosuspension was stabilized using polyvinyl alcohol (PVA), poloxamer 188 (POX), and the combination at various concentrations. Nanosuspension was prepared using solvent-antisolvent precipitation followed by sonication and spray-drying. Spray-dried nanosuspension was characterized, and the optimal formula was used in ODF formulation through the solvent-casting method. Formulations PV2 (PVA 0.4%) and POX1 (POX 0.2%) showed the smallest particle sizes at 306±14.01 nm and 291±7.55 nm, respectively. After reconstitution, PV2 maintained particle size comparably to POX1. Spray-dried PV2 nanosuspension exhibited a 21.48-fold increase in saturated solubility compared to the pure rifampicin, and showed superior drug release, with 79% release versus 58% for the standard rifampicin suspension. ODF containing PV2 showed improved organoleptic properties and enhanced drug dissolution (82% vs 56%) compared to original rifampicin ODF. The formulation of rifampicin into nanosuspension stabilized by PVA and POX, followed by spray-drying, significantly improved solubility and drug release profile. This method also enhanced the organoleptic properties and dissolution of rifampicin in ODF, providing a promising strategy to boost rifampicin’s therapeutic efficacy in TB treatment, particularly for pediatric patients.

Background: Breast cancer is a leading cause of morbidity and mortality in women worldwide, with adherence to long-term endocrine therapy proving to be a major clinical challenge. Letrozole (LTZ), a third-generation aromatase inhibitor, is widely used in hormone receptor-sensitive breast cancer; however, its conventional oral tablet form often leads to poor compliance, especially in elderly and dysphagic patients. Objective: The current study aimed to develop and evaluate a patient friendly orodispersible film (ODF) of LTZ to enhance convenience, acceptability, and therapeutic adherence. Methods: LTZ-ODFs were formulated by solvent casting method using hydroxypropyl methylcellulose (HPMC E5) as a film-forming polymer and sodium starch glycolate (SSG) as superdisintegrant and the impact of varying amount of these excipients was evaluated on physicochemical properties and dissolution rate of LTZ. Various formulations (F1-F10) were prepared, the optimized formulation (F3) presented uniform thickness of 0.087 ± 0.013 mm, neutral surface pH (6.9 ± 0.4), excellent folding endurance, and rapid disintegration (14 ± 2 s). Results: In vitro dissolution studies demonstrated more than 95% drug release within 5 min, indicating rapid onset and effective drug dispersion. FTIR spectra confirmed drug excipient compatibility, and stability testing exhibited no significant changes under the accelerated conditions. Conclusion: The developed LTZ-ODF thus may represent a promising alternative delivery system offering improved compliance and enhanced therapeutic efficacy for breast cancer management.

Objectives Orodispersible films (ODFs) are new-generation dosage forms that increase patient compliance, providing ease of drug administration in many patient groups, such as pediatric, geriatric, and patients with physiological and psychiatric disorders. The aim of this study was to conduct preliminary studies to develop ODF containing the poorly water-soluble and oxidation-sensitive drug desloratadine (DL). Materials and Methods In this study, the formulation and process parameters, as well as the characterization method were investigated using 20 film formulations manufactured by the solvent casting method. The films were characterized in terms of their appearance, mechanical properties, thickness, disintegration time, and content uniformity. Various strategies have been applied to increase the chemical stability of DL in the formulations and, therefore to choose suitable antioxidants, and morphological and compatibility studies using differential scanning calorimetry were performed. For increasing drug loading, different film compositions were also evaluated. Results Among the preliminary formulations tested with a casting height of 400 µm, homogeneous, good mechanical properties with tensile strength values between 6.21-10.34 MPa, flexibility, and ODFs with a disintegration time of less than 60s ODFs were developed. By increasing the solubility of DL in the formulation with the selected components, the drug loading capacity was increased to 3% by the desired level. Conclusion One of the enabling formulations, F20, was particle-free with a suitable thickness uniformity (relative standard deviation =4.6%) and content uniformity (acceptance values =5) films were developed.

Rivaroxaban is an anticoagulant and factor Xa inhibitor that acts in deep vein thrombosis. The aim of this study was to prepare a mouth-disintegrating film for the drug to improve its clinical acceptance. As a Biopharmaceutics classification system (BCS) II candidate, the drug requires a significant improvement in solubility to be present as a film. An antisolvent addition method was employed to prepare the cocrystals using gallic acid as a coformer. The optimum nano-crystal formulation (via custom experimental design) was incorporated into a hydroxy propyl methyl cellulose (HPMC) film. The oral films were subjected to physical evaluation, drug content, disintegration time, and drug release studies. Saturation solubility of 0.149 - 1.83 mg/ml was observed. The in vitro release studies showed a drug release of 30±0.14% to 58.2±0.26% at 10min. 49.3±0.18 to 98.7±0.36% at 120min. The optimum formulation solubility and dissolution rate were 1.61mg/ml and 90 %±0.25 at 60min. The X-ray diffraction pattern of the optimum formulation indicated a change in the crystalline nature of rivaroxaban, and the DSC results supported this observation. Films disintegrated in 47s± 0.5 s, and a two-fold increase in drug release from the film (%) was observed in contrast to the pure drug. The nano-cocrystal-incorporated rivaroxaban oral film can be used to improve the therapeutic potential of the drug.

The oral bioavailability of sildenafil citrate is approximately 43%, primarily limited by the low aqueous solubility and first-pass effect. Considering the drug properties and biopharmaceutical considerations, this study aimed to develop an immediate release, taste masked orodispersible film (ODF) of sildenafil citrate for the efficient management of pulmonary arterial hypertension (PAH). The optimization was done by applying 32 full-factorial design. The drug-loaded film was prepared and evaluated for the physical and mechanical parameters like; thickness, disintegration time, tensile strength, elongation, swelling index, content uniformity, disintegration and in vitro drug release in pH 6.2 stimulated salivary fluid. The FTIR and DSC data proved excellent compatibility between the drug and polymers used. The time taken for disintegration by the optimized film was about 62.66 s, while the drug release was observed ~ 96% in 10 min. Pharmacokinetic studies exhibited better sildenafil plasma level (p < 0.05) and Cmax (p < 0.001) of orally disintegrating film which is significantly higher than the oral drug solution. The AUC0–8 (24874.425 ± 1234.45 ng. h/mL) in the oromucosal application was 1.2-fold more (p < 0.0001) than the control. The presence of sweetening and flavoring agents in the formulation masked the drug bitterness, resulting in a higher intake of the formulation in rats compared to the unmasked drug solution, as observed with in vivo taste masking studies. The importance of ODF as a feasible, effective, and optimal approach for delivering sildenafil citrate via oromucosal administration for the treatment of PAH was successfully highlighted by these results.

Orodispersible films (ODFs) have emerged as an advanced and patient-friendly delivery system due to ease of administration, improved patient compliance, quick release and taste-masking of active pharmaceutical ingredients. This research reports the preparation of the ODF containing eugenol and borax (EB-ODF) by a solvent casting technique for treating mouth ulcers. The EB-ODF consisted of Kollidon® VA 64 and hydroxypropyl methylcellulose (HPMC-K250) as the film formers where eugenol and borax were loaded. The thickness of the EB-ODF obtained was 0.119 ± 0.001 mm and the tensile strength was 13.1 ± 1.1 N/mm2 (p > 0.05). The prepared films disintegrated in the oral cavity within 30 s and over 90 % of the eugenol was released from the film in the first 5 min. Furthermore, the combined application of eugenol and borax, loaded in EB-ODF, displayed notable synergetic antibacterial property against both gram-negative and gram-positive bacteria. In an in-vivo study on a rat model with chemical burn-induced oral ulcers, the EB-ODFs treatment group had a 100 % reduction in ulcer area (p > 0.05) after 10 days of treatment and demonstrated a 38.7 % higher reduction in oral ulcer area compared to the Dingpeng Cream treatment group (p < 0.0001). The EB-ODF treatment group The EB-ODF showed minimal oral irritation, scoring only 1 point and a 65 % preference in the taste tests (p < 0.0001). In summary, EB-ODF had successfully overcome the poor palatability of commercially available formulation and provided notable potential for further ulcer treatment development.

In recent years there has been a trend towards creating innovative and patient friendly drug delivery systems which are tailored to each consumer for ensuring drug safety, stability and acceptability. The creation of orodispersible films (ODFs) offers increased comfort and flexibility making it one of the most innovative and promising strategy in drug safety. The film dissolve in oral cavity in few seconds when mixed with saliva. The ODFs can taken with ease and does not require water for administration. ODFs are gaining popularity due to its advantages over other orally administered dosage forms. ODFs offer positive attribute in its ability to customise dosage needs for specific patient population such as Pediatric, elderly, and immobile patients. The purpose of this review paper is to provide information on composition, manufacturing, and characterization of ODFs. The review also provides an overview of polymer used along with the potential drug candidates and focused in printing technology for future market potential. The review suggested that the ODFs is an emerging drug delivery technology for improving patient compliance.

An innovative pharmaceutical form for administering melatonin, based on starch orodispersible fi lm (ODF), was designed and prepared. The composition of the ODF included starch as the polymer matrix, the active drug melatonin, and a plasticizer. Melatonin, a natural hormone produced by the pineal gland in the brain, can be absorbed by passive diffusion across the mucous membrane, resulting in improved bioavailability when compared to conventional oral administration. This study shows a simple and ef fi cient method for preparing melatonin-loaded orodispersible fi lms with a physically stable and commercially viable matrix, suitable for use in the pharmaceutical industry. The fi lms were prepared by treating the starch with microwave irradiation, followed by plasticization with glycerol, melatonin loading and drying by solvent casting. Mechanical tests showed the fi lms ’ robustness, with a modulus of approximately 97 MPa, indicating good handling properties. Moisture uptake analysis showed fast water absorption, reaching about 150% within 2 min, indicating its fast oral disintegration potential. Disintegration tests in arti fi cial saliva and dissolution studies indicated the release of the drug in minutes, indicating the potential properties of the fi lm for oral drug delivery. To the best of our knowledge, there is no melatonin ODF based on starch described in the literature.

Orodispersible films (ODFs) have emerged as innovative pharmaceutical dosage forms, offering patient-specific treatment through adjustable dosing and the combination of diverse active ingredients. This expanding field generates vast datasets, requiring advanced analytical techniques for deeper understanding of data itself. Machine learning is becoming an important tool in the rapidly changing field of pharmaceutical research, particularly in drug preformulation studies. This work aims to explore into the application of machine learning methods for the analysis of experimental data obtained by ODF characterization in order to obtain an insight into the factors governing ODF performance and use it as guidance in pharmaceutical development. Using a dataset derived from extensive experimental studies, various machine learning algorithms were employed to cluster and predict critical properties of ODFs. Our results demonstrate that machine learning models, including Support vector machine, Random forest and Deep learning, exhibit high accuracy in predicting the mechanical properties of ODFs, such as flexibility and rigidity. The predictive models offered insights into the complex interaction of formulation variables. This research is a pilot study that highlights the potential of machine learning as a transformative approach in the pharmaceutical field, paving the way for more efficient and informed drug development processes.

Orally-dissolving films, sometimes called orodispersible films (ODF), are a type of oral solid dosage form that dissolves quickly in the mouth without chewing or drinking liquids. These innovative pharmaceutical formulations have attracted a great deal of attention due to their exceptional ability to improve patient compliance and convenience, especially in children, the elderly, and patients with dysphagia, who may have trouble swallowing conventional solid dosage forms. The main goal of orodispersible films is to provide a rapid and effective drug delivery through the oral mucosa. This method of administration has several advantages, such as increased bioavailability, rapid action, and low first-pass metabolism. Orodispersible films have shown effectiveness in the treatment of a wide variety of ailments including mouth ulcers, allergic diseases, cold and cough, sore throat, nausea and restlessness. In the field of pharmacological intervention, these thin, flexible films, designed to quickly disintegrate upon contact with saliva, offer a viable therapeutic strategy. Plasticizers, medicines and organoleptic chemicals are among the substances that are used during the manufacturing of the film. These elements are essential to the normal structure and effectiveness of the film. For example, plasticizers are compounds that are added to film materials to improve their flexibility and toughness. They function by reducing the tension between polymer chains, thereby increasing the film's elasticity and resistance to cracking or breaking. On the other hand, drugs are incorporated into the film structure to accomplish certain therapeutic goals. The purpose of this study is to provide an in-depth review on the fundamental concepts and processes that govern the formulation and evaluation of film, as well as examine the critical factors involved in the packaging process.

No abstract available

Orally fast-dissolving medicine delivery techniques are increasingly common at present. Due to the desire for these delivery systems, oro-dispersible film (ODF) was recently introduced for the delivery of medicines via the oral route. Most of drugs are delivering through oral route in the form of tablets, capsules and liquids, because they are simple to make and have a greater level of patient compliance. But these conventional dosage forms have many problems including big size of dosage form, and fear of chocking. Oral rapid disintegrating/oro-dispersible drug delivery systems were created to tackle such issues. Fast dissolving films were invented for the patients who have swallowing issues with conventional/traditional oral solid dosage forms. They also have a quick onset of effect, taking only a few seconds, because the drug is absorbed directly from the injection site to the systemic circulation, avoiding first-pass metabolism. In the preparation of films, polymers, surfactants, flavoring agents, coloring agents, sweetening agents, saliva stimulating agents, drug, and plasticizer are used. The drug incorporated in ODF should have pleasing taste, low molecular weight, high stability, and high aqueous solubility. Solvent and semisolid casting, hot melt extrusion, and rolling techniques are routinely used to prepare ODFs. Thickness, loss on drying, tensile strength, and elongation percentage are commonly assessed for evaluating ODFs, as well as their resistance to tearing, weight variation, folding endurance, pH, swelling property, transparency, disintegration, dissolution rate, and stability. The purpose of this review article is to provide a quick overview of ODF delivery systems.

Peptide drugs offer considerable potential for treating a diverse range of diseases. Yet, their clinical application is generally restricted to injectable therapies. The main challenge hindering their broader use through globally accessible, patient-friendly, and non-invasive delivery routes such as oral or buccal, lies in their poor ability to cross biological barriers effectively. Here, we demonstrate that enzymes can be harnessed to transiently reduce these barriers and improve absorption. As a proof of concept, we employ a mucin-specific protease (mucinase) and a phospholipase to increase mucus diffusivity and epithelial cell membrane permeability, respectively. In a canine model, we show that enteric capsules containing both enzymes, and the peptide drug desmopressin achieved a relative bioavailability of 155 % compared to the drug alone. Additionally, a buccal patch loaded with phospholipase and semaglutide displayed a 5-fold higher bioavailability and lower variability (71.5 % reduction in the coefficient of variation) compared to the commercially available oral tablet. These results suggest that enzymatic modulation of biological barriers holds promise as a strategy to improve non-invasive delivery of peptides and potentially other macromolecular drugs.

No abstract available

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 (1950–1982) saw limited attempts to explore this delivery route. The exploratory growth phase (1983–1993) 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 (1994–2009) 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 (2010–2025) 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.

Mucoadhesive films are attractive for buccal drug delivery because of their extended retention on the mucosal surface, enabling sustained drug delivery to and across the tissue. In this study, poly(2‐hydroxyethyl ethyleneimine) (P2HEEI) was synthesized by reacting linear polyethyleneimine (L‐PEI) with 2‐bromoethanol and combined with chitosan to formulate mucoadhesive films for buccal delivery of haloperidol. The polymer displayed excellent solubility in water, a low glass transition temperature (−31.6 °C) and low toxicity in human dermal skin fibroblast cells. This polymer was then blended with chitosan before films were formed by a casting technique. Differential scanning calorimetry and scanning electron microscopy confirmed that chitosan and P2HEEI were fully miscible in the blends. The films based on chitosan‐P2HEEI blends were more elastic and had enhanced mechanical properties. Films containing haloperidol were also formulated. The release of haloperidol from the films increased as the P2HEEI content in the blends was raised. Mucoadhesion of these films on ex vivo sheep buccal mucosal tissues was evaluated using a tensile method. All films were mucoadhesive but increasing P2HEEI content in the blend gradually reduced adhesion to the buccal mucosa.

The first-pass effect and low water solubility are crucial limitations that hinder the drug from being absorbed into the systemic circulation, followed by oral administration. The mucoadhesive buccal delivery system offers direct drug absorption through the mucosa, reaching systemic circulation and bypassing the hepatic first-pass metabolism. This approach ensures high bioavailability and overcomes the swallowing difficulties associated with traditional oral delivery systems. Here, we developed mucoadhesive buccal films for oral delivery of poorly water-soluble drugs using hot-melt extrusion (HME). Poly(2-ethyl-2-oxazoline) (PEtOx), a potential pharmaceutical excipient with high biocompatibility and versatility, was used as the primary matrix for solubility enhancement. Fenofibrate (FB), a typical Biopharmaceutics Classification System (BCS) class II drug with virtually insolubility in water, was used as the model drug. Hydroxypropyl cellulose (HPC), hydroxypropyl methylcellulose (HPMC), and polyethylene oxide (PEO) were combined with PEtOx to adjust the mucoadhesive property. The prepared films were in vitro characterized to delineate the impact of key formulation factors on the mechanical properties, bioadhesion, and solubility enhancement effect. We demonstrated that the complexation of PEtOx with 20% PEO (F8) resulted in over 95% drug release within 2 h, representing an over 5-fold enhancement in solubility compared to the free drug. This F8 formulation exhibited significant bioadhesion among the other formulations, with a 2.2- to 2.7-fold increase in Peak Force (PAF) and work of adhesion (WAD) relative to the control group. This study investigates HME as a continuous fabrication process for developing PEtOx-based buccal film, demonstrating a potential bioadhesive drug delivery system with a solubility improvement effect.

Buccal drug delivery is ideal for first-pass drugs, enabling systemic delivery through the buccal mucosa while bypassing hepatic metabolism. This review highlights amphiphilic mucoadhesive films that deliver functionalized permeation enhancers and smart polymers for controlled, sustained release in the buccal environment. Buccal tissue’s layered structure, permeation barriers, saliva washout, and rapid turnover underscore the need for dual-functional systems. These systems, with mucoadhesive properties for retention and enhancers for absorption, improve drug efficacy against mucosal barriers. Smart polymers responsive to pH, temperature, enzymes, and light adjust release profiles to the local environment, enhancing therapy and reducing dosing. Advances in nanocomposite, multilayer, in situ forming films, and 3D-printed and biosensor-integrated films further boost buccal delivery. Nanocomposite films enhance bioavailability, multilayer films ensure stability, in situ films solidify for snug fit, and 3D printing allows personalized designs. Biosensors enable real-time treatment monitoring and adjustments. This review discusses formulation innovations, showing the promise of mucoadhesive and permeation-enhancing technologies for greater therapeutic efficacy, patient compliance, and clinical potential.

Fluconazole (FZ) is a potential antifungal compound for treating superficial and systemic candidiasis. However, the use of conventional oral drug products has some limitations. The development of buccal film may be a potential alternative to oral formulations for FZ delivery. The present study involved the development of novel FZ-loaded solid lipid nanoparticles (FZ-SLNs) in pectin solutions and the investigation of their particle characteristics. The particle sizes of the obtained FZ-SLNs were in the nanoscale range. To produce pectin films with FZ-SLNs, four formulations were selected based on the small particle size of FZ-SLNs and their suitable polydispersity index. The mean particle sizes of all chosen FZ-SLNs formulations did not exceed 131.7 nm, and the mean polydispersity index of each formulation was less than 0.5. The properties of films containing FZ-SLNs were then assessed. The preparation of all FZ-SLN-loaded pectin films provided the mucoadhesive matrices. The evaluation of mechanical properties unveiled the influence of particle size variation in FZ-SLNs on the integrity of the film. The Fourier-transform infrared spectra indicated that hydrogen bonds could potentially form between the pectin-based matrix and the constituents of FZ-SLNs. The differential scanning calorimetry thermogram of each pectin film with FZ-SLNs revealed that the formulation was thermally stable and behaved in a solid state at 37 °C. According to a drug release study, a sustained drug release pattern with a burst in the initial stage for all films may be advantageous for reducing the lag period of drug release. All prepared films with FZ-SLNs provided a sustained release of FZ over 6 h. The films containing FZ-SLNs with a small particle size provided good permeability across the porcine mucosa. All film samples demonstrated antifungal properties. These results suggest the potential utility of pectin films incorporating FZ-SLNs for buccal administration.

Abstract With the rapid development of buccal films (BFs), the demand for film-forming materials and preparation techniques has increased. Cellulose ethers (CEs) exhibit favorable properties, such as effective film formation, mucosal adhesion, and biocompatibility; as such, they are most commonly employed as film-forming materials, essential for BF fabrication. CE-based BFs, classified as orodispersible and buccal mucoadhesive films, can be prepared through solvent casting, inkjet printing, three-dimensional printing, electrospinning, and hot melt extrusion. Hydrophilic CE-based orodispersible films can rapidly dissolve or disintegrate upon contact with saliva to release drugs. High-viscosity or hydrophobic CEs can serve as protective layers for BFs, controlling the unidirectional release of drugs and mitigating the effects of saliva and buccal movements. These mucoadhesive films can firmly adhere to the buccal mucosa for an extended period, prolonging drug release time and enhancing bioavailability. CEs come in various types and grades, exhibiting different rheological and physicomechanical properties, which also provide options for customized design to specific patients. This review provides an overview of CE-based BF technology, analyzes the challenges and development directions of this film, and identifies key areas for scientific research, such as the interactions of bioadhesive materials in buccal mucosal drug delivery. The objectives of this review are to (i) highlight the value of their application in oral drug delivery and (ii) promote the broader adoption of BF-based patient-centric dosing. GRAPHICAL ABSTRACT

No abstract available

The buccal route offers a non-invasive method for drug administration that improves systemic absorption by bypassing hepatic first-pass metabolism. This article summarises recent innovations, including the incorporation of nanoparticles and 3D printing technologies, with a particular focus on challenges in biologics delivery and clinical translation. The discussion encompasses anatomical considerations, mechanisms of adhesion, formulation design, and evaluation procedures, with applications ranging from local therapies to systemic treatments for conditions such as chronic pain, neurological disorders, and immunisation. Limitations such as reduced drug-loading capacity and saliva-induced erosion are critically examined, alongside potential solutions offered by novel polymer systems. The paper also explores emerging prospects, including the role of artificial intelligence in design optimisation and evolving regulatory frameworks that could accelerate the clinical adoption of buccal films. Keywords: Buccal films, mucoadhesive drug delivery, nanotechnology, 3D printing, therapeutics, regulatory guidelines.

No abstract available

It was the aim of this study to evaluate the potential of reverse micelles (RM) and hydrophobic ion pairs (HIP) for incorporation of semaglutide into self-emulsifying oral drug delivery systems. Reverse micelles loaded with semaglutide were formed with a cationic (ethyl lauroyl arginate, ELA) and an anionic surfactant (docusate, DOC), whereas HIP were formed between semaglutide and ELA. Maximum solubility of the peptide and the rate of dissolution was evaluated in various lipophilic phases (glycerol monocaprylocaprate:caprylic acid 1:4 (m/m), glycerol monolinoleate:caprylic acid 1:4 (m/m) and glycerol monocaprylocaprate:glycerol monolinoleate 1:4 (m/m)). Self-emulsifying drug delivery systems (SEDDS) loaded with RM and HIP were characterized regarding size distribution, zeta potential, cytocompatibility and Caco-2 permeability. Droplet sizes between 50 and 300 nm with polydispersity index (PDI) around 0.3 and zeta potentials between − 45 mV (RMDOC) and 36 mV (RMELA) were obtained. RM provided an almost 2-fold higher lipophilicity of semaglutide than HIP resulting in a 4.2-fold higher payload of SEDDS compared to HIP. SEDDS containing RM or HIP showed high cytocompatibilities with a cell survival above 75% for concentrations up to 0.1% on Caco-2 cells and acceptable hemolytic activity. Permeation studies across Caco-2 monolayer revealed an at least 2-fold increase in permeability of semaglutide for the developed formulations. Hydrophilicity of semaglutide limits its absorption after oral administration by poor membrane permeability. Lipid-based delivery systems show an enhanced permeation of the lipid bilayer, thus improving the oral bioavailability of drugs. However, the hydrophilic character of semaglutide restricts direct incorporation into lipid-based delivery systems. Two different methods to enhance the lipophilicity of semaglutide enabling the incorporation into self-emulsifying drug delivery systems are described, yielding high semaglutide payload and an increased Caco-2 permeation of this GLP-1 analogue. These methods pave the way for more efficient oral delivery of semaglutide.

Among the established routes for drug administration, oral and parenteral methods stand out as the most prevalent. Despite the patient-compliant oral formulations, there is a potential risk of asphyxiation, and these formulations are subject to first-pass metabolism leading to a significant reduction in bioavailability. Conversely, parenteral delivery is often associated with pain and various challenges such as vascular damage or thrombosis with the intravenous route and a small risk of nerve damage with intramuscular injections. Although infrequent, such complications are noteworthy. Mucosal drug delivery has emerged as a promising approach due to its direct systemic drug absorption, rapid onset of action compared to oral formulations, and reduced systemic drug exposure. The oromucosal region (buccal and sublingual areas) offers a distinct advantage for drug delivery, given their high vascularity and anatomical compliance. Various formulations like tablets, gels, and patches have been authorized for utilization on the buccal mucosal epithelium. Amid all the buccal formulations, films/patches exhibit more favorable outcomes in terms of simplicity of application, patient adherence, and drug consistency and have been investigated for small molecules, peptides, and immunotherapy. Mucoadhesive polymers represent the cornerstone for formulating a mucoadhesive product. Polymers such as HPMC, CMC, and Pullulan have already received approval, whereas natural polymers like chitosan and alginate are currently under scrutiny. This review presents concise vital information for those readers who are working in the area of buccal drug delivery.

The buccal cavity, also known as the oral cavity, is a complex anatomical structure that plays a crucial role in various physiological processes. It serves as a gateway to the digestive system and facilitates the initial stages of food digestion and absorption. However, its significance extends beyond mere digestion as it presents a promising route for drug delivery, particularly to the brain. Transferosomes are lipid-based vesicles that have gained significant attention in the field of drug delivery due to their unique structure and properties. These vesicles are composed of phospholipids that form bilayer structures capable of encapsulating both hydrophilic and lipophilic drugs. Strategies for the development of buccal transferosomes for brain delivery have emerged as promising avenues for pharmaceutical research. This review aims to explore the various approaches and challenges associated with harnessing the potential of buccal transferosomes as a means of enhancing drug delivery to the brain. By understanding the structure and function of both buccal tissue and transferosomes, researchers can develop effective formulation methods and characterization techniques to optimize drug delivery. Furthermore, strategic approaches and success stories in buccal transferosome development are highlighted, showcasing inspiring examples that demonstrate their potential to revolutionize brain delivery.

No abstract available

Geriatric patients are more likely to suffer from multiple chronic diseases that require using several drugs, which are commonly ingested. However, to enhance geriatric patients’ convenience, the electrospun nanofiber system was previously proven to be a successful alternative for the existing oral dosage forms, i.e., tablets and capsules. These nanofibers prepared either as single- or multi-layered fibers could hold at least one active compound in each layer. They might also be fabricated as ultra-disintegrated fibrous films for oral cavity administration, i.e., buccal or sublingual, to improve the bioavailability and intake of the administered drugs. Therefore, in this work, a combination of nifedipine and atorvastatin calcium, which are frequently prescribed for hypertension and hyperlipidemia patients, respectively, was prepared in a coaxial electrospinning system for buccal administration. Scanning electron microscopy image showed the successful preparation of smooth, non-beaded, and non-porous surfaces of the drug-loaded nanofibers with an average fiber diameter of 968 ± 198 nm. In contrast, transmission electron microscopy distinguished the inner and outer layers of those nanofibers. The disintegration of the drug-loaded nanofibers was ≤12 s, allowing the rapid release of nifedipine and atorvastatin calcium to 61% and 47%, respectively, after 10 min, while a complete drug release was achieved after 120 min. In vitro, a drug permeation study using Franz diffusion showed that the permeation of both drugs from the core–shell nanofibers was enhanced significantly (p < 0.05) compared to the drugs in a solution form. In conclusion, the development of drug-loaded nanofibers containing nifedipine and atorvastatin calcium can be a potential buccal delivery system.

The current research work aimed to prepare an optimized and evaluate fast-dissolving oral thin film of Apixaban using polyvinyl alcohol as a film former. The oral thin film of Apixaban enhances the solubility, bioavailability, and therapeutic efficacy in thrombus, pulmonary embolism, and venous thromboembolism. The chemical compatibility and thermal analysis were investigated with the help of FTIR, and DSC. The optimization was performed with the Box-Behnken design. The concentrations of film former (PVA: X1), plasticizer (PEG 200: X2), and superdisintegrant (cross povidone: X3) were considered as independent factors and the critical quality attributes for the oral films are disintegration time, dissolution, and folding endurance. The ANOVA comprised of Quadratic model which predicted p-values of 0.0039, 0.0105, and 0.0020 significant. The scanning electron microscopy assessed the texture of the film. An optimized batch P6 disintegrated within 19 seconds, released the drug (99.07 %) within 10 min and had a folding endurance of 116. The results conclude that optimized batch P6 of oral thin film of Apixaban significantly minimizes the deep vein thrombosis, pulmonary embolism, and venous thromboembolism due to fastest onset of action and improved solubility. Thus, the complications associated with the clotting of blood is sharply reduces.

The present study aimed to develop an ondansetron microemulsion and incorporate it into an oral thin film. In the design of experiments, a central composite design was utilized to optimize the formulations, focusing on the concentrations of hydroxypropyl methylcellulose (HPMC K15) (X1) and HPMC K4 (X2) as independent variables. The optimized batch designated as FB-1, exhibited a drug content of 101±0.5%, a film weight of 49.8±0.8mg, a minimum disintegration time of 47±0.05 seconds, a thickness of 0.12±0.2mm, and a pH of 6.8 ±0.05, along with desirable mechanical properties, including a tensile strength of 150g/cm². Characterization of the optimized film includes FTIR, DSC for drug interaction, SEM for morphology, and evaluations of in vitro drug release and ondansetron loading effectiveness. The optimized batch exhibited a remarkable drug release profile, achieving approximately 88.83% release at the 5 min mark. This rapid dissolution continued, surpassing 95 % within the first 10 min, demonstrating the highest dissolution rate observed. The developed ME-loaded OTFs significantly enhanced drug release compared to the marketed film Vomikind-Fast strip 4mg (Mankind Pharma) showed a 64% release at 5 min and 65% at 10min, while Emefilm 4mg (Delvin Formulations) had a release rate of 64% at 5 min and 68% at 10min. By improving the solubility and bioavailability of ondansetron, this microemulsion-embedded film technology offers a dosage form that is both easy to administer and improves compliance among patients.

Objective: This study aimed to develop and optimize an Oral Thin Film (OTF) formulation of escitalopram oxalate to enhance patient compliance, improve drug acceptability, and facilitate rapid systemic absorption. Methods: A Central Composite Design (CCD) under Response Surface Methodology (RSM) was employed to optimize the formulation. Polymer (300–500 mg) and plasticizer (100–300 mg) concentrations were selected as independent variables, and their effects on critical response parameters—tensile strength, folding endurance, disintegration time, and dissolution rate-were evaluated. The optimized OTF was characterized for thickness, disintegration, and dissolution behaviour. Results: The optimal polymer and plasticizer concentrations were identified as 400 mg and 220 mg, respectively, yielding desirable film properties. The OTF thickness ranged from 0.48 to 0.57 mm, with formulations between 0.50 and 0.55 mm exhibiting the most favorable dissolution and disintegration profiles. The optimized OTF exhibited a tensile strength of 15.3 N/mm², folding endurance of 159 folds, and a disintegration time of 73 sec. Dissolution studies demonstrated 98% drug release within 10 min, confirming rapid dissolution for a fast onset of action. Conclusion: The study successfully developed an optimized OTF formulation of escitalopram oxalate, supporting the global shift toward patient-centric drug delivery. The formulation enhances therapeutic outcomes by ensuring rapid systemic absorption and improved patient adherence.

The aim of the current study was to formulate and evaluate dompridone nanoparticles and loaded in oral fast dissolve fi lm, for enhance the solubility of poor water soluble dompridone by nanoparticles and fasten the action by prepared as oral thin fi lm and also to improve patient compliance. Domperidone is the recommended medication for nausea and vomiting brought on by viral infections, chemotherapy, migraines, and food poisoning. Domperidone nanoparticles were made using two type of polymers (hydroxypropyl methylcellulose HPMC-K15 and methylcellulose MC-A4C) in a range of ratios (1:1, 1:2, and 1:3) drug:polymer ratio by solvent antisolvent technique. In nanoparticle formulation, HPMC-K15 and MC-A4C were selected due to their advantageous characteristics: they are water-soluble, form robust fi lms, are biologically compatible, and have a proven history in pharmaceutical applications. The prepared formula undergoes to characterization for particle size, PDI, FESEM and x-ray diffraction. The results obtain show all formulas within nano size range and monodisperse. The X-ray powder diffraction examination showed that the dompridone had changed from a crystalline to amorphous state. Following that, the optimum nanoparticles formula was used to prepare the oral fi lm using the technique of solvent casting with HPMC E15 acting as a fi lm forming agent and glycerin as a stabilizer. The prepared oral fi lm, appear as a white, opaque, soft thin fi lm with drug content 98.85 ± 1.13 %, and a good folding endurance. Invitro release of drug show, the cumulative proportion of dopamine released from the fi lm containing the nanoparticles was 43 %, while only 21 % for fi lm consist of pure dompridone, at 2 min.

BACKGROUND Cardiovascular diseases, including hypertension, are the prominent source of death globally. High blood pressure is responsible for heart failure and also damages the vital organs of the body, which also creates mortality. The activation of the sympathetic nervous system in the primary sunrise period is a highly critical condition, and several persons have lost their tissue due to the unavailability of medicine at this time. OBJECTIVE The present research deals with the progress of fast-dissolving oral thin film (OTF) of Ambrisentan for the prevention and cure of hypertension. METHODS The OTF was established using the solvent casting method. The compatibility of Ambrisentan with film former HPMC E15 was checked with FTIR and DSC. The optimization was assessed using the design of the experiment using 32 Box-Behnken designs. The independent parameters were filmed former (X1: HPMC E15), plasticizer (X2: PEG 400), and super disintegrant (X3: cross povidone) and dependable parameters were disintegration time (Y1) and dissolution release (Y2). RESULTS The optimized batch F7 showed the least disintegration time (9 sec), folding endurance of (99), content uniformity (98.57 %), pH (6.4), and dissolved within 5 min. The scanning electron microscopy confirmed the evenness and smoothness of the film with a particle size of 10 μm. Patent related with OTF (Indian- 202321050359), US (11701339). CONCLUSION The investigation indicated that fast dissolving oral thin film of Ambrisentan improves the solubility and therapeutic efficacy in the prevention and treatment of cardiovascular complications. The prompt release of Ambrisentan minimizes the mortality associated with heart attack and hypertension.

This comprehensive review delves into the recent advancements and diverse applications of oral thin film (OTF) technology in the field of pharmaceuticals. The aim is to provide a thorough exploration of the evolution of OTFs, their unique characteristics, and their expanding role in drug delivery systems. A systematic analysis of the literature was conducted to gather information on the formulation techniques, properties, and challenges associated with OTFs. Additionally, recent developments, innovations, and future trends in OTF technology were examined to understand the dynamic landscape of this drug delivery system. The review highlights the key properties of OTFs, including rapid disintegration, enhanced bioavailability, and patient-centric advantages. Various manufacturing techniques, such as solvent casting, hot melt extrusion, and 3D printing, were explored for their impact on OTF formulation. Challenges, including stability issues and taste masking complexities, were identified. Recent innovations, such as nanotechnology integration, personalized medicine applications, and the use of digital health platforms, showcase the ongoing efforts to overcome these challenges. Oral thin film technology stands at the forefront of pharmaceutical innovation, offering a patient-friendly and adaptable drug delivery system. As evidenced by recent developments, the integration of advanced technologies, personalized medicine approaches, and sustainable practices positions OTFs as a transformative force in the future of drug delivery. The exploration of these advancements and applications contributes to a deeper understanding of the potential impact of OTF technology on healthcare.

Abstract Nutraceuticals have been gradually accepted as food ingredients which can provide health benefits and protection against several diseases. However, most nutraceuticals are susceptible to the changes in the external environment, resulting in a poor stability and absorption. One such relatively novel, inventive, and patient-centered innovation routed in this direction is oral thin film (OTF). OTFs are ultra-thin, stamp-sized, portable and patient-centric formulations with no need for water. This route allows for the absorption of drugs through the oral mucosa, effectively bypassing hepatic first-pass metabolism in the liver and avoiding degradation or metabolism within the gastrointestinal tract. Accordingly, OTFs hold tremendous potential in gaining patient compliance, convenience and pharmacotherapy. This review highlights the utilization OTFs for nutraceutical delivery, including their types, preparation methods and the potential of OTFs as carriers for delivering plant extracts, bioactive molecules, vitamins, proteins and microorganisms. Moreover, the quality evaluation methods and applications of OTFs are summarized.

HIV infections among children have been on the decline since the introduction of infant HIV prophylaxis regimens including the HIV reverse transcriptase inhibitor, zidovudine (ZDV). This makes adherence to ZDV and other HIV medications paramount for the survival of young infants and children across the globe. However, the large dose volume and extremely bitter taste of ZDV often results in infants spitting up the medication, resulting in inaccurate dosing. Inclusion of ZDV into an oral thin film (OTF) would reduce the dose volume required, thus improving adherence to the medication regimen. To overcome the poor taste of ZDV, we created encapsulated ZDV (eZDV) formulations via spray-drying and evaluated polymer selection and ZDV particle size as potential avenues for effectively reducing the release of ZDV in simulated salivary fluid (SSF). The combined use of Eudragit E PO (EPO) and ethylcellulose (EC) was found to be the most effective polymer coating for reducing the release of ZDV. The optimal formulation ratio was determined to be 5:20:75 (EC:EPO:ZDV) to maintain high drug load while still reducing the dissolution of ZDV in SSF. Additionally, mortar-and-pestling ZDV prior to spray drying allowed for less variability and a more homogenous spread of eZDV throughout an OTF. These factors ultimately resulted in eZDV loaded OTFs that were able to successfully reduce the release of ZDV in SSF below its taste detection threshold.

Introduction Avanafil (AVA) is a very efficient phosphodiesterase type 5 inhibitor for the treatment of erectile dysfunction. However, it has limited bioavailability when taken orally and considerable first-pass metabolism. Enhancing its solubility and choosing an alternative delivery route may enhance its effectiveness and duration of action. Methods Eight complex formulations were elaborated and analyzed at various ratios using different polyethylene glycols and hydroxypropyl-beta-cyclodextrin (HP-β-CD). Sublingual tablets containing AVA were designed and optimized using the Quality-by-design approach. The tablets’ pre-compression and post-compression properties were evaluated. The in-vivo pharmacokinetic behavior of the optimized tablet was assessed and compared with that of the commercial oral tablets in human volunteers. Results The HP-β-CD–AVA inclusion complex (1:1 molar ratio) showed an optimum solubilization capacity with an amount suitable for incorporation into sublingual tablets. The total amounts of superdisintegrants and Plasdone XL and the percentage of starch significantly influenced the length of time it took for 80% of the AVA to be released from the sublingual tablets, the tablet hardness, and the length of time for tablet disintegration. The optimized AVA sublingual tablet exhibited a 5.98-fold increase in the AVA mean residence time over the commercial tablet, with greater plasma exposure over 72 hours and 1356.42% relative bioavailability. Conclusion The sublingual tablets of the solubility-enhanced HP-β-CD–AVA inclusion complex represent a promising strategy to improve AVA bioavailability and bypass the first-pass effect. Furthermore, their extended activity offers potential clinical benefits, particularly for ED patients, such as ease of administration and reduced side effects.

The present work involves the formulation of sublingual films of Cilnidipine, a BCS Class II drug, faces a major problem due to its bioavailability of 13% in oral dosage form. To increase solubility and bioavailability, nanocrystals were prepared using antisolvent crystallization technique. Solubility of prepared Cilnidipine crystals were studied then subjected for FTIR, DSC, SEM, XRD and In-vitro dissolution studies for characterization and evaluation. This reveals a significant increase in drug dissolution and solubility with a decrease in particle size compared to pure Cilnidipine. The crystals also showed compatibility with the drug and excipients, with smaller crystals. Powder X-ray diffraction revealed decreased intensity of peaks compared to pure drug. Crystals prepared using ethanol as a solvent under ultrasonication (Probe) showed the highest solubility and dissolution rate at 60 minutes, with better results in drug content and compared to pure drug. Anti-solvent crystallization method was successful in formulating cilnidipine crystals with high dissolution rates to eliminate solubility-related bioavailability issues. Further Cilnidipine crystals were formulated into Fast Dissolving Sublingual Films by solvent-casting method. The fast-dissolving films of Cilnidipine were prepared using HPMC E5, HPMC E15 and HPMC E50 as film forming polymers and PEG400 was used as plasticizer. Films were evaluated for physical characteristic such as uniformity of weight, thickness, folding endurance, drug content uniformity, surface pH, tensile strength. Fourier transform infrared spectroscopy and In- vitro release studies. All films were found to be satisfactory when evaluated for thickness, weight uniformity, folding endurance and drug content. The optimized formulation F2 showed satisfactory pH and drug content (93.7%). The in-vitro drug release in optimized formulation F2 was found to more than 95.55% within 10 min and satisfactory stability. Fast dissolving films of Cilnidipine crystals can be considered suitable for clinical use in the treatment of Hypertension and hypertensive associated vascular disorders where a quicker onset of action is desirable along with the convenience of administration.

No abstract available

The aim of this study was to prepare sodium glycocholate liposomes (SGC-Lip) encapsulating semaglutide (Sml) to improve oral bioavailability and better exert hypoglycemic effect. In this paper, SGC-Lip was prepared by reverse-phase evaporation method with particle size around 140 nm, potential around -27 mV, rounded morphology and better stability. The hypoglycemic and intestinal uptake effects of SGC-Lip and cholesterol-containing liposomes (CH-Lip) were comparatively investigated in rats, and the oral safety of SGC-Lip was examined by cytotoxicity assay. The results indicate that SGC-Lip can achieve a hypoglycemic effect of 40% of the initial value within 12 hours, and the AAC0-12h is approximately six times that of CH-Lip without sodium glycocholate. The results of the cytotoxicity tests indicate that SGC-Lip has good oral safety. SGC-Lip enhances the absorption of semaglutide in the small intestinal villi via an apical sodium-dependent bile acid transporter (ASBT)-mediated pathway with the highest penetration at the ileal site. In summary, the oral bioavailability of semaglutide can be improved by encapsulating semaglutide in SGC-Lip and utilizing the stabilizing and permeation-promoting effects of SGC on liposomes.

Sublingual buprenorphine is used for opioid use disorder and neonatal opioid withdrawal syndrome. The study aimed to develop a full physiologically based pharmacokinetic (PBPK) model that can adequately describe dose- and formulation-dependent bioavailability of buprenorphine. Simcyp (v21.0) was used for model construction. Four linear regression models (i.e., untransformed or log transformed for dose or proportion sublingually absorbed) were explored to describe sublingual absorption of buprenorphine across dose. Published clinical trial data not used in model development were used for verification. The PBPK model’s predictive performance was deemed adequate if the geometric means of ratios between predicted and observed (P/O) area under the curve (AUC), peak concentration (Cmax), and time to reach Cmax (Tmax) fell within the 1.25-fold prediction error range. Sublingual buprenorphine absorption was best described by a regression model with logarithmically transformed dose. By integrating this nonlinear absorption profile, the PBPK model adequately predicted buprenorphine pharmacokinetics (PK) following administration of sublingual tablets and solution across a dose range of 2–32 mg, with geometric mean (95% confidence interval) P/O ratios for AUC and Cmax equaling 0.99 (0.86–1.12) and 1.24 (1.09–1.40), respectively, and median (5th to 95th percentile) for Tmax equaling 1.11 (0.69–1.57). A verified PBPK model was developed that adequately predicts dose- and formulation-dependent buprenorphine PK following sublingual administration. SIGNIFICANCE STATEMENT The physiologically based pharmacokinetic (PBPK) model developed in this study is the first to adequately predict dose- and formulation-dependent sublingual buprenorphine pharmacokinetics. Accurate prediction was facilitated by the incorporation of a novel nonlinear absorption model. The developed model will serve as the foundation for maternal-fetal PBPK modeling to predict maternal and fetal buprenorphine exposures to optimize buprenorphine treatment for neonatal opioid withdrawal syndrome.

OBJECTIVE Sublingual buprenorphine has demonstrated efficacy for treatment of the neonatal opioid withdrawal syndrome (NOWS), but the current formulation used in clinical practice contains 30% ethanol. Ethanol as a pharmacologically active excipient ideally should be removed from neonatal formulations. The objective of this study was to determine the relative bioavailability of a novel ethanol-free -formulation (CHF6563) compared with the commonly used ethanolic solution in a phase I, open-label, 2-period, -single-dose, crossover study in healthy adults. METHODS Eighteen adult opioid-naïve volunteers were administered one of the formulations in a randomized crossover treatment. After a 10-day washout period, subjects received the other formulation. Serial blood samples were drawn for pharmacokinetic analysis over 48 hours. RESULTS The geometric mean ratio (90% CIs) of the ethanol-free buprenorphine solution AUC0-last was 0.80 (0.65-0.99) and Cmax was 0.81 (0.66-0.99) compared with reference ethanolic formulation. The -ethanol-free formulation had a greater degree of intersubject variability than the ethanol-containing -reference formulation (coefficient of variation of 59% vs 31.5%, respectively, for AUC0-last). CONCLUSIONS In an adult population, a novel ethanol-free formulation of buprenorphine containing widely used excipients demonstrated a slight decrease in bioavailability when compared with an ethanolic solution. These results will inform those seeking to develop ethanol-free pediatric drug formulations.

Bypassing the GI tract and first-pass metabolism, sublingual medication administration boosts bioavailability and achieves quick therapeutic effects. This technique takes advantage of the sublingual area's weak mucosal barrier and abundant vascularization to speed up the beginning of action and improve the efficacy of the medicine. Additional improvements to medication performance and patient compliance have been made possible by recent developments in sublingual formulations, including nanoencapsulation, fast-dissolving tablets, and sublingual films. Emerging trends in the field include personalized medicine, which tailors treatments based on individual patient needs, and the integration of digital health technologies for dose monitoring and adherence tracking. Additionally, innovations in bioenhancers and permeation enhancers aim to overcome challenges related to drug solubility and absorption. Despite these advancements, challenges such as drug stability, taste masking, and patient compliance persist. Future research focuses on addressing these limitations through enhanced formulation techniques, improved patient education, and streamlined regulatory processes. Overall, sublingual drug delivery continues to evolve, offering significant benefits for therapeutic efficacy and patient care while paving the way for future developments in pharmacotherapy.

Purpose: Sodium N-[8-(2-hydroxybenzoyl)amino]caprylate (SNAC) is a well-known penetration enhancer widely used in commercial applications. This study aims to broaden its properties through a novel strategy of converting it into its phenolate salts. The objective is to investigate the synthesis of SNAC phenolate salts, specifically SNAC–choline (SNAC-CH), SNAC–sodium (SNAC-Na), and SNAC–phosphatidylcholine (SNAC-PC), and to explore their potential application in improving the oral absorption of semaglutide. Methods: The synthesis of SNAC phenolate salts was confirmed through 1H-NMR, FTIR, and an elemental analysis of C, H, N, and O. In vivo testing was conducted to assess the oral delivery of semaglutide using these synthesized SNAC phenolate salts. Pharmacokinetic (PK) values were measured to evaluate the impact on drug absorption. Results: The synthesis of SNAC phenolate salts (SNAC-CH, SNAC-Na, and SNAC-PC) was successfully achieved under appropriate conditions, and their structures were confirmed using analytical techniques such as IR, NMR, and CHN elemental analysis. The paradigm of their use was evaluated through an oral pharmacokinetic (PK) in vivo study using SNAC phenolate salts, which did not impair the original SNAC PK values. This suggests that this strategy holds promise as a potential new effective enhancer for oral absorption. Conclusions: The utilization of SNAC phenolate salts presents a novel and promising strategy for extending the verity of penetration enhancers’ molecules and properties. Synthesizing phenolate salts represents a new chemical strategy that may open new avenues in molecular development. This approach holds future potential to enhance the oral delivery of peptide drugs like semaglutide without compromising therapeutic efficacy. Overall, it offers significant advancements in the field by providing a potential alternative to injectable peptides through oral delivery systems.

Background The benefit of exogenous melatonin is based on its bioavailability, which depends on the galenic form, the route of administration, the dosage, and the individual absorption and rate of hepatic metabolism. Objective The objective of this study is to investigate the bioavailability of melatonin after administration of an oral prolonged-release tablet (PR form) and an immediate-release sublingual spray (IR form). The main metabolite of melatonin, 6-sulfatoxymelatonin (6-SMT), was also measured, which has not been done in previous studies. Its determination is important as an index of the hepatic transformation of melatonin. Methods In this single-center, open-label, randomized, crossover study, 14 healthy male volunteers received one tablet of the PR form (1.9 mg melatonin) or two sprays of the IR form (1 mg melatonin) during two visits separated by a washout period. Blood samples were collected over 7 and 9 h for the IR and PR form, respectively, to determine the main pharmacokinetic parameters. Results The observed kinetics were consistent with those expected for immediate and prolonged-release forms. Pulverization of the spray resulted in an early, high plasma melatonin peak ( C _max: 2332 ± 950 pg/mL; T _max: 23.3 ± 6.5 min), whereas tablet intake produced a lower peak ( C _max: 1151 ± 565 pg/mL; T _max: 64.2 ± 44.2 min; p  < 0.001 for comparison of C _max and T _max) followed by a plasma melatonin plateau and a more prolonged decay over time. Plasma melatonin/6-SMT AUC_0–540/420 ratio was 0.09 for the PR form and 0.16 for the IR form. Both galenic forms were well tolerated. Conclusions The results suggest that the galenic forms containing melatonin assessed in this study are suitable for the treatment of certain sleep disorders such as sleep onset delay and transient nocturnal awakenings for the IR form and insomnia for the PR form. Trial Registry Registration number: NCT04574141.

ABSTRACT Introduction A GLP-1 Receptor Agonist, semaglutide, is given in the management of type 2 diabetes mellitus and obese individuals. However, oral semaglutide exerts very low bioavailability due to multiple gastrointestinal and biopharmaceutical barriers. Delivery of oral semaglutide becomes difficult due to instability in GI fluids, degradation through proteolysis by various enzymes, and mucus diffusion limitation; epithelial permeability restricts the oral absorption of the drug, due to which the oral bioavailability of semaglutide is exceedingly low. This review identifies methods that enhance oral bioavailability as well as treatment efficacy of semaglutide. Areas covered This review provides a broad perspective on the drug and the various formulation strategies that can be developed to increase semaglutide’s oral bioavailability, encompassing work on enteric coating, gut-targeted delivery, etc. Databases searched include Scopus, google scholar, PubMed, clinicaltrials.gov etc. This review also discussed and summarized all patents and clinical trials related to semaglutide formulations. Expert opinion Although various formulation approaches have been explored to improve semaglutide’s oral bioavailability, this review proposes novel and promising strategies for gut-targeted delivery and enteric coating. These methods aim to prevent semaglutide from acidic degradation or neutralization in the stomach and from enzymatic degradation, thereby enhancing its intestinal uptake.

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To evaluate the relative bioavailability of sublingual vs. oral levothyroxine (L‐T4) in post‐thyroidectomy patients, aiming to overcome gastrointestinal absorption variability.

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Orodispersible sublingual films (OSFs) composed of hydrophilic polymers were loaded with poloxamer-188 and d-α-tocopheryl polyethylene glycol succinate (TPGS-1000) mixed micelles to improve the oral bioavailability of a poorly soluble drug, ebastine (EBT). Mixed micelles formed by thin-film hydration method were incorporated into orodispersible sublingual film, consisting of HPMC and glycerol, using solvent casting technique. The mixed micelles and films were thoroughly evaluated for physicochemical characterization (size, polydispersity index, zeta potential, entrapment efficiency, thickness, weight, surface pH studies, disintegration time, swelling indices, mechanical properties, FTIR, PXRD, DSC, SEM, AFM, in vitro drug release, in vivo bioavailability, and toxicological studies). The results showed that the average particle size of mixed micelles was 73 nm. The mean zeta potential and PDI of the optimal mixed micelles formulation were −26 mV and 0.16, respectively. Furthermore, the maximum entrapment efficiency 82% was attained. The film’s disintegration time was in the range of 28 to 102 s in aqueous media. The integrity of micelles was not affected upon incorporation in films. Importantly, the micelles-loaded films revealed rapid absorption, high permeability, and increased bioavailability of EBT as compared to the pure drug. The existence of ebastine loaded mixed micelles in the films enhanced the bioavailability about 2.18 folds as compared to pure drug. Further, the results evidently established in-vitro and in-vivo performance of bioavailability enhancement, biocompatibility, and good safety profile of micelles-loaded orodispersible EBT films. Finally, it was concluded that film loaded with poloxamer-188/TPGS-1000 mixed micelles could be an effective carrier system for enhancing the bioavailability of ebastine.

In a pivotal study, apomorphine sublingual film (APL; KYNMOBI®) was an effective and generally well-tolerated on-demand treatment of “OFF” episodes in patients with Parkinson’s disease (PD), approved across the dose range of 10–30 mg. Pharmacokinetics and comparative bioavailability of APL and two subcutaneous (SC) apomorphine formulations (SC-APO [APOKYN®] and SC-APO-GO [APO-go® PEN]) were evaluated in a randomized, three-way crossover, open-label study (NCT03292016). Patients with PD and “OFF” episodes received an open-label randomized sequence of single doses of SC-APO and SC-APO-GO at the currently prescribed dose (2/3/4/5 mg) and APL doses with similar plasma exposure (15/20/25/30 mg) with ≥ 1-day washout between formulations. Plasma pharmacokinetics of apomorphine and apomorphine sulfate (major inactive metabolite) were measured 0–6 h postdose. Median time to maximum plasma concentration (tmax) of apomorphine was 0.63–0.75 h for APL and 0.25–0.38 h for SC-APO and SC-APO-GO. Geometric mean maximum plasma concentration (Cmax) of apomorphine was 4.31–11.2 ng/ml across APL doses and was generally lower compared with SC apomorphine formulations within dose groups. Area under the concentration-time curve from time 0 to infinity (AUC∞) was similar across apomorphine formulations within most dose groups. Relative bioavailability of APL was ~ 17% of SC apomorphine by AUC∞; SC-APO and SC-APO-GO had similar bioavailability (98% and 83% by AUC∞ and Cmax, respectively). Apomorphine sulfate exposure was ~ three-fold higher for APL versus SC-APO and SC-APO-GO by AUC∞ and Cmax. In patients with PD and “OFF” episodes, APL demonstrated lower Cmax and relative bioavailability but similar exposures (AUCs) versus SC apomorphine within the approved dose range. ClinicalTrials.gov, NCT03292016.

BACKGROUND Obesity is a major risk factor for many leading causes of illness and death worldwide. Data are needed regarding the efficacy and safety of the nonpeptide glucagon-like peptide-1 (GLP-1) receptor agonist orforglipron as a once-daily oral therapy for weight reduction in adults with obesity. METHODS In this phase 2, randomized, double-blind trial, we enrolled adults with obesity, or with overweight plus at least one weight-related coexisting condition, and without diabetes. Participants were randomly assigned to receive orforglipron at one of four doses (12, 24, 36, or 45 mg) or placebo once daily for 36 weeks. The percentage change from baseline in body weight was assessed at week 26 (primary end point) and at week 36 (secondary end point). RESULTS A total of 272 participants underwent randomization. At baseline, the mean body weight was 108.7 kg, and the mean body-mass index (the weight in kilograms divided by the square of the height in meters) was 37.9. At week 26, the mean change from baseline in body weight ranged from -8.6% to -12.6% across the orforglipron dose cohorts and was -2.0% in the placebo group. At week 36, the mean change ranged from -9.4% to -14.7% with orforglipron and was -2.3% with placebo. A weight reduction of at least 10% by week 36 occurred in 46 to 75% of the participants who received orforglipron, as compared with 9% who received placebo. The use of orforglipron led to improvement in all prespecified weight-related and cardiometabolic measures. The most common adverse events reported with orforglipron were gastrointestinal events, which were mild to moderate, occurred primarily during dose escalation, and led to discontinuation of orforglipron in 10 to 17% of participants across dose cohorts. The safety profile of orforglipron was consistent with that of the GLP-1 receptor agonist class. CONCLUSIONS Daily oral orforglipron, a nonpeptide GLP-1 receptor agonist, was associated with weight reduction. Adverse events reported with orforglipron were similar to those with injectable GLP-1 receptor agonists. (Funded by Eli Lilly; GZGI ClinicalTrials.gov number, NCT05051579.).

Abstract Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are peptide-derived analogs that were initially investigated to treat type 2 diabetes. Recently, a drug targeting the receptors of both GLP-1 and glucose-dependent insulinotropic polypeptide (GIP) (tirzepatide) has been introduced to the market, and its indications have expanded to include treating obesity. Here, we review the pharmacokinetics, pharmacokinetic drug−drug interactions (DDIs), and pharmacokinetic modeling approaches of four currently available GLP-1 RAs (exenatide, liraglutide, dulaglutide, and semaglutide) and tirzepatide. To address the extremely short half-life (2 min) of native human GLP-1, structural modifications have been applied to GLP-1 RAs and a dual GLP-1/GIP RA. These include amino acid sequence substitutions, fatty acid conjugation using a linker, and fusion with albumin or the IgG fragment crystallizable (Fc) region, resulting in minimal metabolism and renal excretion. Due to their diverse structures, the pharmacokinetic profiles vary, and a prolonged half-life may be associated with an increased risk of adverse events. Clinically significant drug-metabolizing enzyme- and transporter-mediated DDIs are yet to be reported. Mechanism-of-action-mediated DDIs are currently limited to those involving delayed gastric emptying, and most studies have found them to be clinically insignificant. However, significant changes in exposure were observed for oral contraceptives and levothyroxine following the administration of tirzepatide and oral semaglutide, respectively, indicating the need for close monitoring in these instances. Thirty models have been developed to predict pharmacokinetics and physiologically based pharmacokinetic modeling can be useful for assessing mechanism-of-action-mediated DDIs. Alterations in the volume of distribution and clearance resulting from other mechanisms of action (eg, reduced fat mass, changes in cytochrome P450 activity, and glomerular filtration rate) are key factors in determining pharmacokinetics. However, the DDIs mediated by these factors remain poorly understood and require further investigation to ensure that GLP-1 RAs can be safely used with concomitant medications.

The passive membrane permeation of small-molecule drugs and small hydrophobic peptides is relatively well understood. In contrast, how long polar peptides can pass through a membrane has remained a mystery. This process can be achieved with permeation enhancers, contributing significantly to the oral transcellular absorption of important peptide drugs like semaglutide — the active pharmaceutical ingredient in Ozempic, which is used as Rybelsus in a successful oral formulation. Here we now provide a detailed, plausible molecular mechanism of how such a polar peptide can realistically pass through a membrane paired with the permeation enhancer salcaprozate sodium (SNAC). We provide both simulation results, obtained with scalable continuous constant pH molecular dynamics (CpHMD) simulations, and experimental evidence (NMR, DOSY, and DLS) to support this unique permeation mechanism. Our combined evidence points toward the formation of permeation-enhancer-filled, fluid membrane defects, in which the polar peptide can be submerged in a process analogous to quicksand. This study explores how oral semaglutide (Rybelsus) crosses the gastrointestinal barrier. Findings suggest that semaglutide can embed in epithelial membranes with a permeation enhancer, offering molecular-level insight into oral peptide absorption.

Oral absorption remains challenging for peptides, proteins, and other drug substances with limited stability or permeability. Sodium N-(8-[2-hydroxybenzoyl]amino)caprylate (SNAC), also known as salcaprozate sodium, is an oral permeation enhancer used in approved drug products. This review summarizes the physicochemical properties and mechanisms of action of SNAC and evaluates its clinical and emerging preclinical applications. A structured literature search was conducted in PubMed and Scopus, supplemented as needed with ClinicalTrials.gov and regulatory documents. The search covered 2015–2026, with earlier key publications included where necessary for historical context. After screening, 71 sources were included in the narrative synthesis. The review examines the proposed mechanisms of SNAC-mediated permeation enhancement, including local pH modulation, membrane-mediated effects, peptide self-association, and context-dependent effects on epithelial permeability. Clinical evidence is summarized for oral semaglutide, cyanocobalamin, unfractionated heparin, ibandronate, and investigational peptide products. Emerging applications beyond metabolic diseases are discussed together with formulation strategies and safety considerations. Recent preclinical findings suggesting changes in gut microbiota and inflammatory markers are critically evaluated in the context of the available clinical safety experience, while their relevance to humans remains unconfirmed. Overall, SNAC reliably enhances permeation in vitro and in vivo, yet the resulting oral bioavailability remains low and variable and is strongly dependent on payload, formulation, and gastrointestinal conditions. Long-term safety and the clinical relevance of recent preclinical microbiome findings remain important areas for future investigation.

The oral delivery of peptide therapeutics remains constrained by poor intestinal permeability and the challenge of enhancing epithelial transport without compromising mucosal integrity. Although sodium N-(8-[2-hydroxybenzoyl]amino) caprylate (SNAC) enables gastric absorption of oral semaglutide and has also been explored for small-intestinal absorption of other peptide drugs, its suitability for enteric intestinal delivery of semaglutide remains unexplored. Here, we performed a comparative mechanistic evaluation of three permeation enhancers (SNAC, N-dodecyl-β-D-maltoside, and lauroyl-l-carnitine) for enteric delivery of semaglutide. Mechanisms were screened in epithelial monolayers and in situ intestinal absorption in rats, and the enhancers carried forward were formulated into enteric-coated capsules and evaluated in beagle dogs, with the leading candidate taken in to cynomolgus monkeys. In differentiated Caco-2 monolayers, all enhancers increased semaglutide transport but exhibited distinct transport mechanisms and barrier-response profiles. SNAC increased permeability without increasing mannitol transport or disrupting ZO-1, indicating a largely non-paracellular, cargo-dependent profile. DDM markedly increased paracellular marker transport and disrupted tight-junction organization, consistent with a primarily paracellular mode of action associated with reduced barrier recoverability. LLC showed a more favorable balance between transport enhancement and barrier recovery, while also increasing intracellular semaglutide-associated fluorescence and FD4 permeability. Rab5 immunostaining and dynasore inhibition indicated a dynamin-sensitive uptake component alongside partial tight-junction modulation. In rats, LLC produced the greatest increase in semaglutide absorption, and this effect was substantially attenuated by dynasore co-treatment. Transmission electron microscopy and tissue immunofluorescence further supported the presence of LLC-associated micelle-like structures, Rab5-related intracellular trafficking and junctional remodelling, with no overt tissue injury on local or systemic histology. For large-animal translation, citric acid and L-arginine improved semaglutide stability in intestinal fluids, and the resulting LLC-containing enteric formulation markedly increased systemic exposure in orally dosed beagle dogs and in cynomolgus monkeys following intraduodenal delivery. Collectively, these findings identify LLC as a promising permeation enhancer within the present SNAC/DDM/LLC comparison for enteric intestinal delivery of semaglutide and highlight how coordinated uptake-related and barrier-modulating mechanisms can support intestinal semaglutide absorption.

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Oral delivery of proteins, including glucagon-like peptide 1 (GLP-1) receptor agonists, is impeded by low gastrointestinal permeation. Oral semaglutide has been developed for once-daily oral administration by co-formulation of the GLP-1 analogue semaglutide with an absorption enhancer, sodium N-(8-[2-hydroxybenzoyl] amino) caprylate (SNAC, 300 mg). A randomised, partially double-blind, placebo-controlled thorough QT/corrected QT (QTc) trial was conducted to confirm the absence of unacceptable QTc interval prolongation with SNAC. QT is defined as interval on the electrocardiogram, measured from the start of the QRS complex to the end of the T wave. Part A of the study sought to identify an appropriate dose of SNAC (which was substantially higher than that used in the oral semaglutide co-formulation) for QTc assessment. Three sequential healthy volunteer cohorts were randomised to escalating single oral doses of SNAC (1.2, 2.4 or 3.6 g) or placebo. Following identification of an appropriate dose, a cross-over trial was conducted (Part B). Healthy volunteers received one of four treatment sequences, including single oral doses of SNAC, moxifloxacin (positive control) and placebo. Primary objectives were to (1) assess adverse events (AEs) with escalating SNAC doses and (2) confirm that SNAC does not cause unacceptable QTc interval prolongation versus placebo, using the Fridericia heart rate-corrected QT interval (QTcF). All subjects completed Part A (N = 36) and 46 subjects completed Part B. In Part A, all AEs were mild to moderate in severity; no relationship was identified between AE incidence and SNAC dose. SNAC 3.6 g, the maximum investigated SNAC dose, was selected for Part B. There was no unacceptable prolongation of the QTcF interval with SNAC 3.6 g, and assay sensitivity was demonstrated with moxifloxacin as the positive control. There was no significant exposure–response relationship between SNAC concentration and QTcF interval, and no instances of QTc interval > 450 ms or increases > 30 ms. This QT/QTc trial demonstrates that SNAC doses 12-fold higher than the 300 mg dose used in the oral formulation of semaglutide do not cause unacceptable prolongation of the QTcF interval. Clinicaltrials.gov identifier: NCT02911870. Medications that are taken orally can be broken down by acid in the stomach before they are absorbed and therefore be less effective. Oral semaglutide is a novel type 2 diabetes medication that is formulated with the absorption enhancer sodium N-(8-[2-hydroxybenzoyl] amino) caprylate (SNAC), which helps to protect against semaglutide degradation in the stomach. Regulatory authority guidelines recommend that new therapies should be tested for prolongation of the QT interval, an important part of the heart’s electrical cycle. A previous trial demonstrated that semaglutide alone, which is currently available as an injectable diabetes therapy, did not prolong the QT interval when given in doses higher than those used in patients. Therefore, the current trial was conducted to assess whether the SNAC component of oral semaglutide has any relevant prolonging effect on the QT interval. Following regulatory guidelines for trials evaluating prolongation of the QT interval, the first part of the trial aimed to find a suitably high dose of SNAC. The second part of the trial aimed to confirm that SNAC does not prolong the QT interval. The results of this trial demonstrated that a 3.6 g dose of SNAC, which is 12-fold higher than the amount contained in oral semaglutide, does not prolong the QT interval. The safety and tolerability of SNAC 1.2 g, 2.4 g and 3.6 g were assessed in this trial and no concerns were identified. These results, taken alongside those of the previous QT interval study with subcutaneous semaglutide, indicate no relevant effect of oral semaglutide on the QT interval.

The peptide, octreotide, is used to treat acromegaly and neuroendocrine tumours. It is administered by either a long-acting injection or by an oral capsule. Although the oral route is preferrable, food interference necessitates dosing octreotide on an empty stomach and bioavailability is only ∼0.7%. Buccal film administration avoids the fasting constraints of oral octreotide and offers the potential for improved systemic bioavailability. This study presents a Quality by Design (QbD)- informed strategy to create a mucoadhesive pullulan-based buccal film co-entrapping octreotide with a bile salt permeation enhancer, sodium glycodeoxycholate (GDC). Pullulan was selected from a panel of candidate polymers based on film-forming performance and compatibility with octreotide and GDC, enabling reproducible formulation at relatively high entrapment levels despite the tendency of them to associate. Atomic force microscopy of films revealed concentration-dependent nanoscale roughness and microdomain formation at high GDC and octreotide levels. However, these structural features did not compromise key critical quality attributes (CQAs) including mechanical robustness, rapid hydration/disintegration, and acceptable content uniformity. Critical performance attributes (CPAs) using isolated porcine buccal mucosae demonstrated that films containing 10% w/w GDC (relative to pullulan) enhanced tissue uptake and octreotide permeation and via reversible non-destructive epithelial modulation. Stability testing confirmed >90% chemical recovery and conformational integrity of octreotide in films. UHPLC-HR-MS/MS confirmed identical fragmentation patterns for film-released and native octreotide, confirming the peptide's intact cyclic backbone and the absence of chemical modification after formulation and after >60 days storage at ambient environment. This is the first report to integrate nanoscale structural analysis with systematic QbD- informed evaluation of formulation quality and performance, establishing pullulan-GDC buccal films as a robust adaptable platform for future multilayer oromucosal peptide film development.

Background/Objectives: Oral delivery of semaglutide (Rybelsus) relies on sodium N-(8-[2-hydroxybenzoyl]amino)caprylate (SNAC) to enhance peptide absorption. However, formulation constraints and SNAC’s localized gastric mechanism have prompted the exploration of alternative enhancers. This study evaluated whether sodium caprate (C10), a well-characterized medium-chain fatty acid (MCFA), could achieve systemic exposure comparable to SNAC-based formulations when co-formulated in an immediate-release (IR) tablet. Methods: Preformulation studies assessed the physicochemical properties and buffering capacity of C10. Mechanistic feasibility was evaluated through Caco-2 transport studies and rat pharmacokinetic (PK) trials using aqueous suspensions, comparing the concentration-dependent effects of C10 and SNAC. Based on these findings, three IR tablet architectures (monolayer, bilayer, and dry compression-coated) were developed. The optimized formulation was evaluated in beagle dogs (14 mg semaglutide) and compared with the SNAC-based reference product. Results: C10 exhibited sufficient buffering capacity to neutralize acidic environments. In Caco-2 and rat PK studies, C10 enhanced semaglutide absorption in a concentration-dependent manner, yielding exposure levels equivalent to SNAC at matched doses. Among the tablet designs, the monolayer tablet showed the highest dissolution similarity (f2 = 67.8) to Rybelsus. In beagle dogs, the optimized monolayer formulation produced pharmacokinetic parameters, including Cmax, AUClast, and t1/2, that overlapped with those of the SNAC-based reference drug product under matched dosing conditions. Conclusions: These results demonstrate that C10 can effectively support oral semaglutide delivery when incorporated into a rationally designed IR tablet. The findings support the feasibility of MCFA-based permeation enhancer platforms as formulation alternatives to SNAC for oral peptide therapeutics.

Oromucosal administration of drugs in films, tablets, lozenges, and other dosage forms provides a convenient systemic administration route for pediatric and elderly patients, and for patients who cannot swallow capsules or tablets easily. Developing buccal and sub-lingual peptide formulations requires preclinical models that align with the non-keratinized oromucosal epithelial structures of humans, of which pigs and dogs are the most suitable. We sourced discarded fresh porcine oromucosal tissues from an abattoir. The mucosae were dissected from the underlying smooth muscle using controlled heating and then mounted in either Franz Diffusion Cells or in novel low-volume 3D-printed resin-cured inserts. Peptide-permeation enhancer combinations were added to the donor side, and permeated molecules were sampled from the receiver side and quantified by ultra-high performance liquid chromatography (uHPLC). For the inserts, transepithelial electrical resistance (TEER) values of mounted mucosae were measured using EVOM chopstick electrodes. Tissue histology was examined following incubation in both Franz diffusion cells and 3D inserts. The optimal concentration of permeation enhancer was selected when aqueous mixtures of peptide and enhancer produced an increase in permeation. Peptide permeation reached 4.3% over 3 h in three-dimensional (3D) inserts and 1.7% in Hilltop chamber models, the latter simulating direct exposure from a buccal film. Layer-by-layer polymeric mucoadhesive films containing peptide-enhancer combinations were developed and applied to mucosal tissue for permeation studies using diffusion chambers. Ex vivo peptide permeation across porcine buccal mucosae reached 2% when mucosae were exposed to the optimal combination of glycodeoxycholate (GDC) incorporated into the buccal films. These ex vivo screening studies provide a pathway to subsequent pharmacokinetic evaluation of peptide-loaded film formulations administered via the oromucosal route in pigs and people.

Abstract Semaglutide (SEM) is a GLP-1 analogue, administered subcutaneously or orally. Due to its large molecular structure, it has poor oral absorption and bioavailability. The reported oral bioavailability is 0.4% to 1% in the fasting state. Sodium N-[8-{2-hydroxybenzoyl} amino] caprylate (SNAC) is used as a permeation enhancer to improve gastric permeability and oral bioavailability. This study developed a semi-mechanistic pharmacokinetic (PK) model to predict the steady-state pharmacokinetics of oral SEM, primarily using published clinical data and literature-derived parameters. The present study investigated the impact of SNAC on the gastric absorption of SEM. The semi-mechanistic PK model was developed for the intravenous (IV) and oral formulations. The oral absorption model was developed for SEM at different single doses with varying amounts of SNAC. The dose, SNAC concentration, gastrointestinal permeability, and intestinal first-pass effect impact the PK of the oral SEM. Steady-state PK studies were used to validate the single-dose oral PK model. IV, single-dose, and multiple-dose oral PK models were developed and validated. The developed semi-mechanistic model could be useful for further development of mechanistic, physiologically based pharmacokinetic (PBPK) models for formulation development, drug interactions, and the influence of pharmacokinetics in special populations.

Glucagon-like peptide-1 (GLP-1) receptor agonists (GLP-1RAs) were first introduced for the treatment of type 2 diabetes (T2D) in 2005. Despite the high efficacy and other benefits of GLP-1RAs, their uptake was initially limited by the fact that they could only be administered by injection. Semaglutide is a human GLP-1 analog that has been shown to significantly improve glycemic control and reduce body weight, in addition to improving cardiovascular outcomes, in patients with T2D. First approved as a once-weekly subcutaneous injection, semaglutide was considered an ideal peptide candidate for oral delivery with a permeation enhancer on account of its low molecular weight, long half-life, and high potency. An oral formulation of semaglutide was therefore developed by co-formulating semaglutide with sodium N-(8-[2-hydroxybenzoyl]amino)caprylate, a well-characterized transcellular permeation enhancer, to produce the first orally administered GLP-1RA. Pharmacokinetic analysis showed that stable steady-state concentrations could be achieved with once-daily dosing owing to the long half-life of oral semaglutide. Upper gastrointestinal disease and renal and hepatic impairment did not affect the pharmacokinetic profile. In the phase III PIONEER clinical trial program, oral semaglutide was shown to reduce glycated hemoglobin and body weight compared with placebo and active comparators in patients with T2D, with no new safety signals reported. Cardiovascular efficacy and safety are currently being assessed in a dedicated outcomes trial. The development of an oral GLP-1RA represents a significant milestone in the management of T2D, providing an additional efficacious treatment option for patients.

Recently, two oral-administered peptide pharmaceuticals, semaglutide and octreotide, have been developed and are considered as a breakthrough in peptide and protein drug delivery system development. In 2019, the Food and Drug Administration (FDA) approved an oral dosage form of semaglutide developed by Novo Nordisk (Rybelsus®) for the treatment of type 2 diabetes. Subsequently, the octreotide capsule (Mycapssa®), developed through Chiasma’s Transient Permeation Enhancer (TPE) technology, also received FDA approval in 2020 for the treatment of acromegaly. These two oral peptide products have been a significant success; however, a major obstacle to their oral delivery remains the poor permeability of peptides through the intestinal epithelium. Therefore, gastrointestinal permeation enhancers are of great relevance for the development of subsequent oral peptide products. Sodium salcaprozate (SNAC) and sodium caprylate (C8) have been used as gastrointestinal permeation enhancers for semaglutide and octreotide, respectively. Herein, we briefly review two approved products, Rybelsus® and Mycapssa®, and discuss the permeation properties of SNAC and medium chain fatty acids, sodium caprate (C10) and C8, focusing on Eligen technology using SNAC, TPE technology using C8, and gastrointestinal permeation enhancement technology (GIPET) using C10.

No abstract available

Drugs administered by means of extravascular routes of drug administration must be absorbed into the systemic circulation, which involves the movement of the drug molecules across biological barriers such as epithelial cells that cover mucosal surfaces or the stratum corneum that covers the skin. Some drugs exhibit poor permeation across biological membranes or may experience excessive degradation during first-pass metabolism, which tends to limit their bioavailability. Various strategies have been used to improve drug bioavailability. Absorption enhancement strategies include the co-administration of chemical permeation enhancers, enzymes, and/or efflux transporter inhibitors, chemical changes, and specialized dosage form designs. Models with physiological relevance are needed to evaluate the efficacy of drug absorption enhancement techniques. Various in vitro cell culture models and ex vivo tissue models have been explored to evaluate and quantify the effectiveness of drug permeation enhancement strategies. This review deliberates on the use of in vitro and ex vivo models for the evaluation of drug permeation enhancement strategies for selected extravascular drug administration routes including the nasal, oromucosal, pulmonary, oral, rectal, and transdermal routes of drug administration.

Despite being an approved antiemetic for more than five decades, the clinical usefulness of prochlorperazine is limited by its low solubility and inconsistent absorption in the gastrointestinal tract, which presents challenges for nanotherapeutic interventions. Here, we report the preparation of a highly soluble and permeable nanofiber formulation of prochlorperazine using the Quality-by-Design approach. The final nanofiber formulation with drug entrapment of 88.02 ± 1.14 % was obtained at 20.0 kV, with a flow rate of 0.5 ml/h and tip-to-collector distance of 19.9 cm. Physio-mechanical properties, such as thickness (0.42 ± 0.02 mm), pH resistance (7.04 ± 0.08), folding endurance (54 ± 5), and tensile strength (0.244 ± 0.02 N.mm-2), were appropriate for packaging and application to oromucosal surfaces. The content uniformity (93.48-106.63 %) and weight variation (<1.8 mg) of the optimal nanofiber formulation were within the permissible limits prescribed for orodispersible films. Microscopical investigations confirm a randomly deposited and dense network of woven nanofibers with an average diameter of 363 ± 5.66 nm. The drug particles were embedded homogeneously on the fiber in the nanoform (4.27 ± 1.34 nm). The spectral analysis using TEM-EDS shows diffraction peaks of sulfur and chlorine, the elemental constituents of prochlorperazine. The drug was amorphized in the nanofiber formulation, as led by the decline of the crystallinity index from 87.25 % to 7.93 % due to electrostatic destabilization and flash evaporation of the solvent. The enthalpy of fusion values of the drug in the nanofiber mat decreased significantly to 23.6 J/g compared to its pristine form, which exhibits a value of 260.7 J/g. The nanofibers were biocompatible with oral mucosal cells, and there were no signs of mucosal irritation compared to 1 % sodium lauryl sulfate. The fiber mats rapidly disintegrated within <1 s and released ≈91.49 ± 2.1 % of the drug within 2 min, almost 2-fold compared to the commercial Stemetil MD® tablets. Similarly, the cumulative amount of the drug permeated across the unit area of the oromucosal membrane was remarkably high (31.28 ± 1.30 μg) compared to 10.17 ± 1.11 μg and 13.10 ± 1.79 μg from the cast film and drug suspension. Our results revealed these nanofiber formulations have the potential to be fast-dissolving oromucosal delivery systems, which can result in enhanced bioavailability with an early onset of action due to rapid disintegration, dissolution, and permeation.

Background: Buccal administration offers direct access to systemic circulation, improving drug bioavailability when compared with the conventional oral route. This advantage depends on the formulation’s ability to remain in contact with the buccal mucosa. Attributes such as adhesion and viscosity are suggested to be correlated and contribute to enhanced residence time at the administration site. Methods: Buccal formulations with varying hydroxypropyl cellulose concentrations were prepared. Adhesion, viscosity, and residence time were assessed using a novel combined qualitative and quantitative approach. Drug permeation was evaluated in vitro using a biomimetic membrane and ex vivo using porcine buccal tissue, and it was further enhanced by adding the permeation enhancer benzalkonium chloride. Permeability measurements were integrated with residence time to estimate effective drug delivery. Results: Increasing HPC concentration improved both adhesion and viscosity, with 2% HPCs (F2) showing the strongest effect (45.5 ± 13.7 g), correlating with longer residence time (43.4% drug retained at 2 min vs. ~20% for 0–1% HPC). Although the polymer slightly reduced apparent permeability, when residence time was considered, drug flux increased 1.6-fold compared to the polymer-free formulation (F0), rising from 12.9 × 10−5 cm/min (F0) to 19.4 × 10−5 cm/min (F2) after 2 min. The addition of BKC further enhanced permeation, with apparent permeability increasing 1.5-fold vs. F2 and 2.5-fold vs. F0. Conclusions: Buccal liquid preparations’ efficacy is influenced by residence time and subsequent drug permeation. Residence time benefits from the synergistic effects of adhesion and viscosity, highlighting the importance of experimentally assessing these parameters during the development of oromucosal products.

No abstract available

Abstract Objectives In this study, the comparative bioavailability of semaglutide following the administration of oral (PO) and subcutaneous (SC) doses in healthy subjects was evaluated. The pharmacokinetics of semaglutide of these formulations at lower doses (SC dose of 0.25 mg; PO dose of 3 mg) was examined by utilizing a sensitive bioanalytical method. Methods Twenty-two subjects were administered either 0.25 mg SC or 3 mg PO and blood samples were taken up to 504 h. The samples were assayed for semaglutide with an analytical range of 0.05–50 ng/mL. The pharmacokinetic parameters were estimated using a non-compartmental approach and were used to evaluate the comparative bioavailability of semaglutide. Results The pharmacokinetics of semaglutide was characterized following the administration of low subcutaneous and oral doses. The comparative bioavailability (PO relative to SC) was 0.66 % at the doses administered. Overall, the study drug was well tolerated, and no serious adverse events were reported. Conclusions The bioavailability of semaglutide following oral and subcutaneous administrations has been determined using a validated bioanalytical method. This method will enable more investigations into the pharmacokinetics of all formulations of semaglutide at lower doses, which will enable a better understanding of its’ disposition in healthy subjects and in patients.

The trial (NCT04016974) investigated the pharmacokinetics, pharmacodynamics, safety and tolerability of oral semaglutide, the first orally administered glucagon‐like peptide‐1 analogue for type 2 diabetes, in healthy Chinese subjects.

Background Prescribing information instructs taking oral semaglutide (a glucagon-like peptide-1 analogue) in the fasting state, followed by a post-dose fasting period of ≥ 30 min. This trial compared the recommended dosing schedule with alternative schedules. Methods This was a randomised, single-centre, multiple-dose, open-label, five-armed, parallel-group trial in healthy subjects who received once-daily oral semaglutide (3 mg for 5 days followed by 7 mg for 5 days). Subjects ( n  = 156) were randomised to five dosing schedules: 2-, 4-, or 6-h pre-dose fast followed by a 30-min post-dose fast (treatment arms: 2 h–30 min, 4–30 min, 6 h–30 min); 2-h pre-dose fast followed by an overnight post-dose fast (treatment arm: 2 h–night); or overnight pre-dose fast followed by a 30-min post-dose fast (reference arm: night–30 min). Semaglutide plasma concentration was measured regularly until 24 h after the 10th dose. Endpoints included area under the semaglutide plasma concentration–time curve during a 24-h interval after the 10th dose ( AUC _0–24h) (primary endpoint) and maximum observed semaglutide plasma concentration after the 10th dose ( C _max) (secondary endpoint). Results Compared with an overnight pre-dose fast (reference arm: night–30 min), shorter pre-dose fasting times in the 2 h–night, 2 h–30 min, 4 h–30 min, and 6 h–30 min treatment arms resulted in significantly lower semaglutide AUC _0–24h and C _max after the 10th dose (estimated treatment ratio ranges: 0.12–0.43 and 0.11–0.44, respectively; p  < 0.0001 for all comparisons). Semaglutide AUC _0–24h and C _max after the 10th dose were similar for the 2 h–30 min and 2 h–night treatment arms. Conclusion This trial supports dosing oral semaglutide in accordance with prescribing information, which requires dosing in the fasting state. Trial Registration ClinicalTrials.gov (NCT04513704); registered August 14, 2020. Oral semaglutide is a human glucagon-like peptide-1 analogue that has been approved for the treatment of type 2 diabetes. It has been established that taking oral semaglutide with food or large volumes of water decreases absorption of the drug in the body. Current prescribing information instructs taking oral semaglutide on an empty stomach (known as the fasting state), with 120 mL/4 oz of water, then waiting for at least 30 min before consuming any food, water, or taking other oral medications. This study investigates whether different dosing schedules for oral semaglutide could potentially offer more flexibility to patients in the timing of their oral semaglutide dosing. The trial, conducted in healthy volunteers, compares the dosing schedule described in the prescribing information with different fasting times before (pre-dose) and after (post-dose) taking oral semaglutide during the day or evening, to see if there were any effects on the concentration of drug in the body. Compared to the recommended overnight fasting period, shorter pre-dose fasting periods of 2–6 h with a 30-min post-dose fast considerably reduced semaglutide exposure in the body. Similarly, semaglutide exposure was also reduced with a 2-h pre-dose fast combined with post-dose overnight fasting. These findings further support the current prescribing information, which states that patients should take their oral semaglutide dose after an overnight fast.

No abstract available

The absorption, distribution and elimination of oral semaglutide, the first oral glucagon-like peptide-1 receptor agonist for treating type 2 diabetes, was investigated using a population pharmacokinetic model based on data from clinical pharmacology trials. A previously developed, two-compartment pharmacokinetic model, based on subcutaneous and intravenous semaglutide, was extended to include data from six oral semaglutide trials conducted in either healthy volunteers or subjects with renal or hepatic impairment. Five trials employed multiple doses of oral semaglutide (5–10 mg) and one was a single-dose (10 mg) trial. In a separate analysis, the model was re-estimated using data from a trial in subjects with type 2 diabetes. The model accurately described concentration profiles across trials. Post-dose fasting time, co-ingestion of a large water volume, and body weight were the most important covariates affecting semaglutide exposure. Bioavailability was 0.8% when oral semaglutide was dosed using the recommended dosing conditions (30 min post-dose fasting time, administered with ≤ 120 mL of water), increasing with a longer post-dose fasting time and decreasing with higher water volume. Within-subject variability in bioavailability was 137%, which with once-daily dosing and a long half-life translates into 33% within-subject variability in steady-state exposure. There was no significant difference in oral bioavailability of semaglutide in healthy subjects and subjects with type 2 diabetes. The updated model provided a general characterisation of semaglutide pharmacokinetics following oral, subcutaneous and intravenous administration in healthy subjects and subjects with type 2 diabetes. Within-individual variation of oral bioavailability was relatively high, but reduced considerably at steady state. NCT01572753, NCT01619345, NCT02014259, NCT02016911, NCT02249871, NCT02172313, NCT02877355.

Oral semaglutide is a novel tablet formulation of the human glucagon-like peptide-1 analogue semaglutide. In two trials, the effects of prior food ingestion (food effect), post-dose fasting period and water volume with dosing (dosing conditions) on oral semaglutide pharmacokinetics were investigated. Subjects received once-daily oral semaglutide for 10 days. In the food-effect trial, 78 healthy subjects were randomised 1:1:1 to fed (meal 30 min pre-dose; 240 mL water with dosing), fasting (overnight until 4 h post-dose; 240 mL) or reference (fasting overnight until 30 min post-dose; 120 mL) arms. In the dosing conditions trial, 161 healthy men were randomised into eight dosing groups (overnight fasted with 50/120 mL water and 15/30/60/120 min post-dose fasting). Semaglutide plasma concentrations were measured frequently until 504 h after the 10th dose. In the food-effect trial, limited or no measurable semaglutide exposure was observed in the fed arm, while all subjects in the fasting arm had measurable semaglutide exposure. Area under the semaglutide concentration–time curve (AUC0–24h,semaglutide,day10) and maximum semaglutide concentration (Cmax,semaglutide,day10) were numerically greater by approximately 40% for the fasting versus reference arm (p = 0.082 and p = 0.080, respectively). In the dosing conditions trial, AUC0–24h,semaglutide,day10 and Cmax,semaglutide,day10 were not different between water volumes (p = 0.541 and p = 0.676), but increased with longer post-dose fasting (p < 0.001). Administration of oral semaglutide in the fasting state with up to 120 mL water and at least 30 min post-dose fasting results in clinically relevant semaglutide exposure. These dosing conditions have been used in the oral semaglutide phase 3 trials and are part of the approved label. ClinicalTrials.gov identifiers NCT02172313, NCT01572753.

Semaglutide, a glucagon‐like peptide‐1 (GLP‐1) analogue, has been coformulated in a tablet with the absorption enhancer, sodium N‐(8‐[2‐hydroxybenzoyl] amino) caprylate (SNAC). We investigated tablet erosion and the pharmacokinetics of oral semaglutide administered with 2 different water volumes and evaluated the relationships between these parameters. In a randomized, single‐center (Quotient Sciences, UK), open‐label, 2‐period crossover trial, 26 healthy men received single doses of 10 mg oral semaglutide with 50 or 240 mL water while fasting. Tablet erosion and gastrointestinal transit were assessed by gamma scintigraphy. Semaglutide and SNAC plasma concentrations were measured until 24 and 6 hours, respectively, after administration. Complete tablet erosion (CTE) occurred in the stomach irrespective of water volume administered with the tablet (primary end point). Mean time to CTE was 85 versus 57 minutes with 50 versus 240 mL water (ratio 50/240 mL, 1.51; 95% confidence interval, 0.96‐2.37; P = .072). Area under the semaglutide concentration‐time curve from 0 to 24 hours (AUC0‐24h,semaglutide) and maximum semaglutide concentration (Cmax,semaglutide) were ∼70% higher with 50 versus 240 mL water (P = .056 and P = .048, respectively). Median time to maximum semaglutide concentration (tmax,semaglutide) was 1.5 hours independent of water volume with dosing. Higher AUC0‐24h,semaglutide and Cmax,semaglutide and longer tmax,semaglutide were significantly correlated with longer time to CTE and later gastric emptying of tablet and water (all P < .05). The safety profile was as expected for the GLP‐1 receptor agonist drug class. In conclusion, the oral semaglutide tablet erodes in the stomach irrespective of water volume with dosing. Slower tablet erosion in the stomach results in higher semaglutide plasma exposure.

The first oral glucagon-like peptide-1 receptor agonist (GLP-1RA) comprises semaglutide co-formulated with the absorption enhancer, sodium N-(8-[2-hydroxybenzoyl] amino) caprylate (SNAC). Oral semaglutide may alter the pharmacokinetics of co-administered drugs via effects of semaglutide or SNAC. Two separate one-sequence crossover trials investigated the effects of oral semaglutide and SNAC on the pharmacokinetics of ethinylestradiol, levonorgestrel, furosemide and rosuvastatin. Healthy, postmenopausal women (n = 25) received once-daily combined ethinylestradiol and levonorgestrel (Trial 1) and healthy male and female subjects (n = 41) received single doses of furosemide and rosuvastatin (Trial 2), either alone, with SNAC alone or with oral semaglutide. Lack of drug–drug interaction was concluded if 90% confidence intervals (CIs) for the ratio of area under the plasma concentration–time curve (AUC) or maximum concentration (Cmax), with/without oral semaglutide, were within a pre-specified interval (0.80–1.25). The AUC values of ethinylestradiol and levonorgestrel were not affected by oral semaglutide co-administration (estimated ratios [90% CI] 1.06 [1.01–1.10] and 1.06 [0.97–1.17], respectively); Cmax was not affected. The no-effect criterion was not met for furosemide or rosuvastatin for the AUC (1.28 [1.16–1.42] and 1.41 [1.24–1.60], respectively) or Cmax. SNAC alone did not affect the AUC or Cmax of ethinylestradiol, levonorgestrel or rosuvastatin; the Cmax of furosemide was slightly decreased. Adverse events were similar to those previously observed for GLP-1RAs (both trials). Co-administration with oral semaglutide did not affect the pharmacokinetics of ethinylestradiol or levonorgestrel. There was a small increase in exposure of furosemide and rosuvastatin; however, these increases are not expected to be of clinical relevance. NCT02845219 and NCT03010475.

Dysphagia is highly prevalent in patients with amyotrophic lateral sclerosis (ALS). Riluzole is a US Food and Drug Administration‐approved treatment for ALS. Riluzole oral film (ROF; Exservan™) contains riluzole in a polymer‐based film matrix. The ROF is administered by placing on the tongue, where it dissolves and the drug is ingested with the saliva. Two clinical trials assessed the safety and tolerability of the ROF. Bioavailability and pharmacokinetics (PK) were evaluated in an open‐label, randomized, single‐dose, replicate crossover study of 50 mg of ROF and riluzole 50‐mg tablets in 32 healthy volunteers. The second study was a videofluoroscopic swallowing examination conducted with nine patients with ALS before and after receiving a single dose of 50 mg of ROF. The primary outcome was change on penetration‐aspiration scale (PAS) scores from pre‐ to post‐dose. Overall, the PK parameters for ROF and riluzole tablets were comparable between treatments and administrations when administered under fasting conditions. Administration of ROF with food resulted in a 15% reduction in area under the curve and a 45% reduction in maximum serum concentration. A total of 44 treatment‐emergent adverse events (AEs) were reported in the study; all were mild in severity. No serious AEs were observed and no subjects discontinued due to AEs. In the swallowing study, very little numerical or categorical change was observed following the dose of ROF. No evidence of deterioration of swallowing function was observed post‐dose. The ROF was bioequivalent to riluzole tablets, was well tolerated, and had no detrimental effect on swallowing.

ABSTRACT Background Oral semaglutide comprises the glucagon-like peptide-1 analog, semaglutide, and sodium N-(8-[2-hydroxybenzoyl] amino) caprylate (SNAC). Levothyroxine has similar dosing conditions to oral semaglutide. This trial investigated if oral semaglutide co-administered with levothyroxine affects thyroxine (T4) exposure and if multiple placebo tablets co-administered with oral semaglutide affect semaglutide exposure. Research design and methods In this one-sequence crossover trial, 45 healthy subjects received levothyroxine (600 μg single-dose) alone, or with concomitant SNAC 300 mg or concomitant oral semaglutide 14 mg at steady-state. Subjects also received oral semaglutide 14 mg at steady-state alone or with five placebo tablets once-daily for 5 weeks. Results A 33% increase in total T4 exposure was observed with levothyroxine/oral semaglutide vs levothyroxine alone, but baseline-corrected maximum concentration (C max) was unaffected. SNAC alone did not affect total T4 exposure, whereas C max was slightly decreased. A 34% decrease in semaglutide exposure was observed when oral semaglutide was co-administered with placebo tablets, and C max also decreased. Conclusions Levothyroxine pharmacokinetics were influenced by co-administration with oral semaglutide. Monitoring of thyroid parameters should be considered when treating patients with both oral semaglutide and levothyroxine. Oral semaglutide exposure was influenced by co-administration with multiple tablets, which is addressed in the dosing guidance.

To investigate whether upper gastrointestinal (GI) disease has any effect on the exposure of oral semaglutide, an important consideration given that its absorption occurs primarily in the stomach.

Purpose The aim of this review was to provide all the pharmacokinetic data for semaglutide in humans concerning its pharmacokinetics after subcutaneously and oral applications in healthy and diseased populations, to provide recommendations for clinical use. Methodology The PubMed and Embase databases were searched to screen studies associated with the pharmacokinetics of semaglutide. The pharmacokinetic parameters included area under the curve plasma concentrations (AUC), maximal plasma concentration (Cmax), time to Cmax, half-life (t1/2), and clearance. The systematic literature search retrieved 17 articles including data on pharmacokinetic profiles after subcutaneously and oral applications of semaglutide, and at least one of the above pharmacokinetic parameter was reported in all included studies. Results Semaglutide has a predictable pharmacokinetic profile with a long t1/2 that allows for once-weekly subcutaneous administration. The AUC and Cmax of both oral and subcutaneous semaglutide increased with dose. Food and various dosing conditions including water volume and dosing schedules can affect the oral semaglutide exposure. There are limited drug–drug interactions and no dosing adjustments in patients with upper gastrointestinal disease, renal impairment or hepatic impairment. Body weight may affect semaglutide exposure, but further studies are needed to confirm this. Conclusion This review encompasses all the pharmacokinetic data for subcutaneous and oral semaglutide in both healthy and diseased participants. The existing pharmacokinetic data can assist in developing and evaluating pharmacokinetic models of semaglutide and will help clinicians predict semaglutide dosages. In addition, it can also help optimize future clinical trials.

Type 2 diabetes mellitus (T2DM) is a chronic metabolic disorder often associated with obesity and elevated cardiovascular risks. Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) have become integral to T2DM management due to their clinical benefits of glucose regulation and weight loss. However, their subcutaneous administration presents challenges to patient adherence, limiting their widespread use. Oral semaglutide (Rybelsus®), the first oral GLP-1 RA approved for T2DM, addresses these challenges through an innovative co-formulation with sodium N-(8-[2-hydroxybenzoyl] amino) caprylate, which enhances gastric absorption and stability. This review provides a comprehensive overview of the clinical development of oral semaglutide, with a focus on early-phase trials. Phase 1 studies investigated pharmacokinetics, pharmacodynamics, safety, and dose-response relationships, demonstrating a dose-dependent reduction in hemoglobin A1c (HbA1c) and body weight with an acceptable safety profile. Additionally, pharmacological evaluations of interactions with food, dosing condition, disease states, and concomitant medications supported the determination of an optimal dosing regimen for further clinical studies. Phase 2 dose-finding trials confirmed significant HbA1c and weight reductions comparable to subcutaneous semaglutide, which guided dose selection for phase 3 trials. Phase 3 trials, including the Peptide InnOvatioN for Early diabEtes tReatment program, demonstrated significant reductions in HbA1c, weight loss, and cardiovascular safety, positioning oral semaglutide as a transformative option in diabetes care. The study highlights comprehensive clinical strategies and provides an insight into the future development of oral GLP-1 RAs and other oral peptide drugs.

BackgroundOral semaglutide is a tablet co-formulation of the human glucagon-like peptide-1 (GLP-1) analog semaglutide with the absorption enhancer sodium N-(8-[2-hydroxybenzoyl] amino) caprylate (SNAC). The absorption of coadministered oral drugs may be altered due to enhancement by SNAC, potential gastric emptying delay by semaglutide, or other mechanisms. Two one-sequence crossover trials investigated the effect of oral semaglutide on the pharmacokinetics of lisinopril, warfarin, digoxin, and metformin.MethodsIn trial 1, 52 healthy subjects received lisinopril (20 mg single dose) or warfarin (25 mg single dose) with subsequent coadministration with SNAC alone (300 mg single dose), followed by oral semaglutide 20 mg once daily (steady state). In trial 2, 32 healthy subjects received digoxin (500 μg single dose) or metformin (850 mg twice daily for 4 days), with subsequent coadministration with SNAC alone followed by oral semaglutide, as in trial 1.ResultsThere were no apparent effects of oral semaglutide on area under the plasma concentration–time curve (AUC) and maximum plasma concentration (Cmax) for lisinopril, warfarin, and digoxin. The AUC of metformin was increased by 32% (90% confidence interval 1.23–1.43) by oral semaglutide coadministration versus metformin alone, whereas the Cmax was unaffected. SNAC alone did not affect exposure of lisinopril, warfarin, digoxin, or metformin. Adverse events were in line with those previously observed for GLP-1 receptor agonists.ConclusionsOral semaglutide or SNAC alone did not appear to affect the exposure of lisinopril, warfarin, or digoxin, and, based on its wide therapeutic index, the higher metformin exposure with oral semaglutide was not considered clinically relevant.

Background The oral soluble film (OSF) is a new drug delivery system. Whether montelukast sodium OSF has similar pharmacokinetic (PK) properties and bioequivalence to chewable tablet (CT) should be investigated. Methods This study, conducted at Haikou People’s Hospital, consisted of two trials: a randomized, open-label, single-dose, 3-sequence, 3-period crossover trial under fasting conditions and a randomized, open-label, single-dose, 2-sequence, 2-period crossover trial under fed conditions. Healthy volunteers were randomized 1:1:1 to receive single-dose oral montelukast sodium OSF without water, OSF, or CT with water in the fasting trial, and 1:1 to receive OSF or CT with water in the fed trial in each period, with a 7-day washout period. Randomization was performed according to random number tables generated using computer. Blood samples were collected over a 24-h period. Plasma drug concentrations were tested using high-performance liquid chromatography-tandem mass spectrometry. The primary PK parameters were maximum plasma drug concentration (Cmax), area under the plasma drug concentration-time curve (AUC) from t=0 to the last quantifiable concentration (AUC0–t), and AUC from t=0 to infinity (AUC0–∞). The other PK parameters included time to Cmax (Tmax), terminal elimination rate constant (λz), and half-life (t1/2). Safety was also assessed. Analysis of variance on log-transformed primary PK parameters was applied to analyze the bioequivalence between the OSF and CT. The bioequivalence margin was 80–125%. Results From November 2018 to January 2019, 30 subjects were included in each trial. The PK parameters between OSF and CT were numerically similar. All 90% confidence intervals (CIs) of the geometric mean ratio (GMR) for the primary PK parameters fell within 80–125%, confirming the bioequivalence of montelukast sodium OSF and CT under fasting and fed conditions. In the fasting trial, 6 (20%) adverse events (AEs) were reported, including 3 (10%) cases after OSF administration without water and 3 (10%) after OSF administration with water, with no serious AEs. No AEs were recorded in the fed trial. Conclusions Montelukast sodium OSF is bioequivalent to CT, with acceptable safety. The OSF is an alternative option of CT. Trial Registration ClinicalTrials.gov identifiers: NCT05528198 (the fasting trial) and NCT05531994 (the fed trial).

The change of injectable semaglutide into verbally administered portion of drug or other consumable forms shows a significant progress in peptide-located diabetes medicines. This study evaluates the feasibility, pharmacokinetics, and temporary balance of oral semaglutide brought through capsule and liquid formulations in Sprague–Dawley rats. Injectable semaglutide (1 mg/mL) was reformulated using SNAC-located next-release sciences. Both oral formulations illustrated agreeable bioavailability (0.8–0.9%) relative to the injectable form. Pharmacokinetic reasoning told deferred Tmax for the tablet distinguished to the liquid, unpaid to formulation excipients. Stability experiment over 30 days designated maintained potency (95–97%) accompanying gentle opalescence in the liquid expression, inciting plans for enhanced expression plannings. These judgments provide basic evidence advocating future long-term ICH-obedient support studies and expression refinement for numbering spoken GLP-1 agonist development.