索马鲁肽与口溶膜

Introduction Halitosis is a major issue that negatively affects individuals' social interactions and quality of life. This study aimed to evaluate the effects of oral dissolving film (ODF) on halitosis and oral pathogenic bacteria. Objective To compare and evaluate the effects of ODF and tongue cleaner on reducing halitosis-related compound concentrations and oral pathogenic bacteria. Methods A pilot, single-center, non-randomized, before-after comparative study was conducted with 30 adults with halitosis. The experimental group (n=15) consumed ODF three times daily for 7 days, while the control group (n = 15) used a tongue cleaner for the same period. H2, H2S, CH3SH, and total VSCs were measured using a halitosis analyzer, and seven oral pathogenic bacterial species were analyzed by qPCR. Results Due to poor compliance, one participant from each group dropped out, resulting in 28 participants included in the final analysis. In the ODF group, H2 and CH3SH significantly decreased by 55.1% and 54.4%, respectively (p < 0.05), and Streptococcus mutans also significantly decreased by 27.9% (p = 0.022). The control group did not reach statistical significance for any halitosis parameters, and Treponema forsythia significantly increased by 5.8% (p = 0.047). Conclusion ODF exhibited significant reductions in key halitosis-associated compounds and demonstrated antimicrobial activity against cariogenic bacteria. This suggests ODF may serve as a convenient alternative approach for both halitosis management and dental caries prevention. Further large-scale, randomized trials are warranted to confirm these preliminary findings. This study was registered in https://trialsearch.who.int (KCT0010244).

Oral drug delivery films (ODFs) have emerged as a patient-centric alternative to conventional oral dosage forms, offering significant advantages in terms of convenience, compliance, and safety. Designed as thin, flexible strips, ODFs disintegrate or dissolve rapidly in the oral cavity, enabling self-administration without the need for water or chewing. This unique feature makes them especially suitable for pediatric and geriatric populations, bedridden patients, and individuals with swallowing difficulties (dysphagia), Parkinson’s disease, mucositis, nausea, or vomiting. By minimizing the risk of choking and enhancing therapeutic compliance, ODFs have gained wide acceptance as fast-dissolving drug delivery systems. Their adaptability in terms of size, shape, and formulation further supports their role as a promising platform in modern drug delivery. This review explores the potential of ODFs as a patient-centric approach, highlighting their formulation aspects, therapeutic applications, and future scope in addressing unmet clinical needs.

Oral dissolving film adalah lembaran tipis yang cepat larut ketika terkena air liur. Tujuan dari penelitian ini adalah untuk mengeksplorasi penggunaan ekstrak jahe merah sebagai tambahan dalam oral dissolving film serta untuk mengkaji karakteristiknya. Metode yang digunakan adalah studi literatur, di mana peneliti mengumpulkan data dari jurnal yang tersedia di situs scholar, dokumen, ensiklopedia, dan sumber lainnya. Beberapa penelitian sebelumnya menunjukkan bahwa penambahan ekstrak herbal lain dalam oral dissolving film  telah efektif dalam menyegarkan mulut dan mengandung antioksidan. Namun, diperlukan penelitian lebih lanjut untuk meningkatkan akurasi metode analisis dan memperkuat metodologi yang digunakan.

Montelukast Sodium (MS) is widely used for managing asthma and allergic rhinitis due to its leukotriene receptor antagonist properties. However, traditional oral dosage forms often lead to challenges in patient compliance and delayed onset of action. This study focuses on the design, development, and optimization of oral dissolving films (ODFs) of Montelukast Sodium, aimed at improving patient compliance and ensuring rapid drug release. Using the solvent casting method, various formulations were prepared with different concentrations of hydroxypropyl methylcellulose (HPMC), Eudragit, and Xanthum Gum and plasticizers like polyethylene glycol (PEG). The films were evaluated for their thickness, drug content uniformity, disintegration time, in vitro dissolution, and mechanical properties. The optimized ODFs F5 demonstrated rapid disintegration (10 seconds) and high drug release (99.99% within 5 minutes), indicating their potential to enhance therapeutic efficacy and patient adherence. Keywords: HPMC, Eudragit, Xanthum Gum, PEG, Film.

Jaundice is a clinical condition characterized by elevated bilirubin levels, leading to yellow discoloration of skin and mucous membranes. Herbal remedies have gained significant importance due to their safety and therapeutic efficacy. Phyllanthus amarus, a medicinal plant widely used in traditional medicine, possesses hepatoprotective, antiviral, and antioxidant properties. The present study aims to develop and evaluate a fast dissolving oral film (ODF) containing methanolic extract of Phyllanthus amarus. Fast dissolving films are novel drug delivery systems that dissolve rapidly in the oral cavity without the need for water, improving patient compliance, especially in pediatric and geriatric populations. The films were prepared using the solvent casting method with suitable polymers such as HPMC, along with plasticizers, sweeteners, and flavoring agents. The formulated films were evaluated for parameters including thickness, weight variation, folding endurance, disintegration time, and drug content uniformity. The results demonstrated rapid disintegration, good mechanical strength, and uniform drug distribution. Thus, Phyllanthus amarus oral films offer a promising herbal drug delivery system with improved bioavailability and patient acceptability.

Fast-dissolving oral delivery systems are solid dosage forms, which disintegrate or dissolve within 1 min when placed in the mouth without drinking water or chewing. This facilitates the rapid absorption in the oral cavity and reduces first-pass effects. The aim of this study is to formulate and evaluate the Fast dissolving Oral film of Promethazine hydrochloride as a strong antihistamine which are used to reduce nausea, motion sickness and improved bioavailability of drugs as compared to conventional solid oral dosage forms. The films were prepared Hydroxy propylmethyl cellulose E15 as a film base synthetic polymer and PEG400 (Poly Ethylene Glycol 400) as a plasticizer by solvent casting method. SLS (Sodium Lauryl Sulfate) and MCC (Micro Crystalline Cellulose) used as a surfactant in different concentration. Sucrose used as a sweetening agent and strawberry as a flavoring agent. Films were found to be satisfactory when evaluated for thickness, weight uniformity, in-vitro drug release, folding endurance, drug content and disintegration time. The surface pH of all the films was found to be neutral or minor change. Films in vitro drug release studies also done by using USP dissolution apparatus. The in vitro drug release in optimized formulation F2 was found to be 14.36% in 2 min. The optimized formulation F2 also showed satisfactory pH, drug content (97.41±0.54%), effective in vitro drug release (96.03±0.68% in 16 min), disintegration time of 09 seconds and satisfactory stability.The Promethazine hydrochloride fast dissolving oral film was formulated. The given film disintegrates within nine seconds which release drug rapidly and gives action.

No abstract available

Purpose Due to impairments in memory and judgment, it is difficult for dementia patients to understand why they need medicine. Moreover, they often have swallowing difficulties. In this investigation, an oral dissolving film of rivastigmine tartrate (RT-ODF) was developed, offering a unique and convenient formulation for dementia patients. Methods RT-ODF was developed using a solvent-casting technique. Sodium alginate and sodium carboxymethyl cellulose were used as film-forming polymers, and glycerol was used as a plasticizer. A full factorial design (3^2) was employed to estimate the impact of two factors at three levels: polymer concentration (1, 1.5, and 2% w / v ) and plasticizer concentration (30, 40, and 50% w / v ) on the responses, i.e., the tensile strength (TS), the disintegration time (DT), and the quantity of drug released (Q10 min). Results The optimized formula (A1) that had the highest desirability value (0.923) exhibited the lowest tensile strength (3.67 ± 0.72 MPa), the shortest disintegration time (20 ± 2.0 s), and the highest percentage of drug released after 10 min (97.12 ± 2.01%). It was composed of 1% w / v sodium alginate (ALG-Na) and plasticized with 30% w / v glycerol. The pharmacokinetic study revealed that the RT-ODFs enhanced the drug’s bioavailability by 1.91-fold relative to the reference product (Exelon® capsule). Conclusion Oral dissolving films of rivastigmine tartrate could be a promising approach to promote drug bioavailability and convenience for geriatric patients.

: Silver nanoparticles, also referred to as AgNPs, gaining particular significance at the moment as nanotechnology explores a number of interesting molecular techniques in the field of material sciences. Silver nanoparticles have become an effective new antimicrobial agent with improved efficacy with an inherent limitation of inducing toxicity to living tissues. This work will give an idea for researcher at developing Radix bupleuri silver nanoparticles, its characterization and subjected to various evaluation like visual examination, UV Visible spectral analysis, FTIR Spectroscopy, SEM analysis, TEM analysis and antiviral study. The Oral dissolving Film is prepared using Polyethylene glycol polymer and the characterized silver nanoparticles are incorporated to the above developed Polyethylene glycol oral dissolving film and evaluated for anti-microbial activity against COVID-19 viral strains. This work aids researchers in doing research in the synthesized Radix bupleuri silver Nanoparticles incorporated in a Polyethylene glycol oral dissolving film for a promising efficiency against COVID-19 viral strains.

The present study aimed to optimize a mouth‐dissolving film (MDF) made from Pongamia pinnata stem bark extract to increase patient compliance and accelerate oral disease therapy. Several stem bark extracts were prepared, and karanjin was used as an herbal marker for the extracts. The ethanolic extract showed the maximum yield (12.10% ± 0.09%) and cytotoxic activity against human oral cancer (KB 3‐1) and embryonic kidney cell lines. The MDF formulation was focused on incorporating a fixed amount of the extract and varying concentrations of HPMC E5 polymer, along with evaluating the performance of plasticizers like PEG 400 and propylene glycol (PG). An optimized formulation was determined based on disintegration time, wetting time, and folding endurance. The formulation consisted of HPMC E5 as a film‐forming polymer, PG as a superior plasticizer, ascorbic acid as an antioxidant, and other ingredients contributing to solubility, dispersion, sweetening, and appearance. High‐performance thin‐layer chromatography‐mass spectrometry analysis confirmed higher levels of karanjin in the optimized formulation, ensuring its successful incorporation and stability. Taste masking evaluations indicate a favorable taste profile and a high potential for patient compliance. The stability study displayed no significant changes in the physical characteristics of the film, affirming its stability and quality. In conclusion, the developed herbal‐based optimized MDF presents a promising drug delivery system, offering enhanced patient compliance, taste masking, and stability. The MDF holds great potential for effective treatment and management of oral diseases, providing convenience and improved therapeutic outcomes.

In an effort to guarantee patient acceptability, safety, efficacy, and compliance, companies and researchers have been working on developing innovative drug delivery methods for the past few decades. The creation of new drugs takes a lot of money, effort, and time these days, but the trend is toward innovative medication delivery methods. Through a variety of methods, this delivery system facilitates both local and systemic drug response. The oral fast-dissolving film preparation (OFDFs) using this innovative method aids patients who are immobile, elderly, and pediatric. The goal of this review study is to provide information about potential therapeutic candidates and polymers for use in OFDFs, as well as specifics about the creation, information and examination of OFDFs. It also focuses on both positive aspects and drawbacks that have an impact on the film's formulation. These films have good patient compliance, are pharmacoeconomic, and can be administered on their own. Oral fast dissolution films can be formulated using a variety of methods, the best of which being the solvent casting process. Buccal films are often made of hydrophilic polymers and other excipients, which dissolve fast and release the integrated APIs in a matter of seconds. There is potential for market and business development with oral fast dissolving films since they have many advantages in terms of accessibility, administration and withdrawal, retentivity, low enzymatic movement, economy, and high patient compliance. The mechanism of action, benefits, composition, formulation, evaluation, packaging and marketed formulations of oral fast dissolving films are highlighted in this prepared review. covers the topics around cutting-edge quick-solving methods as well.

BACKGROUND Oral dissolving films are portable dosage forms that consist of active pharmaceutical ingredients incorporated into film-forming polymers such as starch. Starches obtain optimum filmogenic properties by gelatinization and blending with other polymers. The high starch content of bitter yam (Dioscorea dumetorum Pax) gives it yet unexplored potential for orodispersible films. OBJECTIVES This study aimed to investigate the effect of pregelatinization on the physicochemical properties of bitter yam starch. Additionally, our objective was to evaluate the potential of both native starch (NS) and pregelatinized starch (PS), incorporated into polymer blends, as biopolymeric materials for use in orally dissolving films (ODFs). MATERIAL AND METHODS Native and pregelatinized wild Dioscorea dumetorum Pax (bitter yam) starch were prepared and characterized using physicochemical, microscopic and rheological methods, Fourier-transform infrared spectroscopy, X-ray diffractometry (XRD), and differential scanning calorimetry (DSC). Oral dissolving films with varying hydroxylpropylmethyl cellulose (HPMC)-to-starch ratios (1:1, 1:2 and 2:1) were formulated and evaluated based on organoleptic properties, surface morphology, folding endurance, weight and thickness, pH, and disintegration time. RESULTS Pregelatinization improved the swelling, solubility and hydration capacity of the starch. Although no changes were observed in the crystalline nature upon gelatinization, DSC analysis revealed remarkable changes in the thermal behavior of the NS after pregelatinization. Both NS and PS did not produce continuous films without HPMC. Flexibility of the starch increased with increasing HPMC concentration films, and PS-based films had higher folding endurance compared to NS films. Native starch-based films had smoother surfaces and higher thicknesses than PS films. All the starch films demonstrated disintegration times longer than 15 min, and slightly acidic pH values. CONCLUSIONS Pregelatinization of bitter yam starch, followed by blending with HPMC at a 2:1 ratio, resulted in the most effective oral film formulation. Further studies focusing on optimizing disintegration rates and pH would help confirm the suitability of this starch for use in ODF formulations.

The objective of present research work was to select cyclodextrins derivative for inclusion complex with Ezetimibe and formulate fast dissolving film to enhance pharmacokinetic and pharmacodynamic performance of drug.In this work, Hydroxypropyl Methylcellulose (HPMC) E5 and E15 were used as primary film-forming polymers in various combinations with pectin and glycerine as a plasticizer. The solvent casting method was employed to prepare the films. To improve the solubility and dissolution rate of Ezetimibe—a BCS Class II drug with low water solubility—inclusion complexes were developed using β-cyclodextrin, confirmed via FTIR, DSC, and XRD analyses. A 3² factorial design was implemented to systematically study the impact of formulation variables on key film characteristics such as disintegration time, drug content uniformity, folding endurance, and in vitro drug release. Among the formulations, batch F3 showed the most promising results, withRapid disintegration within 22 seconds, High drug content (98.87%), Superior tensile strength and folding endurance, Maximized drug release (above 95% within 5 minutes). The optimized batch followed first-order release kinetics, as validated by kinetic modelling (Higuchi, Korsmeyer-Peppas, and Hixson-Crowell models).Stability studies of batch F3 under accelerated conditions demonstrated excellent physicochemical stability for up to 3 months, confirming formulation robustness.The study concludes that Ezetimibe-loaded oral films developed using HPMC E5/E15, pectin, and glycerine can serve as a patient-friendly, fast-dissolving alternative dosage form with improved bioavailability and therapeutic efficacy, opening avenues for innovative drug delivery systems in lipid-lowering therapy.  

Insomnia and anxiety disorders are highly prevalent conditions that significantly impair daily functioning. Notably, a bidirectional relationship exists between these two disorders: heightened cortical excitability secondary to anxiety disrupts sleep onset mechanisms, while prolonged sleep insufficiency impairs prefrontal cortical regulation of emotional processing, thereby exacerbating anxiety symptoms. This creates a vicious cycle that worsens both conditions. To address this clinical challenge, we developed a combination therapy using two pharmacological agents with complementary mechanisms of action. Given the potential adverse neurological effects associated with conventional anxiolytics and hypnotics, we specifically selected two short-acting drugs with favorable safety profiles: melatonin and buspirone hydrochloride. To address insomnia accompanied by anxiety, we have designed and prepared a Bedside-savior:a compound oral fast-dissolving film containing melatonin and buspirone hydrochloride. Unlike traditional tablets or capsules, this immediate-release film offers distinct advantages for our target patients. Since it requires no water for administration, it prevents sleep disruption caused by nighttime drinking. Its ease of use makes it ideal for children, elderly individuals, and those with swallowing difficulties. Furthermore, the medication is rapidly absorbed through the sublingual venous plexus, enabling quick onset of action to simultaneously ease anxiety and promote faster sleep initiation-all without the need to get out of bed.

Oral candidiasis is a type of yeast infection of the oral mucosa caused by Candida albicans. India has the highest prevalence of Candida bloodstream infections. The first line treatment of this infection includes miconazole, fluconazole, itraconazole, nystatin and clotrimazole. Among all, miconazole is the safest medicine with high therapeutic index. However, its efficacy is compromised because of multidrug resistance and low bioavailability. Beauvericin, a cyclic hexadepsipeptide with exceptional antifungal action against Candida, can be combined with miconazole to increase its potency. The mouth dissolving film (MDF) of this drug combination was prepared by quality by design approach and statistically optimized by the 32 full factorial design. The developed films were evaluated for surface morphology, mechanical strength and dissolution time. The developed optimized formulation exhibited lowest disintegration time (19 sec) with a high drug release (92.78±0.49 % for miconazole and 89.78±0.78 % for beauvericin) and an average tensile strength of 2.69MPa. These findings proved the efficiency of developed mouth dissolving films bearing miconazole and beauvericin in the treatment of oral candidiasis.

Clindamycin hydrochloride is a broad-spectrum antibacterial drug belonging to BCS Class 1, characterized by high solubility and rapid absorption. However, conventional oral administration of clindamycin is associated with adverse gastrointestinal effects such as pseudomembranous colitis, nausea, vomiting, and diarrhoea, largely due to disruption of flora. Intravenous or intramuscular administration can further lead to azotaemia, anaphylactic shock, abscess formation and local irritation, which limit patient compliance. To minimize the systemic side effects and improve patient compliance, oral fast dissolving films (OFDF) were developed as an alternative drug delivery system, offering rapid disintegration, faster absorption, and avoiding gastrointestinal irritation. Clindamycin Hydrochloride was formulated using Quality by Design (QbD) principles and optimized with Custom Design, incorporating pullulan – carrageenan polymer blends and optimizing key parameters such as folding endurance, disintegration time, drug content, drug release. The optimized formulation demonstrated – 93.1% in vitro drug release, 92.6% drug content, folding endurance (258) and disintegration time (44seconds) – all within QTPP specifications. The optimized OFDF demonstrated consistent, robust performance, fulfilling the predefined quality criteria.

Background: Self-administered orally dissolving films (ODFs) encapsulating inactivated influenza vaccines represent an effective strategy for stimulating mucosal immunity. While this vaccination method offers several advantages over conventional influenza vaccines, a comparative efficacy study remains lacking. Methods: Female BALB/c mice were immunized with inactivated A/PR/8/34 (H1N1) either via orogastric inoculation or through the oral mucosal delivery using pullulan and trehalose-based ODF vaccines. Each group received equivalent antigen doses across three immunizations. Humoral responses and antibody functionality were assessed using sera collected post-immunization. After lethal viral challenge, other immunological and virological parameters were determined in corresponding tissues. Body weight and survival were monitored over a 14-day period after challenge. Results: ODF vaccination elicited significantly higher virus-specific IgA levels, HAI titers, and neutralizing antibody activity than oral gavage. After the viral challenge, ODF-immunized mice exhibited stronger IgG and IgA responses in respiratory tissues, increased antibody-secreting cells in lungs and spleen, and elevated germinal center B cells and CD8+ T cell responses. Both vaccination methods reduced lung pro-inflammatory cytokines and provided full protection against lethal challenge; however, the ODF group showed lower cytokine levels, better weight maintenance, and reduced viral loads. Conclusions: ODF vaccination elicits more robust systemic and mucosal immune responses than oral vaccination and may serve as a promising alternative method of influenza vaccine delivery.

Oral fast dissolving films (OFDFs) are the most innovative oral solid pharmaceutical dosage form, especially for elderly and pediatric patients who may have dysphagia. Bilastine (BLA), is a second – generation antihistamine used to manage allergy symptoms; it is very slightly soluble in water. The main objective of this research was to enhance the solubility and dissolution rate of BLA by complexation technique. Ternary complex of BLA: methyl β- cyclodextrin (M-β-CD): soluplus® 5% w/w was prepared via solvent evaporation technique as a trial to enhance its solubility to be prepared as OFDF by incorporated into aqueous polymeric solution. Seven formulas of OFDFs were prepared using the solvent casting method using Polyvinyl alcohol, Hydroxy propyl methyl cellulose E5, and Pullulan as polymers that form film, PEG 400, and glycerin as plasticizers. The prepared films were estimated for their physical, and mechanical properties, drug content, and dissolution rate. The results showed that,the prepared complex enhanced the solubility of the BLA in water (11 times more than the pure BLA in distilled water) and it was easily utilized for the preparation of the OFDFs. The PVA-based formulation in the presence of glycerin as a plasticizer (F4), showed a homogenous clear film with accepted folding endurance (300), the shortest disintegration time (16.66 seconds), and complete release within five minutes. In conclusion, complexation of BLA with M-β CD was an efficient method for enhancing its solubility and dissolution rate to be easily prepared as OFDF with acceptable physical properties.

Fast-dissolving films are becoming a popular alternative to fast-dissolving tablets. These films dissolve quickly when they come in contact with a wet surface, like the tongue, and can be taken without needing extra liquid. This makes them convenient and helps patients stick to their treatment, especially children, older adults, and people who have trouble swallowing pills or fear choking. Because the drug in these films is absorbed directly into the bloodstream through the mouth, it avoids problems in the digestive system and bypasses the first-pass effect (which happens when the liver breaks down the drug before it reaches the rest of the body). This type of formulation is gaining popularity in over-the-counter products in the U.S. for things like pain relief and motion sickness.  

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.

Daun saga rambat (Abrus precatorius L.) dapat menjadi alternatif pada pengobatan sariawan yang biasa dimanfaatkan oleh masyarakat secara turun – temurun dengan cara ditumbuk sampai lumat dan kemudian ditambah air matang untuk dikumur atau bahkan diminum. Daun saga rambat memiliki aktivitas sebagai antijamur, karena tanaman ini mengandung senyawa metabolit sekunder berupa flavonoid, saponin, alkaloid dan steroid yang dapat menghambat pertumbuhan jamur Candida albicans. Penelitian ini bertujuan untuk menentukan variasi polimer HPMC dan PEG 400 yang menghasilkan mutu fisik terbaik dari sediaan oral thin film ekstrak daun saga (Abrus precatorius L.) yang memenuhi syarat mutu. Sediaan dibuat sebanyak 4 formula dengan perbedaan konsentrasi pada PEG 400 yaitu F1 dengan konsentrasi 5%, F2 dengan konsentrasi 10%. F3 dengan konsentrasi 15%. Dan F4 dengan konsentrasi 20%. Hasil penelitian menunjukkan variasi konsentrasi berpengaruh terhadap mutu sediaan oral thin film, formula 3 merupakan formula formula terbaik berdasarkan uji waktu hancur (48 detik), uji ketahanan lipat (201,2) dan persen pemanjangan (85,71%).

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.

Starch is a natural biopolymer used as a film-forming polymer on oral thin film (OTF). Its solubility can increase by modifying enzymes to form maltodextrin (MDX). Sorghum is a potential plant because it contains relatively high starch, 72.3-75.1%. The concentration of film-forming and plasticizers in OTF will significantly affect its disintegration and mechanical properties. This study aimed to obtain the optimal formula for OTF cetirizine HCl based on MDX-sorghum as a film-forming and triethyl citrate as a plasticizer using the Response Surface Methodology (RSM). Sorghum starch was enzymatically modified and characterized physically and mechanically. The formula is optimized based on the disintegration and mechanical properties of the film on the contour plot using Central Composite Design (CCD) in RSM. The percentage error between the predicted and actual values in the response validates the suggested model. The results showed that the production of MDX-sorghum was successful with a characteristic value of dextrose equivalent (DE) 6,3±0,13; swelling power of 2.87; solubility of 52.9%; and a yield of 86.71%. Response data from the 14 formulas obtained include disintegration time of 85-172 seconds, elongation 64.86-109.32%, and tensile strength from 1.4 to 3.57 MPa. The optimal formula suggested a concentration of 4.56% MDX-sorghum and 10% triethyl citrate, with desirability of 0.87. The model validation results show an error percentage of <5%, so the suggested model can be accepted.

Background: Fast dissolving oral thin films (FDTFs) offer a promising delivery platform for drugs with poor aqueous solubility and bioavailability. Eugenol, a natural compound with diverse pharmacological properties, faces challenges in oral delivery due to its low aqueous solubility and high volatility. Objective: This study aimed to develop a fast dissolving oral thin film formulation of eugenol to enhance its bioavailability and facilitate convenient administration. Methods: The FDTFs were prepared using a solvent casting method with hydroxypropyl methylcellulose (HPMC) and polyethylene glycol (PEG) as film-forming agents. The formulations were optimized based on criteria such as film thickness, folding endurance, tensile strength, disintegration time, and drug release profile. Characterization studies to evaluate the physicochemical properties of the optimized formulation. Results: The optimized eugenol-loaded FDTFs exhibited desirable mechanical properties, rapid disintegration, and enhanced drug release compared to conventional dosage forms. Conclusion: The developed fast dissolving oral thin film of eugenol holds promise as a novel delivery system for enhancing the bioavailability of eugenol.

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.

The present study aimed to evaluate the stability profile of Betahistine Dihydrochloride in its pure active pharmaceutical ingredient (API) form and as an Oral Thin Film (OTF) formulation through forced degradation studies under various stress conditions. Degradation studies were performed under acidic (0.1N HCl), alkaline (0.1N NaOH), oxidative (3% H₂O₂), and thermal (100°C) conditions to assess the intrinsic stability of the drug and to establish the stability-indicating capability of the developed analytical method. Samples were analyzed at predetermined time intervals up to 48 hours. The results demonstrated that Betahistine Dihydrochloride is susceptible to all applied stress conditions, with oxidative degradation showing the highest extent of degradation (20.76% for API and 13.23% for OTF at 48 hours). Acidic and thermal stress also produced significant degradation, with 17.64% and 18.23% degradation observed for the API, respectively. Alkaline degradation was comparatively moderate (16.56% at 48 hours). In all stress conditions, the OTF formulation exhibited lower degradation than the pure API, indicating a protective effect of the polymeric film matrix. Chromatographic analysis confirmed clear separation of degradation products from the parent drug peak, demonstrating the specificity and stability-indicating nature of the analytical method. Overall, the study concludes that Betahistine Dihydrochloride is particularly susceptible to oxidative and thermal stress, while the OTF formulation offers improved stability compared to the pure drug. These findings emphasize the importance of appropriate storage conditions and provide essential data for formulation development and stability assessment in accordance with ICH guidelines

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.

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.

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Oral thin films (OTFs) signify a groundbreaking advancement in drug delivery systems, characterised by their swift disintegration and user-friendly administration, improved patient compliance, and capacity to enhance the bioavailability of pharmaceuticals characterised by limited solubility in aqueous environments. The current study concentrated on development and assessment of OTFs incorporating esomeprazole as well as domperidone for the effective management of gastrointestinal disorders. Both drugs exhibit limited aqueous solubility and variable oral bioavailability, which can compromise their therapeutic performance when administered through conventional oral dosage forms. The developed OTFs were intended to provide fast disintegration in the oral cavity, the effective release of medication and enhanced patient outcomes convenience, especially for children, older adults, and individuals with swallowing difficulties. A systematic formulation approach was employed to optimize the concentrations of Film-forming polymers, plasticisers, and additional functional additives to obtain films with suitable mechanical characteristics and desirable drug liberation characteristics. The prepared films were subjected to comprehensive physicochemical characterization, including assessment of appearance, folding endurance, thickness, weight consistency, swelling index, drug content, surface pH, as well as disintegration duration. The optimized formulations demonstrated satisfactory mechanical integrity and disintegrated rapidly within 12–32 seconds. Analysis of drug content verified a consistent distribution of the active pharmaceutical ingredients, with esomeprazole content ranging from 93.54% to 99.12% and domperidone content from 96.42% to 99.83%. In vitro dissolution studies revealed efficient releasing of drug from optimized films, with cumulative releases of 97.53% for esomeprazole and 98.87% for domperidone within 25 minutes, indicating the suitability of the formulation for rapid therapeutic action. Compatibility studies using analytical techniques validated the lack of substantial drug–excipient interactions, while thermal analysis demonstrated adequate stability of both drugs throughout the formulation process. Overall, the findings establish that oral thin films comprising esomeprazole and domperidone represent auspicious alternative to conventional oral dosage forms via providing fast drug release, enhanced patient adherence and the possibility to improve therapeutic efficacy. Further pharmacokinetic and clinical investigations are recommended to substantiate the in vivo performance and medicinal benefits of the optimized formulation.

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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.

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: Vortioxetine hydrobromide is an atypical antidepressant used in the treatment of major depressive disorder (MDD). However, its oral bioavailability is limited due to poor solubility and first-pass metabolism. To address these challenges, a buccal film formulation of vortioxetine hydrobromide was developed. Buccal films offer a convenient, patient-friendly alternative to oral tablets, providing improved bioavailability due to direct absorption through the buccal mucosa. The formulation was designed to enhance drug release, optimize the physicochemical properties, and ensure stability. This research focuses on the formulation, evaluation, and potential therapeutic benefits of buccal films for vortioxetine hydrobromide.

Seizure clusters, characterized by sudden, repeated seizures within a short duration, pose a significant clinical challenge requiring immediate and effective intervention to prevent progression into life-threatening status epilepticus. Traditional treatment options, such as rectal or intravenous benzodiazepines, often face limitations, including social stigma, delayed administration, and limited accessibility in home settings. Diazepam buccal film has emerged as a novel, non-invasive, and patient-friendly therapeutic option that ensures rapid drug absorption via the buccal mucosa, bypassing gastrointestinal metabolism and enabling faster seizure termination. This study undertakes a systematic review and meta-analysis to evaluate the efficacy, safety, and clinical outcomes of diazepam buccal film for managing seizure clusters. A comprehensive search of relevant clinical trials, observational studies, and case reports was conducted across major databases, focusing on outcomes such as seizure termination time, adverse effects, and patient compliance. Meta-analysis results demonstrate that diazepam buccal film significantly reduces seizure duration compared to placebo and other oral benzodiazepines, with a mean reduction time of approximately 7-10 minutes. Furthermore, safety profiles from included studies indicate that adverse effects were generally mild, including drowsiness (18%), headache (12%), and oral discomfort (9%), with no reported serious adverse events. Patient compliance was notably higher due to the convenience of administration. Keywords: Diazepam, Buccal film, Seizure clusters, Benzodiazepines, Meta­analysis, Systematic review, Epilepsy treatment, Seizure termination, Rapid drug absorption, Status epilepticus, Acute seizure management, Pharmacokinetics, Buccal drug delivery, Non­ invasive therapy, Pediatric seizures, Refractory epilepsy, Emergency seizure treatment, Home­based seizure care, Epilepsy in adults, Seizure prevention, Therapeutic outcomes, Pharmacological interventions, Seizure duration reduction.

This study explores the development of buccal films as an innovative drug delivery system for hypertension management, combining candesartan cilexetil (CC) and hydrochlorothiazide (HCTZ). Utilizing a solvent casting technique, films were prepared with various polymers, including PVA, PVP, and CMC Na, and enhanced with plasticizers to improve solubility and bioavailability. The films were evaluated for physicochemical and mechanical properties, disintegration time, and drug content uniformity. Results demonstrated that the films were visually uniform, with excellent folding endurance and a neutral pH. The formulation containing PVA, PVP, and CMC Na exhibited the fastest disintegration rate and superior bioadhesion. The use of Dynamic Mechanical Thermal Analysis (DMTA) confirmed the miscibility of the drugs within the polymeric matrix, ensuring effective delivery. This novel formulation offers significant advantages by improving patient compliance and bypassing first-pass metabolism, presenting a promising alternative for hypertension treatment.

Chlorthalidone is a thiazide-like diuretic drug used in the treatment of hypertension. It belongs to class IV of Biopharmaceutical Classification System (BCS) and exhibits first pass metabolism leading to low bioavailability. The present work was undertaken to formulate mucoadhesive buccal film of chlorthalidone with an objective to improve bioavailability, therapeutic efficacy, and patient compliance. Film formulations were prepared by solvent casting method using a combination of different grades of hydrophilic polymer, Hydroxypropyl methylcellulose with suitable plasticizer. Other important excipients used were solubilizing agents to increase solubility and permeation enhancers to increase the permeability of the drug. The developed films were evaluated for physicochemical characteristics such as thickness, content uniformity, surface pH, and in vitro drug release etc. The optimized formulation containing a combination of hydrophilic and hydrophobic polymers showed good tensile strength, mucoadhesive strength and optimum in vitro diffusion results. The Ex vivo Drug permeation through porcine oral mucosa at the end of 8 hours was found to be 87.2±0.93%.

A buccal film is a thin film of medication placed between the gum and cheek and left to dissolve. It is commonly used as a method of drug delivery, particularly for medications that need to be administered in small doses over a long period of time. The film typically contains active pharmaceutical ingredients in a variety of forms, including powders, granules, or gels. It is typically placed with a device, such as a spatula, and it dissolves rapidly and completely after being placed in the mouth. The benefits of buccal films include convenience, compliance, improved patient outcomes, and better patient satisfaction. The main disadvantage is that the dosage may not be as accurate as with other drug delivery methods. Buccal films is that they are an effective and safe method of administering medication to patients. Buccal films offer a fast and easy method of delivering drugs, with minimal risk of side effects, making them a preferred method of drug delivery for many patients and healthcare professionals.

Buccal film technology has emerged as a promising approach for diabetes management due to its unique advantages over conventional dosage forms. This review paper explores the significance of buccal films in diabetes management, highlighting their benefits, challenges, and potential applications. Additionally, we delve into the biocompatibility and safety considerations associated with buccal films, addressing concerns related to patient acceptability and long-term use. The review emphasizes the need for further research and development to fully harness the potential of buccal films in revolutionizing diabetes treatment. Type 2 diabetes mellitus (T2DM) is a prevalent metabolic disorder characterized by insulin resistance and impaired glucose regulation. The conventional oral antidiabetic medications for T2DM have limitations such as poor patient compliance, gastrointestinal side effects, and hepatic first-pass metabolism. Buccal film formulations have emerged as a promising alternative for the improved management of T2DM, offering direct drug absorption through the buccal mucosa, bypassing the gastrointestinal tract and hepatic metabolism. This review paper aims to discuss the development and evaluation of buccal film formulations for the effective and convenient treatment of T2DM, focusing on formulation strategies, drug candidates, evaluation techniques, patient compliance, and future perspectives.

Drug solubility and dissolution remain a significant challenge in pharmaceutical formulations. This study aimed to formulate and evaluate repanglinide (RPG) nanosuspension-based buccal fast-dissolving films (BDFs) for dissolution enhancement. RPG nanosuspension was prepared by the antisolvent-precipitation method using multiple hydrophilic polymers, including soluplus®, polyvinyl alcohol, polyvinyl pyrrolidine, poloxamers, and hydroxyl propyl methyl cellulose. The nanosuspension was then directly loaded into BDFs using the solvent casting technique. Twelve formulas were prepared with a particle size range of 81.6–1389 nm and PDI 0.002–1 for the different polymers. Nanosuspensions prepared with soluplus showed a favored mean particle size of 82.6 ± 3.2 nm. The particles were spherical and non-aggregating, as demonstrated by SEM imaging. FTIR showed no interaction between soluplus and RPG. Faster dissolution occurred for the nanosuspension in comparison with pure RPG (complete release vs 60% within 30 min). The nanosuspension was successfully incorporated into BDFs. The optimum film formula showed 28 s disintegration time, and 97.3% RPG released within 10 min. Ex-vivo permeation profiles revealed improved RPG nanosuspension permeation with the cumulative amount of RPG permeated is103.4% ± 10.1 and a flux of 0.00275 mg/cm2/min compared to 39.3% ± 9.57 and a flux of 0.001058 mg/cm2/min for pure RPG. RPG was successfully formulated into nanosuspension that boosted drug dissolution and permeation. The selection of the ultimate NP formula was driven by optimal particle size, distribution, and drug content. Soluplus NPs were shown to be the successful formulations, which were further incorporated into a buccal film. The film was evaluated for ex-vivo permeation, confirming successful RPG formulation with improved performance compared to pure drugs.

BACKGROUND Epinephrine is the first-line treatment for anaphylaxis and is administered via intramuscular (IM) or subcutaneous (SC) injection. AQST-109, a sublingual film containing a prodrug of epinephrine, is in development as an alternative delivery method for the treatment of severe allergic reactions including anaphylaxis. OBJECTIVE To compare the pharmacokinetics (PK) and pharmacodynamics (PD) of epinephrine following administration of AQST-109 to epinephrine delivered by manual IM injection and epinephrine autoinjectors (EAIs). METHODS Data were integrated from two randomized, open-label, Phase I crossover trials evaluating the pharmacokinetics and pharmacodynamics of epinephrine in 54 healthy volunteers. They had no prior medical conditions and were delivered either AQST-109 12 mg or 0.3 mg EpiPen, 0.3 mg generic EpiPen, 0.3 mg Auvi-Q and 0.3 mg manual IM injection. RESULTS AQST-109 yielded comparable epinephrine pharmacokinetics and similar exposure when compared to both the manual IM injection and EAIs. The median time to maximum concentration (Tmax) for AQST-109 was 15 minutes, as compared to EpiPen (10 minutes), generic EpiPen (15 minutes), Auvi-Q (30 minutes) and manual IM (50 minutes). There was also an early, rapid, and consistent increase observed in systolic blood pressure (SBP), diastolic blood pressure (DBP), and heart rate (HR) following the administration of AQST-109. CONCLUSION AQST-109 delivered epinephrine with PK and PD results within the bracketed range of approved IM products. AQST-109 shows promise as an innovative, needle-free, non-device, portable and orally delivered alternative for the first-line treatment of Type I allergic reactions, including anaphylaxis.

Tempuyung leaves (Sonchus arvensis L.) are known to contain flavonoid compounds with potential antihyperuricemic activity. This study aimed to prepare Sonchus arvensis leaf extract and formulate it into a sublingual thin film dosage form to develop a therapeutic formulation for the treatment of hyperuricemia. The study employed a Completely Randomized Design using 24 rats (Rattus norvegicus), divided into six groups: positive control (Allopurinol), negative control, blank, and three treatment groups receiving Sonchus arvensis extract at doses of 50 mg/70 kg BW, 100 mg/70 kg BW, and 200 mg/70 kg BW. The sublingual film formulation was prepared using the solvent casting method. Data were analyzed using ANOVA and LSD tests. The results indicated that Formula 3, with a dose of 200 mg, produced the most significant reduction in uric acid levels. Standardization parameters of the extract, including moisture content, ash content, water-soluble extract, ethanolsoluble extract, and loss on drying, complied with the applicable standards. Evaluation of the sublingual film demonstrated that the formulation met the required characteristics and quality standards for sublingual films. In conclusion, the sublingual film of Sonchus arvensis leaf extract shows potential as an effective antihyperuricemic agent. Keywords: Tempuyung Leaves, Antihyperuricemia, Thin Film

Metformin hydrochloride (HCl) fast-dissolving sublingual films were formulated to enhance bioavailability and minimize side effects through rapid onset of action and optimized drug-release and dissolution characteristics. Initially, the same formulation design with different ratios of metformin HCl (Drug), polymer A and plasticizer B was used to formulate nine batches of sublingual films utilizing solvent casting methods. The film formulations were evaluated based on morphological properties (color, clarity, flexibility and smoothness, trinocular microscopic image of film), physical properties (weight variation, thickness uniformity, folding endurance, surface pH, percentage of moisture loss, disintegration time, content uniformity), incompatibility (differential scanning calorimetry (DSC), Fourier-transform infrared (FTIR)), and drug release pattern. Compatibility studies deduced that there was minimal interaction between metformin HCl (drug) and the excipients (polymer, plasticizer etc), whereas trinocular microscopic images revealed the information about the surface of the film and the distribution of medication and polymer within the fast-dissolving film. Physical characterization of metformin HCl sublingual film was performed via morphological evaluations, weight variation, thickness uniformity, folding endurance, surface pH, percentage of moisture loss, in-vitro disintegration, in-vitro dissolution, drug content uniformity. The best formulation of films among all nine batches of film formulations was P1 with satisfactory outcome with respect to in-vitro dissolution 89.05% within 5 minutes, least disintegration time (28 sec), lowest thickness (221.4 ± 0.87) and optimum folding endurance (195 times). This study presents that the proposed metformin HCl film formulation can dramatically reduce dosage suffices to attain the effective drug concentration at the targeted region. Bangladesh Pharmaceutical Journal 28(2): 152-159, 2025 (July)

Background: Managing OFF episodes in patients with Parkinson’s disease becomes increasingly challenging over time, making it critical to tailor treatment to each patient’s needs and characteristics for effective care. Objectives: Study CTH-301 assessed the long-term safety/tolerability and efficacy of sublingual apomorphine (SL-APO) for the on-demand treatment of OFF episodes. Design: The findings from four post hoc analyses of Study CTH-301, conducted to understand factors influencing SL-APO retention and safety/tolerability, with a particular focus on oropharyngeal treatment-emergent adverse events (TEAEs) are reported. Methods: The first analysis evaluated baseline variables differing between patients who completed the study and those who discontinued due to either lack of efficacy or adverse events to help define patients more likely to benefit from SL-APO therapy: The second and third analyses compared safety/tolerability between the subgroups of patients who were or were not receiving dopamine agonist (DA) treatment, and in those aged <70 or ⩾70 years at baseline, respectively. The fourth analysis examined oropharyngeal TEAEs. Results: Patients in a younger age group, those experiencing morning akinesia or delayed ON, and those taking lower dose/fewer intakes of levodopa and concomitant DAs were more likely to benefit from SL-APO therapy. Patients taking concomitant DAs reported lower rates of DA-related TEAEs and a higher mean SL-APO optimal dose. Specific analyses in patients aged ⩾70 years indicated that this age group reported similar rates of TEAEs and a similar profile of the most common TEAEs compared with the group aged <70 years. A lower total daily dose of SL-APO was associated with a reduced risk of developing oropharyngeal TEAEs. Such events were mostly mild or moderate, occurring within the first months after SL-APO initiation, and generally resolved, with worsening being rare. Conclusion: These analyses provided insights into retention and safety/tolerability of SL-APO, helping clinicians and patients make informed treatment decisions.

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Apomorphine sublingual film (SL-APO) is an on-demand treatment for OFF episodes in patients with Parkinson’s disease (PD). To assess the long-term (≥ 3 years) safety/tolerability and efficacy of SL-APO. Study CTH-301 (http://www.clinicaltrials.gov NCT02542696; registered 2015-09-03) was a phase 3, multicentre, open-label study of SL-APO in PD patients with motor fluctuations, comprised of a dose-titration and long-term safety phase. All participants received SL-APO. The primary endpoint was safety/tolerability (treatment-emergent adverse events [TEAEs]) during the long-term safety phase. Efficacy assessments included the Movement Disorder Society-Unified Parkinson’s Disease Rating Scale (MDS-UPDRS) part III (motor examination), assessed at weeks 24, 36 and 48 during the first year of the long-term safety phase. 496 patients were included and 120 (24.2%) completed the long-term safety phase. Mean duration of SL-APO exposure was 294.3 days. TEAEs related to study drug were experienced by 65.3% of patients (most common: nausea [6.0%], stomatitis [1.8%], lip swelling [1.8%], dizziness [1.6%], oral mucosal erythema [1.6%], mouth ulceration [1.6%]). TEAEs leading to study drug withdrawal were experienced by 34.0% of patients (most common: nausea [5.4%], lip swelling [4.5%], mouth ulceration [2.6%], stomatitis [2.3%]). A clinically meaningful reduction in MDS-UPDRS part III score was observed as soon as 15 min following administration of SL-APO, with peak effects observed approximately 30 min post-dose and sustained up to 90 min post-dose; results were consistent over 48 weeks. SL-APO was generally well tolerated and efficacious over the long term as an on-demand treatment for OFF episodes in patients with PD.

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.

Semaglutide (SGL), a long-acting GLP-1(Glucagon-like peptide) receptor agonist, is a 31-amino acid peptide modified with a C18 fatty diacid for albumin binding. Peptides are fragile and susceptible to degradation during formulation, storage, and transportation. The degradation of peptides resulted in the formation of impurities that may impact safety, efficacy, immunogenicity, and regulatory compliance. The present study examines the effects of pH, temperature, buffer species, and molarity on the stability of SGL. Reverse-phase ultra-performance liquid chromatography (RP-UPLC) was used to separate impurities, followed by liquid chromatography high-resolution mass spectrometry (LC-HRMS) for their molecular weight. The stress stability studies were conducted in thermal stress conditions at 25 °C, 40 °C, 60 °C (for 28 days), and 80 °C (for 7 days). The influence of pH, buffer strength, and buffer species on the degradation of SGL was investigated at 25 °C and 40 °C. The degradation of SGL resulted in thirteen known impurities, and their fragments were identified using LC-MS analysis. Six impurities, such as impurity 4 (m/z = 2717.21), impurity 5 (m/z = 4129.64), impurity 7 (m/z = 3762.28), impurity 8 (m/z = 3456.94), impurity 12 (m/z = 2967.5), and impurity 13 (m/z = 839), were formed across all the testing conditions. These impurities were relatively stable when compared to other formed impurities. The influence of pH on the thermal stability of SGL was demonstrated. The impurities, such as impurity 2 (m/z = 845.13), impurity 9 (m/z = 3397.76), impurity 10 (m/z = 701.0), and impurity 11 (m/z = 4125.7), were absent across all pH conditions, but these impurities were found when water was used as a solvent. The study demonstrated that the pH was a key factor for the thermal degradation of SGL. The degradation pathways were elucidated based on the mass data for known masses. The solution-state thermal stress studies were performed to select the buffer for formulating long-acting PLGA formulations. Moreover, the solution state stress stability data could be helpful for optimization of the pharmaceutical process, in vivo stability of SGL in muscles, storage and transportation of finished products, and determining the shelf-life.

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Despite considerable advances in the systemic delivery of peptides, their susceptibility to gastrointestinal degradation and high molecular weight, which restricts permeability across biological barriers, remain obstacles to oral administration. As a result, most peptide therapies rely on injections to achieve therapeutic effects. Recent studies on a bioinspired suction patch demonstrated positive effects in vivo with three peptides - desmopressin, semaglutide, and teriparatide - yet materials used for patch fabrication were non-degradable. In this work, a more sustainable patch alternative is introduced by replacing previously used materials with biodegradable polymers, aiming for degradation of the patch after removal to reduce environmental impact. A scalable mold casting process was employed to thermally crosslink synthesized and functionalized copolyesters, yielding the desired devices. Mechanical testing across various materials and shapes identified the best-performing polymer, while its degradation was confirmed in both aqueous medium and simulated waste. An ex vivo model using porcine buccal tissue validated the functionality of biodegradable patches, showing enhanced permeation of a poorly permeable dye when combined with a chemical permeation enhancer. In beagle dogs, the bioavailability of semaglutide (4.11 kDa) was substantially improved compared to the commercially available tablet, with an application time of only 10 min. Additionally, the patch achieved a relative bioavailability of 26 % for bremelanotide (1.03 kDa) compared to subcutaneous administration. This work underscores the potential of replacing silicone devices with biodegradable alternatives, providing a more sustainable approach for peptide delivery via the buccal suction patch.

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.

Type 2 diabetes mellitus is a major global metabolic disorder requiring long-term and effective therapeutic management. Conventional antidiabetic drugs are often associated with adverse effects and limited patient compliance. Peptide-based therapies, particularly glucagon-like peptide-1 (GLP-1) receptor agonists, have emerged as promising alternatives. Semaglutide, a lipidated GLP-1 analog with prolonged half-life, offers effective glycemic control along with additional benefits in weight reduction and cardiovascular risk improvement. This review highlights the development of various drug delivery systems for semaglutide, focusing on its pharmacodynamics, pharmacokinetics, and formulation strategies. Currently available formulations include once-weekly injectable forms and the first oral GLP-1 receptor agonist enabled through absorption enhancers. However, challenges such as low oral bioavailability and enzymatic degradation persist. Recent advances in controlled-release and nano- based delivery systems, including nanoparticles, liposomes, microspheres, and self-emulsifying formulations, have shown potential in enhancing stability, permeability, and sustained drug release. Continued innovation in delivery technologies may further improve therapeutic efficacy and patient adherence in diabetes and obesity management.”

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.

Therapeutic proteins and peptides have revolutionized modern biomedicine. However, the large size and complex structure of these macromolecules preclude their oral administration, greatly limiting their applications in patient care. Biochemical degradation in the gastrointestinal tract, mucus, and cellular barrier are the major obstacles to oral development. Small extracellular vesicles (sEVs) are natural nano lipid vesicles serving as essential vehicles for intercellular communication. sEVs are resistant to biochemical degradation, permeable to mucus barriers, and can penetrate cellular barriers. sEVs are thus considered the next-generation vehicles with the potential for oral peptide/protein drug delivery. Herein, we report the use of milk-derived sEVs as delivery vehicles to achieve successful and highly efficient oral delivery of two therapeutic GLP-1 receptor agonists, semaglutide and tirzepatide. We showed that semaglutide and tirzepatide can be efficiently loaded onto sEVs in vitro, and oral gavage of semaglutide-loaded sEVs or tirzepatide-loaded sEVs can effectively lower blood glucose levels in db/db mouse models. This study demonstrates that sEVs is a platform technology for oral peptide drug delivery and opens a new avenue for oral peptide/protein therapeutics delivery.

Semaglutide (SEM) is a glucagon-like peptide-1 (GLP-1) receptor agonist formulated for oral delivery with the absorption enhancer salcaprozate sodium (SNAC). Although oral SEM achieves 0.4-1% bioavailability through gastric epithelial uptake, gastrointestinal (GI) adverse events remain a major cause of therapy discontinuation. This study examined the effects of SEM (0.74 mg/kg/day), SNAC (22 mg/kg/day), and combined SEM-SNAC (1:33 w/w) treatments on microbiota and metabolic function, in healthy Sprague Dawley rats over 21 days. Whilst microbial α-diversity remained stable, SNAC significantly altered β-diversity (PERMANOVA, p < 0.05) and depleted primary fermenters in Muribaculaceae (-62%) and Bacteroidaceae (-77%) compared to the control group. These compositional changes correlated with reduced predicted saccharolytic enzyme abundance and fecal butyrate concentrations (-77% SNAC, -75% SEM-SNAC). Plasma cytokine analysis showed elevated tumor necrosis factor-α (TNF-α, 70%) and suppressed brain-derived neurotrophic factor (BDNF, 85%), consistent with changes in circulating inflammatory and neurotrophic markers from SNAC monotherapy. SNAC-treated animals also exhibited increased liver weight and reduced caecum mass, occurring alongside microbiota compositional changes and altered fermentation-associated markers. Spearman correlations linked Muribaculaceae and Bacteroidaceae loss with decreased saccharolytic enzyme abundance, lower SCFA levels, and increased TNF-α. While these findings are associative and require mechanistic validation, they indicate that chronic SNAC exposure is linked to concurrent microbial, metabolic, and inflammatory marker changes in healthy rats, highlighting the potential need for alternative, microbiota-safe strategies for oral peptide delivery.

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Semaglutide is a glucagon-like peptide-1 receptor agonist widely used for the treatment of type 2 diabetes and obesity. Despite its clinical efficacy, oral administration remains challenging because of its limited gastrointestinal stability, poor epithelial permeability, and low affinity for lipid-based delivery systems. In the present study, a combined hydrophobic ion pairing (HIP) and solid lipid nanoparticle (SLN) approach was explored to improve semaglutide incorporation and delivery-related properties. Semaglutide was complexed with the cationic lipid DOTAP at different molar ratios (1:0-1:18) and subsequently incorporated into cetyl palmitate-based SLNs produced by microfluidic mixing using a herringbone device. The resulting formulations were characterized in terms of particle size, ζ-potential, encapsulation efficiency, morphology, solid-state organization, colloidal stability, release behavior, mucus interaction, cytocompatibility, and epithelial permeability. Among the various formulations prepared, the one prepared with a molar ratio semaglutide: DOTAP of 1:18 and a peptide concentration of 10% (w/w) (F10) showed the best results, combining particle sizes of less than 300 nm with almost complete encapsulation efficiency and a highly positive ζ-potential. FTIR, DSC, TGA and SAXS analyses confirmed the correct formation of the complex and its incorporation into the lipid matrix. The F10 formulation demonstrated good stability under simulated gastrointestinal conditions and a sustained-release profile. The formulation also exhibited strong interactions with mucus, whilst retaining the ability to diffuse through the mucin network. Cytocompatibility studies demonstrated acceptable cell viability at relevant concentrations, whilst permeability experiments through Caco-2 monolayers revealed an approximately 6-fold increase in apparent permeability compared to free semaglutide. Therefore, these findings indicate that the combination of DOTAP-mediated hydrophobic ion pairing and microfluidic-assisted SLN production represents a potentially promising strategy for improving semaglutide encapsulation, gastrointestinal stability, and epithelial transport, while maintaining a favorable balance between mucus interaction and mucodiffusion.

Oral delivery of peptide therapeutics is limited by enzymatic degradation in the gastrointestinal tract and poor intestinal permeability. Semaglutide, a glucagon-like peptide-1 (GLP-1) receptor agonist used for the treatment of type 2 diabetes and obesity, is primarily administered via injection, which may reduce patient compliance. In this study, semaglutideloaded polymeric nanoparticles were prepared using the solvent evaporation method and optimized using a Box–Behnken design. The effects of polymer concentration, surfactant concentration, and homogenization speed were evaluated on particle size, polydispersity index (PDI), and encapsulation efficiency. The optimized formulation was further characterized for physicochemical properties, drug loading, and in vitro drug release behaviour. The optimized nanoparticles exhibited a particle size of 145 ± 8 nm, PDI of 0.18 ± 0.02, and zeta potential of −22.5 ± 1.6 mV. Encapsulation efficiency and drug loading were found to be 78.4 ± 2.3% and 9.6 ± 0.8%, respectively. In vitro release studies showed an initial release of 28.3% within 6 hours, followed by sustained release reaching 85.6% over 48 hours. Stability studies demonstrated minimal changes in physicochemical properties over 30 days. Overall, the developed polymeric nanoparticle system shows promise as an effective strategy for enhancing the oral delivery of semaglutide. Further in vivo studies are required to confirm its bioavailability and therapeutic potential.

Semaglutide (SET) is a glucagon-like peptide-1 (GLP-1) receptor agonist approved for the treatment of type 2 diabetes. Although injectable formulations offer high bioavailability, they are associated with poor patient compliance. In contrast, oral tablets are more convenient but suffer from limited absorption due to SET's hydrophilicity and enzymatic instability in the gastrointestinal tract. To address these challenges, we developed a hydrophobic ion pair (HIP) complex of SET and sodium docusate (SET-DOC), which was further incorporated into a self-emulsifying drug delivery system (SD@SEDDS) to facilitate oral delivery. The optimized SD@SEDDS produced a clear emulsion upon dilution, with a uniform particle size of 85.55  nm, high drug loading (2.64  mg/g), and excellent stability. In vitro transport studies using a Caco-2/HT-29 co-culture model demonstrated enhanced permeability and reduced P-glycoprotein-mediated efflux. In vivo studies in a type 2 diabetic rat model showed that SD@SEDDS significantly reduced blood glucose levels, improved lipid profiles, and exhibited good biocompatibility without observable toxicity. These findings suggested that the combination of HIP technology and SEDDS represented a promising strategy for enhancing the oral delivery efficiency of peptide drugs such as SET.

The development of charge-based self-assembled supramolecules can provide a groundbreaking advancement in the oral delivery of nanoparticles. In this study, we developed a series of positively charged peptide-engineered bile acids (PCBs) for the first time to interact with the negatively charged semaglutide (SG), a widely used Glucagon-like peptide-1 (GLP-1) receptor agonist for the treatment of obesity and diabetes. Among the synthesized PCBs, PCB4 self-assembled with semaglutide via electrostatic interactions to form stable supramolecular nanoparticles, termed positively charged bile acid-saturated semaglutide (PBSG) nanocomplexes, with an average size of approximately 279 nm under aqueous conditions. These PBSG nanocomplexes demonstrated enhanced permeability and absorption through bile acid transporter-driven endocytosis in intestinal cells and tissues, inducing natural breakdown of cell membranes. Notably, PBSG nanocomplex increased the gastrointestinal (GI) permeation and oral absorption of semaglutide, improved therapeutic efficacy in a high-fat diet (HFD)-induced animal model, and inhibited bile acid transporter activity. Moreover, Oral PBSG nanocomplex treatment elevated GLP-1 expression in vivo by facilitating semaglutide delivery and modulating bile acid metabolism at the same time. The development of these novel, charge-based, self-assembling oral peptide nanocomplexes, leveraging positively charged bile acids and transporter-driven uptake, represents a significant advancement in oral nanoparticle delivery and the design of therapeutic nanomaterials.

Nanoparticles (NPs) modified with glycocholic acid (GCA) at surfaces are considered promising tools to overcome oral drug delivery barriers. However, question on the influence of surface GCA density over delivery efficiency arises due to ligand-induced changes in surface properties of NPs. To answer this question, we engineered GCA-modified nanoparticles (GCA NPs) with different surface densities, and their surface hydrophobicity, mucus penetration, cellular uptake, apparent permeability coefficient (Papp), intracellular trafficking behavior and oral bioavailability were compared. The results turned out that GCA NPs were found with increased surface hydrophobicity, which limited their transport across mucus layer. Nanoparticles with 50 % surface GCA density (50 % GCA NPs) demonstrated optimal performance. Compared to 100 %GCA NPs, 50 %GCA NPs exhibited an 83.28 % improvement in mucosal penetration capability, while a 250.67 % increase in cellular uptake was noticed when comparing with PEG NPs. Overall, the 50 % GCA NPs significantly enhanced trans-epithelial transport across Caco-2/E-12 co-cultured monolayers, achieving a Papp value of 3.30 × 10-6 cm/s, while the Papp values of 100 %GCA NPs and PEG NPs were 2.23 × 10-6 cm/s and 1.73 × 10-6 cm/s. In vivo studies confirmed their therapeutic potential: oral administration of semaglutide (SMG)-loaded 50 % GCA NPs increased systemic SMG bioavailability to 12.12 %, achieving sustained glycemic control in type 2 diabetic rats. The optimized formulation exhibited favorable safety profiles and prolonged pharmacological effects. This study establishes a critical equilibrium between enhanced mucosal penetration and ligand-receptor interaction, while mitigating intracellular retention issues associated with high-density GCA-functionalized nanoparticles. These findings indicate that attentions should be paid in ligand-associated surface property alterations, which could exert unexpected influence on the performance of NPs constructed for oral peptide drug delivery.

The management of diabetes relies heavily on macromolecular biologics, which are predominantly administered via subcutaneous injection. However, its invasiveness compromises patient compliance and leads to injection-related complications. Among all the clinically attractive alternatives, mucosal administration, while non-invasive and enabling rapid absorption, faces significant challenges from physiological barriers that limit drug permeability. Herein, we engineered a novel choline-salcaprozate ionic liquid (CS-IL) system that could overcome these limitations and enable efficient mucosal delivery of insulin and semaglutide. To evaluate its potential, comprehensive in vitro and in vivo studies were conducted, which revealed that CS-ILs significantly enhanced drug permeability and mucosal retention via both intranasal and sublingual routes, thereby achieving robust hypoglycemic effects comparable to subcutaneous injection. Notably, a key mechanistic insight uncovered that CS-ILs boost paracellular transport via the transient and safe modulation of intercellular junctions. Consequently, with its compelling biocompatibility profile and potent efficacy across mucosal routes, this versatile IL platform emerges as a promising strategy for clinical translation, potentially revolutionizing non-invasive delivery for diabetes therapeutics.

Oral delivery of macromolecules is hindered by enzymatic degradation, poor epithelial permeability, and rapid gastric transit, leading to low bioavailability. Existing permeation enhancers (PEs), such as salcaprozate sodium and sodium caprate, improve absorption but do not fully address proteolytic degradation and require high doses due in part to short gastrointestinal residence times. We developed the Peroral Mucosal Epithelium Absorption Enhancer (PERMEATE) system, an orally administered polymer film designed to adhere to the small intestinal mucosa, maximizing contact between therapeutics, PEs, and the absorptive tissue. Utilizing Synthetic Tissue-Lining (SYNT™) technology, PERMEATE triggers endogenous catalase-dependent dopamine polymerization to form an in situ polydopamine coating, creating a temporary depot that enhances co-localization and prolongs exposure to the absorptive mucosa. We assessed PERMEATE’s potential to enhance the oral bioavailability of semaglutide (SEMA). High-throughput screening using the GI tissue robotic interface system (GI-ORIS) identified glycocholic acid (GCA) and ammonium carbonate (NHCO) as effective PEs when combined with SYNT. Ex vivo studies (n=8–24) and in vivo tests in Sprague-Dawley rats (n=5–11/group) demonstrated a 200-fold increase in bioavailability compared to SEMA alone (P=0.0001) and a 6-fold increase relative to SEMA+PE without SYNT (P=0.0011). In Yorkshire pigs (n=3–4), PERMEATE achieved a 2.4% absolute bioavailability, a 6-fold improvement over SEMA+PE controls (P=0.0316). These results suggest PERMEATE as a promising platform for improving oral macromolecule delivery through enhanced mucosal adhesion and prolonged therapeutic contact, supporting further development for clinical application.

Semaglutide is a lipopeptide with important applications in the treatment of diabetes, obesity, and other conditions. This class of drug (glucagon-like peptide-1 agonists and other lipidated peptides) may be susceptible to aggregation due to the tendency of lipopeptides to self-assemble into various nanostructures. Here, we show using cryogenic-TEM, small-angle X-ray scattering, and molecular dynamics simulations that semaglutide in aqueous solution undergoes slow aggregation into spherical micelles in water at sufficiently high concentration. A small population of needle-shaped fibril aggregates is also observed. At a lower concentration, dimer and trimer structures are formed. The micelles, once formed, are stable toward further aging. The aggregation influences the effect of semaglutide on the permeability of an epithelial gut model membrane of Caco-2 cells. These findings are expected to be important in understanding the long-term stability of semaglutide solutions and the potential effects of aggregation on therapeutic efficacy.

The advancement of the oral route for macromolecules has gained a lot of attention due to its noninvasive nature, safe and challenging in active research but with limited success. Oral administration poses challenges due to poor solubility, short half-life, quick elimination and the physical, chemical and biological barriers of the gastrointestinal tract. Approaches of past for improving oral absorption, such as enhancers, mucoadhesive delivery and enzyme inhibitors have been taken over by novel approaches like advanced liposomes, self-nanoemulsifying drug delivery system, nanoparticles and targeted delivery. Eudratech™ Pep, Peptelligence, Rani Pill and Pharm Film are the emerging technologies for delivering oral proteins and peptide. Calcitonin, semaglutide and octreotide are the peptides available in the market for oral delivery as outcomes of these technologies.

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.

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.

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.

No abstract available

Desmopressin acetate (DDAVP), a nonapeptide drug, is easily destroyed by heat in the manufacturing process of orodispersible film (ODF). A new challenging study was conducted to improve thermal stability through glycosylation and hydrogen bonding using carbohydrate gums (agar, arabic gum, carrageenan, xanthan gum) using the solvent casting method. Among gum types, xanthan gum strongly showed dual stabilizing effects of DDAVP via covalent glycosylation and hydrogen bonding, minimizing total impurities and optimizing physicochemical properties of ODF under accelerated conditions for six months. The optimized ODF formulation (O-DDAVP ODF) at a DDAVP and xanthan gum ratio of 1:1.5 had a pharmaceutically equivalent dissolution profile as compared with a commercial 0.2 mg commercial Minirin® tablet in four different media: pH 1.2, pH 4.0, and pH 6.8 buffers and deionized water. Furthermore, O-DDAVP ODF showed in vivo bioequivalence to Minirin® tablets in healthy human volunteers. Glycosylation-oriented stabilization of peptide drug using pharmaceutically active excipients against thermal denaturation could be challenged to design patient-friendly ODF.

An orally disintegrating film (ODF) formulation of vitamin D3 that dissolves rapidly in the mouth without drinking or chewing may be a worthwhile alternative to currently available drug products for therapeutic vitamin D supplementation. This study aimed to compare the bioavailability of a single dose of a vitamin D3 25000 I.U. ODF with those of a marketed oral vitamin D3 preparation in healthy subjects. This Phase 1, randomised, parallel-group, open-label study compared the pharmacokinetics of calcifediol [25(OH)D3], the precursor of bioactive vitamin D3, after a single dose of a new vitamin D3 25,000 I.U. ODF with those of a Reference formulation (vitamin D3 25000 I.U./2.5 mL oral solution) in healthy adult subjects using a validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) assay. The primary objective was bioavailability under fed conditions, defined as maximum plasma concentration (Cmax) of 25(OH)D3 and area under the concentration-time curve from time zero to time t, the last quantifiable concentration (AUC0−t). The pharmacokinetics of 25(OH)D3 were also evaluated following the ODF administration under fasting conditions. Subjects were randomised to receive a single dose of the vitamin D3 25000 I.U. ODF or the Reference oral solution under fed conditions or the vitamin D3 ODF under fasting conditions. Forty-eight healthy subjects were randomised and completed the study. Overall, the pharmacokinetic profile was very similar across the three treatment groups, and bioavailability did not significantly differ among treatments. Under fed conditions, mean 25(OH)D3 plasma values for Cmax were 6.68 ± 2.03 versus 6.61 ± 2.62 ng/mL for the Test versus Reference formulations. Corresponding values for AUC0−t were 2364.80 ± 1336.97 versus 2150.52 ± 1622.76 ng/mL × h. Mean Cmax was slightly lower (6.68 ± 2.03 vs 7.23 ± 1.48 ng/mL) and the time to reach peak concentration was delayed (144 h [36–312] versus 42 h (2–480]) with the ODF under fed versus fasting conditions (p = 0.0371). The point estimates and 90 % CIs of the Testfed/Referencefed ratios of the geometric means showed that the bioavailability of exogenous 25(OH)D3 was, both in rate and extent of absorption, slightly higher with the vitamin D3 ODF than the vitamin D3 oral solution under the administration conditions recommended for the vitamin D3 oral solution. Palatability and ease of use of the ODF were satisfactory. The new ODF 25000 I.U. formulation provided a valuable alternative to the marketed oral solution for therapeutic vitamin D supplementation, with a bioavailability that was slightly higher than that of the vitamin D3 oral solution administered under the same conditions. The study was retrospectively registered with the ISRCTN Registry (Registry code: ISRCTN13208948) on 27 November 2020.

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.

The use of two-dimensional (2D) printing technologies of drugs on orodispersible films (ODF) can promote dose individualization and facilitate drug delivery in vulnerable patients, including children. We investigated midazolam pharmacokinetics after the administration of 2D-printed ODF. Midazolam doses of 0.03 and 3 mg were printed on an ODF using a 2D drug printer. We investigated the bioavailability of the two midazolam doses with ODF swallowed immediately (ODF-IS) or delayed after 2 min (ODF-DS) by comparing their pharmacokinetics with intravenous and oral midazolam solution in 12 healthy volunteers. The relative bioavailability of ODF-IS 0.03 mg was 102% (90% confidence interval: 89.4–116) compared to oral solution and for 3 mg 101% (86.8–116). Cmax of ODF-IS 0.03 mg was 95.5% (83.2–110) compared to oral solution and 94.3% (78.2–114) after 3 mg. Absolute bioavailability of ODF-IS 0.03 mg was 24.9% (21.2–29.2) and for 3 mg 28.1% (23.4–33.8) (oral solution: 0.03 mg: 24.4% (22.0–27.1); 3 mg: 28.0% (25.0–31.2)). Absolute bioavailability of ODF-DS was significantly larger than for ODF-IS (0.03 mg: 61.4%; 3 mg: 44.1%; both p < 0.0001). This trial demonstrates the tolerability and unchanged bioavailability of midazolam printed on ODF over a 100-fold dose range, proving the suitability of ODF for dose individualization. Midazolam ODF-IS AUC0–∞ in both doses was bioequivalent to the administration of an oral solution. However, Cmax of the therapeutic dose of ODF-IS missed bioequivalence by a clinically not relevant extent. Prolonged mucosal exposure increased bioavailability. (Trial Registration EudraCT: 2020–003984-24, August 10, 2020).

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.

Glucagon-like peptide-1 (GLP-1), an incretin hormone, plays a crucial role in glucose homeostasis by stimulating insulin secretion, suppressing glucagon release, and delaying gastric emptying. Its therapeutic potential was long realized, leading to the development of the first GLP-1 receptor agonist, exenatide, followed by liraglutide, dulaglutide, semaglutide, and tirzepatide. Semaglutide is available as a weekly subcutaneous injection with high bioavailability. Semaglutide is the only GLP-1 agonist available for oral therapy, used in the treatment of type 2 diabetes mellitus (T2DM). Semaglutide has demonstrated broad clinical efficacy beyond glycemic control, including weight reduction, cardiovascular risk reduction, and, most recently, in the treatment of metabolic dysfunction-associated steatohepatitis (MASH). Semaglutide therapy is associated with the resolution of steatohepatitis and improvement in hepatic fibrosis in patients with MASH. Alongside resmetirom, semaglutide is currently approved for the treatment of non-cirrhotic MASH with moderate-to-advanced fibrosis. Safety considerations include gastrointestinal intolerance, hypoglycemia, rare pancreaticobiliary events, and theoretical concerns of thyroid C-cell tumors, though human risk remains minimal. In summary, semaglutide extends the armamentarium of the hepatologist against the most common liver disease worldwide.

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.

Coumaric acid (CA) is a typical nutrient required in relatively high quantities by the body. It has been proved CA could specifically bind to monocarboxylate Transporter-1 (MCT-1) receptors, a transporter protein expressed on the surface of intestinal epithelial cells, to facilitate its cellular uptake. Although our preliminary research demonstrated semaglutide (SEM) loaded CA modified nanoparticles (SEM@CNP) could improve the absorption of SEM to some extent, the oral bioavailability still remained suboptimal owing to the lysosomal degradation. To address this issue, INF-7 (peptide chain GLFEAIEGFIENGWEGMIDGWYG) and chloroquine (CQ), two lysosomal escape agents (LEAs) with different mechanisms of action, were incorporated with SEM@CNP for oral delivery (SEM@CNP + INF-7, SEM@CNP + CQ). In type II diabetes mice models, SEM@CNP + CQ effectively inhibited postprandial glucose rise with a relative pharmacological bioavailability of 20.63 ± 2.99 %, 1.73 times higher than SEM@CNP (11.90 ± 4.56 %). Mechanistic studies revealed that: 1) after adding LEAs, the exocytosis preference of nanoparticles was altered, tending towards basolateral exocytosis apparently. Regulated exocytosis directionality was linked to the spatial redistribution of MCT-1 receptors. 2) among the two LEAs, CQ demonstrated superior efficacy compared to INF-7. This superiority was attributed to the earlier onset of action and more pronounced degree of membrane disruption induced by CQ. This research provided new insights for the design of oral delivery systems for peptidic drugs.

Semaglutide, a glucagon-like peptide-1 (GLP-1) receptor agonist, constitutes an effective and widely used treatment for type 2 diabetes and obesity. However, challenges such as insufficient oral bioavailability, gastrointestinal side effects, and high costs persist. Overcoming these limitations is essential for improving patient compliance and semaglutide’s safety profile. While advanced technologies such as oral delivery systems offer partial solutions, optimizing the peptide structure is crucial for addressing these issues. Establishing a rapid method to generate a large library of semaglutide mutants will enable high-throughput activity screening. In this study, we introduce a novel “Fits-In-All” approach that combines ribosomally synthesized and post-translationally modified peptide (RiPP) technology with amber stop codon incorporation to generate semaglutide variants. To counter dipeptidyl peptidase-4-mediated cleavage, our method strategically incorporates noncanonical amino acid ornithine at position 8 utilizing microbial modification enzyme OspR in vivo. Furthermore, functional groups are introduced by an orthogonal tRNA/aminoacyl-tRNA synthetase pair recognizing the amber stop codon at position 26, which enabled the click chemistry-based linkage of diverse groups. This approach allows for the generation of a broad array of semaglutide analogues that can be screened for optimal properties. In conclusion, this innovative approach opens new avenues for the design and synthesis of optimized peptide-based GLP-1 receptor agonists.

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.

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.

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.

Salcaprozate sodium (SNAC) is an FDA GRAS-listed permeation enhancer used in oral semaglutide and vitamin B12 formulations. Although its rapid and reversible membrane-perturbing effects are well recognised, it’s in vivo performance is highly variable. Since effective membrane fluidisation requires permeation enhancers to remain as monomers, the critical micelle concentration (CMC) is a key determinant of efficacy. This study investigated the micellization behaviour of SNAC under physiologically relevant conditions. The CMC of SNAC was determined across physiologically relevant pH buffers using complementary techniques, including conductometry, tensiometry, microvolume UV/Visible spectroscopy, and fluorescence spectroscopy. The effects of electrolytes, bile salts, and selected coadministered drugs on SNAC micellization were evaluated. SNAC did not form micelles under gastric conditions due to increased protonation and low solubility. In contrast, SNAC micellized at intestinal pH 6.8 with a CMC of 6.26 ± 0.38 mM. Physiological factors strongly influenced micellization, particularly under intestinal conditions. The presence of electrolytes significantly reduced the CMC to 3.36 ± 0.03 mM, due to reduced electrostatic repulsion and a counter-ion effect. Bile salts showed a biphasic effect, increasing the CMC at low concentrations and promoting mixed micellization at higher concentrations. Coadministered drugs, including aspirin, metformin, nimesulide, ciprofloxacin, and semaglutide, significantly altered SNAC CMC values. Semaglutide showed a non-monotonic effect, decreasing the CMC at low concentrations but increasing it at higher concentrations due to oligomerisation. These findings provide mechanistic insights into SNAC micellization under physiologically relevant conditions and offer a rational basis for optimising SNAC-based oral drug delivery systems.

Oral delivery of therapeutic peptides is limited by degradation by digestive proteases and poor gastrointestinal permeability. We have investigated how physicochemical properties, including degree of lipidation and degree of amino acid sequence modification, along with formulation with a permeation enhancer (PE), influence the enzymatic stability and intestinal absorption of glucagon-like peptide-1(GLP-1) receptor agonists. We compared four peptides: J211 (non-lipidated; modified), J229 (mono-lipidated; modified), MEDI7219 (bis-lipidated; modified), and semaglutide (mono-lipidated control; least modified). J211, J229 and MEDI7219 have similar amino acid modifications in the peptide sequence to reduce the number of labile proteolytic sites. An in vitro head-to-head comparison between MEDI7219 and semaglutide showed that MEDI7219 was more proteolytically stable (% remaining after 90 min) than semaglutide, which was degraded completely within 10 min. Notably, co-formulation with sodium caprate (C10) improved semaglutide stability, and at least doubled its half-life. Results from in vivo studies in rats following intraduodenal bolus administration, showed that in the absence of C10, the absorption of all the peptides was minimal, with cumulative fractions absorbed below 1 % for all four compounds. Co-formulation with C10 increased the bioavailability of the modified peptides by 35-40-fold, with J211, J229, and MEDI7219 reaching 7.5 %, 4 %, and 17.3 % respectively. Semaglutide's bioavailability improved by ∼200-fold, however bioavailability did not exceed 2 %. These results demonstrate that C10 enhances peptide absorption primarily by increasing intestinal permeability but also likely by improving enzymatic stability of a labile peptide like semaglutide. Furthermore, when comparing the three modified peptides, the degree of lipidation positively correlated with increased intestinal absorption in both the presence and absence of C10.

Abstract Disclosure: P.D. Susilo: None. M. Kanelli: None. O. Petropulos: None. C. Dial: None. K. Kadasia: None. M. Buzo Mena: None. J. Liang: None. A. Hayward: None. K.A. Gaspie: None. S.M. Barron: None. R.R. Basani: None. A. Lopes: None. A. Yu: None. Introduction: Incretin peptide therapies have revolutionized obesity and diabetes treatment, yet overcoming oral delivery challenges—such as rapid gastrointestinal transit and limited intestinal absorption—is crucial to improving patient adherence, accessibility, and real-world effectiveness. To address these barriers, we developed the Peroral Mucosal Epithelium Absorption Enhancer (PERMEATE) method, which integrates synthetic tissue lining (SYNT) platform with proprietary permeation enhancers (PEs) to improve intestinal residence time and drive higher absorption. This proof-of-concept study demonstrates PERMEATE's ability to both create and significantly enhance the oral bioavailability of semaglutide (SEMA) in pig and rat models. Methods: A high-throughput ex vivo screen identified single and combination PEs with synergistic effects on SEMA permeation across porcine intestinal tissue. Ex vivo Franz experiments optimized formulation components and ratios to maximize colocalization of SEMA and PEs onto the intestinal tissue. Saline buffer washes were implemented to mimic a dynamic environment physiologically relevant to digestion. Lead formulations were tested in vivo in anesthetized Yorkshire pigs, a physiologically relevant gastrointestinal model, with plasma SEMA concentrations measured via LC-MS/MS over 168 hours. The area under the curve (AUC) was normalized by dose and compared to intravenous SEMA administration (n=4) to determine absolute bioavailability. To enhance replicates and rigor, formulations were also delivered via oral gavage to male rats (650-750 g, n=5-6 per group), with bioavailability assessed over 24 hours using the same methods. Results: Glycocholic acid (GCA) and ammonium carbonate (NHCO) were identified as the most effective PE combination with SEMA and SYNT, achieving a 15.5-fold increase in permeation compared to SEMA control in ex vivo tests. Optimized PERMEATE formulations improved colocalization of SEMA by 71.5-fold compared to a SEMA+PE control, after two washes, highlighting the ability of PERMEATE to create a localized depot and achieve prolonged residence time. In vivo, PERMEATE demonstrated a SEMA bioavailability of 2.4±1.6% in Yorkshire pigs (n=4), representing a significant 6-fold increase over the SEMA+PE control (0.4±0.3%, n=5; p=0.0316) and SEMA-Only control (0%, n=1). Improved bioavailability compared to controls was also observed in rats, highlighting translatability across multiple mammalian models. Conclusions: The PERMEATE platform, powered by SYNT™, significantly enhances the bioavailability of semaglutide (SEMA) in preclinical models, demonstrating up to a 6-fold improvement compared to controls. These findings underscore the potential of PERMEATE as a transformative platform for optimizing the oral delivery of macromolecule therapeutics. Presentation: Sunday, July 13, 2025

Despite the established efficacy of glucagon-like peptide-1 receptor agonists, treatment intensification in type 2 diabetes (T2D) remains limited by clinical inertia, nonadherence, and reluctance toward injectables. Oral semaglutide, enabled by permeation enhancer-based gastric absorption, offers a peptide-based oral option with robust glycemic efficacy, meaningful weight reduction, and low hypoglycemia risk. The review integrates evidence from the Peptide Innovation for Early Diabetes Treatment (PIONEER) program, cardiovascular outcomes data, pharmacokinetic studies, and contemporary American Diabetes Association/American Association of Clinical Endocrinology-aligned recommendations, and translates these into practical guidance for Indian physicians. It addresses patient profiles most suited for initiation, dose escalation, administration instructions, gastrointestinal tolerability, nonresponse, Ramadan use, elderly patients, concomitant oral contraceptives and levothyroxine, diabetic retinopathy, gallstone risk, and oral-versus-injectable semaglutide selection. The central message is that oral semaglutide can be positioned as a high-efficacy oral incretin option for Indian patients with T2D, provided that treatment is individualized, dosing instructions are reinforced, and counseling is optimized to improve adherence, tolerability, and long-term outcomes.

Sodium caprate (C10) has been widely evaluated as an intestinal permeation enhancer for the oral delivery of macromolecules. However, the effect of C10 on the intestinal absorption of peptides with different physicochemical properties and its permeation-enhancing effect in vivo remains to be understood. Here, we evaluated the effects of C10 on intestinal absorption in rats with a glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GIP-GLP1) dual agonist peptide (LY) and semaglutide with different enzymatic stabilities and self-association behaviors as well as the oral exposure of the LY peptide in minipigs. Furthermore, we investigated the mechanism of action (MoA) of C10 for improving the intestinal absorption of the LY peptide in vivo via live imaging of the rat intestinal epithelium and tissue distribution of the LY peptide in minipigs. The LY peptide showed higher proteolytic stability in pancreatin and was a monomer in solution compared to that in semaglutide. C10 increased in vitro permeability in the minipig intestinal organoid monolayer to a greater extent for the LY peptide than for semaglutide. In the rat jejunal closed-loop model, C10 increased the absorption of LY peptide better than that of semaglutide, which might be attributed to higher in vitro proteolytic stability and permeability of the LY peptide. Using confocal live imaging, we observed that C10 enabled the rapid oral absorption of a model macromolecule (FD4) in the rat intestine. In the duodenum tissues of minipigs, C10 was found to qualitatively reduce the tight junction protein level and allow peptide uptake to the intestinal cells. C10 decreased the transition temperature of the artificial lipid membrane, indicating an increase in membrane fluidity, which is consistent with the above in vivo imaging results. These data indicated that the LY's favorable physicochemical properties combined with the effects of C10 on the intestinal mucosa resulted in an ∼2% relative bioavailability in minipigs.

Labrafac™ MC60 (glycerol monocaprylocaprate) is a lipid-based excipient used in oral formulations as a solubiliser. Due to the high proportions of established permeability enhancers, caprylate (C8) and caprate (C10), in Labrafac™ MC60, we hypothesised that it might behave as an intestinal permeation enhancer. We therefore evaluated this using two paracellular markers (ex vivo) and insulin (in vivo) as model molecules. Ex vivo studies were conducted in isolated muscle-stripped rat colonic mucosae mounted in Ussing chambers. Apical addition of Labrafac™ MC60 (8, 12, and 16 mg/ml) enhanced the apparent permeability coefficients (Papp) of [14C] mannitol and FITC-dextran 4 kDa (FD4) across colonic mucosae. Similar effects were observed in isolated jejunal mucosae, but at higher concentrations (40 mg/ml). The enhancing capacity of Labrafac™ MC60 was transient due to reversibility of reductions in transepithelial electrical resistance (TEER) upon wash-out and effects on fluxes were molecular weight-dependent (MW) as suggested by fluxes of a set of high MW FITC-dextrans. The permeability enhancing effects of Labrafac™ MC60 ex vivo were maintained in the presence of simulated intestinal fluids, FaSSIF and FaSSCoF, in both jejunal and colonic mucosae, respectively. Following intra-intestinal regional instillations to rats, the relative bioavailability of 50 IU/kg insulin ad-mixed with Labrafac™ MC60 was 5 % in jejunum (40 mg/ml) and 6 % in colon (8 mg/ml). When Labrafac™ MC60 was combined with PEG-60 hydrogenated castor oil (1 % v/v), this further increased the bioavailability of insulin to 8 % in jejunum. Absorption enhancement was also maintained in the presence of FaSSIF in jejunal instillations. Histology after 120 min exposure to Labrafac™ MC60 in vivo for both jejunum and colon was similar to untreated control. Labrafac™ MC60 therefore acts as a non-damaging intestinal permeation enhancer for macromolecules and can be considered as another excipient in screening programmes to develop orally administered macromolecules.

Oral peptide therapeutics are increasingly favored in the pharmaceutical industry for their ease of use and better patient adherence. However, they face challenges with poor oral bioavailability due to their high molecular weight and surface polarity. Permeation enhancers (PEs) like salcaprozate sodium (SNAC) have shown promise in clinical trials, achieving about 1% bioavailability. One proposed mechanism for enhancing permeation is membrane perturbation or fluidization, though direct experimental proof and quantitative analysis of these effects are still needed. This study employs solid-state NMR (ssNMR) to investigate how SNAC interacts with hydrated DMPC liposomes, measuring enhancements in membrane fluidity across interfacial and transmembrane regions. The methodology involves analyzing phosphate lipid headgroups and acyl chains using static 31P chemical shift anisotropy and 2H quadrupolar coupling measurements alongside 1H and 13C magic angle spinning NMR for motional averaging of 1H-1H and 1H-13C dipolar couplings. Our findings indicate an overall increase in the uniaxial motion of phospholipids with SNAC in a PE concentration-dependent manner. It boosts lipid headgroup dynamics and enhancement plateaus at 25% between 24 and 72 mM concentrations. SNAC effectively enhances the fluidity of the hydrophobic center by 43% at 72 mM PE concentration, more significantly than the interfacial region. It is worth noting that the extent of liposome dissolution and conversion to micelles increases as SNAC concentration rises. Including a model peptide drug, octreotide, introduces a competitive equilibrium in this complex PE-lipid-peptide system, further influencing membrane dynamics for peptide permeation. Interestingly, the membrane enhancement does not show the expected plateau, and a less significant lipid mobility increase is observed in the presence of octreotide, suggesting a less substantial impact compared to peptide-free systems, which is likely due to peptide-PE interactions that consume monomeric SNAC, reducing its interaction with the lipid membrane. This study provides the first quantitative and site-specific ssNMR measurements of membrane mobility influenced by one representative PE as a snapshot of PE lipid interaction in a liposome model, demonstrating how peptide drugs modulate competitive equilibria and PE-induced lipid dynamics.

Oral administration of peptide therapeutics faces challenges because of the distinct environment of the gastrointestinal tract. An oral formulation of semaglutide, a glucagon-like peptide 1 receptor agonist, was approved by the U.S. Food and Drug Administration in 2019 as a peptide therapy for the treatment of type 2 diabetes. Oral semaglutide uses sodium N-(8-[2-hydroxybenzoyl] amino) caprylate (SNAC) technology to enhance the absorption of semaglutide in the stomach and protect it from degradation by gastric enzymes. This article presents a summary of studies investigating SNAC technology as an absorption enhancer for a number of molecules and, in particular, explores how SNAC, once coformulated with oral semaglutide, facilitates increased absorption and bioavailability. Practical advice and dispensing information for pharmacists is also provided.