Transmucosal Delivery Research Articles

Sources and Methods for the Production of Xyloglucan, a Promising Stimulus-Sensitive Biopolymer: A Review

Xyloglucan is a highly promising ‘green’ polymer that has found its application in the food and pharmaceutical industries. Due to its molecular structure similarity to mucin, it has remarkable mucoadhesion properties, which has led to a high research interest in this excipient for the development of transmucosal delivery systems. Thermosensitivity is another promising property of xyloglucan derivatives, which is mainly exhibited by synthetic block copolymers such as pluronics and PLGA derivatives. Delivery systems whose mechanism of active ingredient release is based on temperature sensitivity are widely used in many medical fields, ranging from antitumour therapy to intranasal delivery. Thus, conducting research on the possibility of obtaining and using a new mucoadhesive, fully biocompatible and affordable polymer—xyloglucan—is a promising task.

Mucin incorporated electrospun fibrous matrix of zein and PVP: Towards transmucosal propranolol hydrochloride delivery

Mucoadhesive drug delivery systems are being widely explored as a substitute for conventional drug delivery devices. Several polymers and their functional modifications are under investigations. In that scenario, the cohesive influence of mucin in the polymer system itself to the biologically available mucin in the mucosa is a novel approach. The added advantage of mucin in augmenting mucoadhesion was explored. A two-fold increase in the force of adhesion and an eight-fold increase in the work of adhesion were intriguing observations to be noted. Mucin incorporation in the matrix was done via EDC crosslinker. The results of the TNBS assay confirmed 39 % of mucin binding. A three-fold decrease of elongation at break (%) after mucin binding is a piece of quantitative information to corroborate the same. This work also investigates the efficiency of the mucoadhesive matrix towards the release of Propranolol Hydrochloride (PL). Low oral bioavailability of PL demands its administration via mucosal route to avoid hepatic first-pass metabolism. The release study of PL in PBS and permeation through RPMI 2650 cells revealed a burst release followed by a sustained release profile and best fitted with Korsmeyer Peppas model. PL permeation through the cell monolayer without a cell junction opening pursued a transcellular transport mechanism. Drug permeation through porcine buccal mucosa also assured adequate permeation in ex-vivo conditions. The sustained release of PL from MUZPVP and prolonged residence time of the matrix over mucosa due to increased mucoadhesion guarantees an optimistic drug delivery device to the biomedical discipline.

Exploring Mechanisms of Lipid Nanoparticle-Mucus Interactions in Healthy and Cystic Fibrosis Conditions.

Mucus forms the first defense line of human lungs, and as such hampers the efficient delivery of therapeutics to the underlying epithelium. This holds particularly true for genetic cargo such as CRISPR-based gene editing tools which cannot readily surmount the mucosal barrier. While lipid nanoparticles (LNPs) emerge as versatile non-viral gene delivery systems that can help overcome the delivery challenge, many knowledge gaps remain, especially for diseased states such as cystic fibrosis (CF). This study provides fundamental insights into Cas9 mRNA or ribonucleoprotein-loaded LNP-mucus interactions in healthy and diseased states by assessing the impact of the genetic cargo, mucin sialylation, mucin concentration, ionic strength, pH, and polyethylene glycol (PEG) concentration and nature on LNP diffusivity leveraging experimental approaches and Brownian dynamics (BD) simulations. Taken together, this study identifies key mucus and LNP characteristics that are critical to enabling a rational LNP design for transmucosal delivery.

Transmucosal Delivery of Peptides and Proteins Through Nanofibers: Current Status and Emerging Developments.

Advancements in recombinant DNA technology have made proteins and peptides available for diagnostic and therapeutic applications, but their effectiveness when taken orally leads to poor patient compliance, requiring clinical administration. Among the alternative routes, transmucosal delivery has the advantage of being noninvasive and bypassing hepato-gastrointestinal clearance. Various mucosal routes-buccal, nasal, pulmonary, rectal, and vaginal-have been explored for delivering these macromolecules. Nanofibers, due to their unique properties like high surface-area-to-volume ratio, mechanical strength, and improved encapsulation efficiency, serve as promising carriers for proteins and peptides. These nanofibers can be tailored for quick dissolution, controlled release, enhanced encapsulation, targeted delivery, and improved bioavailability, offering superior pharmaceutical and pharmacokinetic performance compared to conventional methods. This leads to reduced dosages, fewer side effects, and enhanced patient compliance. Hence, nanofibers hold tremendous potential for protein/peptide delivery, especially through mucosal routes. This review focuses on the therapeutic application of proteins and peptides, challenges faced in their conventional delivery, techniques for fabricating different types of nanofibers and, various nanofiber-based dosage forms, and factors influencing nanofiber generation. Insights pertaining to the precise selection of materials used for fabricating nanofibers and regulatory aspects have been covered. Case studies wherein the use of specific protein/peptide-loaded nanofibers and delivered via oral/vaginal/nasal mucosa for diagnostic/therapeutic use and related preclinical and clinical studies conducted have been included in this review.

Mucus-Mimicking Mucin-Based Hydrogels by Tandem Chemical and Physical Crosslinking.

Mucosal tissues represent a major interface between the body and the external environment and are covered by a highly hydrated mucins gel called mucus. Mucus lubricates, protects and modulates the moisture levels of the tissue and is capitalized in transmucosal drug delivery. Pharmaceutical researchers often use freshly excised animal mucosal membranes to assess mucoadhesion and muco-penetration of pharmaceutical formulations which may struggle with limited accessibility, reproducibility, and ethical questions. Aiming to develop a platform for the rationale study of the interaction of drugs and delivery systems with mucosal tissues, in this work mucus-mimicking mucin-based hydrogels are synthesized by the tandem chemical and physical crosslinking of mucin aqueous solutions. Chemical crosslinking is achieved with glutaraldehyde (0.3% and 0.75% w/v), while physical crosslinking by one or two freeze-thawing cycles. Hydrogels after one freeze-thawing cycle show water content of 97.6-98.1%, density of 0.0529-0.0648gcm⁻3, and storage and loss moduli of ≈40-60 and ≈3-5Pa, respectively, that resemble the properties of native gastrointestinal mucus. The mechanical stability of the hydrogels increases over the number of freeze-thawing cycles. Overall results highlight the potential of this simple, reproducible, and scalable method to produce artificial mucus-mimicking hydrogels for different applications in pharmaceutical research.

REVIEW ARTICLE: PENGARUH POLIMER PADA SISTEM PENGHANTARAN OBAT TRANSMUKOSAL

Currently, drug delivery systems have been widely researched and developed to enable increased bioavailability by regulating drug release. One of the factors in drug release is a composite polymer which is needed as a protective matrix for the delivery system with the aim of drug stability. One of the drug delivery targets is transmucosal. This review article aims to find out the role of various polymers in transmucosal drug delivery systems. The method used for information is the results from the ScienceDirect, PubMed, Google Scholar, ResearchGate and WoS (Web of Science) databases. The results show that CMC-Na, HPMC, chitosan, pectin, Carbopol, Acebutolol HCL, maintains the duration of the drug's residence time after the absorption process because the polymer has adhesive power.

Synthesis and Evaluation of Boronated 4‐Arm Polyethylene Glycol for Application in Transmucosal Drug Delivery

AbstractPolyethylene glycol (PEG) exhibits poor residence on mucosal membranes in the presence of biological fluid, and the influence of PEG boronation on its properties has never been investigated. This project aimed to synthesise boronated 4‐arm PEG and evaluate their pH stability, thermal properties and mucoadhesiveness for potential transmucosal applications. Two types of boronated 4‐armed PEG (B4PEG1 & B4PEG2) and a boronated linear PEG (BLPEG) were synthesized. The degree of boronation, mucoadhesiveness, thermal and pH stability of the polymers were assessed using 1H NMR spectroscopy, viscometry, thermogravimetric analysis and UV–visible spectroscopy, respectively. Gel Permeation Chromatography was employed to confirm PEG boronation. The respective degrees of boronation for B4PEG1 and B4PEG2 were 32.8 % and 46.2 %. The molecular architecture and degree of PEG boronation had a remarkable influence on mucoadhesiveness, pH, and thermal stability. B4PEG2, with a branched architecture and the greatest degree of boronation, exhibited superior mucoadhesiveness and colloidal stability at pH 4 to 8, relative to B4PEG1 and BLPEG. Boronation improved the thermal stability of 4‐arm PEG. This study is the first to demonstrate that PEG boronation could enhance the pH‐sensitivity, thermal stability and mucoadhesiveness of 4‐arm PEG. Boronated 4‐arm PEGs could serve as mucoadhesive polymeric excipients for transmucosal drug delivery.

Long-Acting Drug Delivery Technologies for Meloxicam as a Pain Medicine.

Meloxicam, a selective COX-2 inhibitor, has demonstrated clinical effectiveness in managing inflammation and acute pain. Although available in oral and parenteral formulations such as capsule, tablet, suspension, and solution, frequent administration is necessary to maintain therapeutic efficacy, which can increase adverse effects and patient non-compliance. To address these issues, several sustained drug delivery strategies such as oral, transdermal, transmucosal, injectable, and implantable drug delivery systems have been developed for meloxicam. These sustained drug delivery strategies have the potential to improve the therapeutic efficacy and safety profile of meloxicam, thereby reducing the frequency of dosing and associated gastrointestinal side effects. The choice of drug delivery system will depend on the desired release profile, the target site of inflammation, and the mode of administration. Overall, meloxicam sustained delivery systems offer better patient compliance, and reduce the side effects, thereby improving the clinical applications of this drug. Herein, we discuss in detail different strategies for sustained delivery of meloxicam.

CONCEPTUAL ANALYSIS OF NASYA KARMA YOGAS IN BAHUGATA VIKARA

In Ayurveda, Pioneers have used all the possible routes of drug administration in different treatments, even from the era when the other medical sciences had not yet evolved. Among them, Nasya Karma, the non-invasive drug administration route with transmucosal nasal drug delivery, is a unique detoxification therapy in Panchakarma that aims at the alleviation of disorders that are related to the head and neck region. Bahugata Vikara is one of the most common neuromuscular ailments that hampers the day-to-day routine of an individual due to impairment of the upper limb. Even with advanced allopathic treatment modalities, patients are not getting satisfactory relief where Nasya karma is the prime treatment modality, especially for Urdhwajatrugata and Bahushirsagata Roga. It acts on higher centers of the brain, controlling different neurological, endocrinal, and circulatory functions, thus showing local and systemic effects. This article attempts to compile the various types of classical Nasya formulations specifically indicated in Bahugata Vikara by different Acharyas from Ayurveda classical texts, relevant information from previous research, and published materials from reputed sources.

Enhancing transmucosal delivery of CBD through nanoemulsion: in vitro and in vivo studies.

Cannabidiol (CBD) has gained significant attention as a complementary and alternative medicine due to its promising therapeutic properties. However, CBD faces obstacles when administered orally due to its poor solubility in water, leading to limited absorption into the bloodstream and low and variable bioavailability. Therefore, the development of innovative delivery approaches that can enhance CBD's bioavailability, facilitate administration, and promote patient adherence is crucial. We propose a new approach for buccal delivery of CBD based on a self-assembling nanoemulsion (NE) made of a mixture of surfactants (Tween 80 and Labrasol) and medium chain triglycerides (MCTs). The NE formulation showed properties suitable for buccal administration, including appropriate size, CBD content, and surface properties, and, if compared to a CBD-MCT solution, it exhibited better control of administered doses, faster dissolution in buccal medium, and enhanced stability. The CBD-NE effectively released its active load within 5h, remained stable even when diluted in simulated buccal fluids, and could be easily administered through a commercially available spray, providing consistent and reproducible doses of NE with optimized properties. In vitro permeation studies demonstrated that the CBD-NE facilitated swift and consistent permeation through the buccal mucosa, resulting in a higher concentration in the acceptor compartment compared to CBD-MCT. Furthermore, the in vivo study in mice showed that a single buccal administration of CBD-NE led to a quicker onset of action than a CBD solution in MCT, while maintaining the same plasma levels over time and leading to typically higher plasma concentrations compared to those usually achieved through oral administration. In conclusion, our CBD-NE represents a promising alternative formulation strategy for buccal CBD administration, overcoming the challenges associated with conventional formulations such as variable bioavailability and low control of administered doses.

A pan-SARS-CoV-2-specific soluble angiotensin-converting enzyme 2-albumin fusion engineered for enhanced plasma half-life and needle-free mucosal delivery.

Immunocompromised patients often fail to raise protective vaccine-induced immunity against the global emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants. Although monoclonal antibodies have been authorized for clinical use, most have lost their ability to potently neutralize the evolving Omicron subvariants. Thus, there is an urgent need for treatment strategies that can provide protection against these and emerging SARS-CoV-2 variants to prevent the development of severe coronavirus disease 2019. Here, we report on the design and characterization of a long-acting viral entry-blocking angiotensin-converting enzyme 2 (ACE2) dimeric fusion molecule. Specifically, a soluble truncated human dimeric ACE2 variant, engineered for improved binding to the receptor-binding domain of SARS-CoV-2, was fused with human albumin tailored for favorable engagement of the neonatal fragment crystallizable receptor (FcRn), which resulted in enhanced plasma half-life and allowed for needle-free transmucosal delivery upon nasal administration in human FcRn-expressing transgenic mice. Importantly, the dimeric ACE2-fused albumin demonstrated potent neutralization of SARS-CoV-2 immune escape variants.

Fabrication and characterization of progesterone loaded pullulan nanofibers for controlled release

Progesterone is a commonly used drug in humans and livestock that possesses huge therapeutic potential in the regulation of pregnancy and fertility in females. The hydrophobicity and need for prolonged therapy of progesterone restrict the exploitation of its therapeutic potential to the fullest. Recently, polymeric nanofibers have evolved as interesting drug carriers, especially for hydrophobic drugs. The present study aimed to encapsulate the hydrophobic drug progesterone in pullulan by electrospinning for controlled delivery. The progesterone was successfully incorporated in pullulan nanofibers and the mean fiber diameter ranged from 68.68 ± 9.71 to 123.12 ± 17.41 nm. Fourier transform infrared spectroscopy revealed the interaction of the drug with the polymer. The zeta potential of progesterone loaded pullulan nanofibers ranged from 0.4 ± 0.01 to −0.5 ± 0.01 indicating suitability for transmucosal delivery. The hydrodynamic diameter of progesterone loaded pullulan nanofibers were significantly (p < 0.05) lesser than the pullulan nanofibers which may promote better drug adsorption and permeation. The cumulative drug release profile indicated prolonged release of progesterone for 7 days from pullulan nanofibers. The kinetic modelling of the drug release revealed Fickian diffusion of progesterone from the polymeric matrix. Cytotoxicity assay revealed optimal survivability of Baby Hamster Kidney cells (60.51 ± 5.81 to 72.39 ± 0.53 %) on exposure to progesterone loaded pullulan nanofibers ensuring biocompatibility. The present study presents process optimization for successful electro-entrapment of progesterone in biopolymer pullulan and its characterization suggesting the potential of progesterone loaded pullulan nanofibers for controlled delivery.

Advances of nanoparticles in transmucosal drug delivery

Advances of nanoparticles in transmucosal drug delivery

Transmucosal Delivery of Nasal Nanovaccines Enhancing Mucosal and Systemic Immunity.

Intranasal vaccines can induce protective immune responses at the mucosa surface entrance, preventing the invasion of respiratory pathogens. However, the nasal barrier remains a major challenge in the development of intranasal vaccines. Herein, a transmucosal nanovaccine based on cationic fluorocarbon modified chitosan (FCS) is developed to induce mucosal immunity. In our system, FCS can self-assemble with the model antigen ovalbumin and TLR9 agonist CpG, effectively promoting the maturation and cross-presentation of dendritic cells. More importantly, it can enhance the production of secretory immunoglobin A (sIgA) at mucosal surfaces for those intranasally vaccinated mice, which in the meantime showed effective production of immunoglobulin G (IgG) systemically. As a proof-of-concept study, such a mucosal vaccine inhibits ovalbumin-expressing B16-OVA melanoma, especially its lung metastases. Our work presents a unique intranasal delivery system to deliver antigen across mucosal epithelia and promote mucosal and systemic immunity.

Formulation and evaluation of paclitaxel-loaded boronated chitosan/alginate nanoparticles as a mucoadhesive system for localized cervical cancer drug delivery.

Cervical cancer remains a significant global health challenge, and there is a need for innovative drug delivery systems to improve the efficacy of anticancer drugs. In this study, we developed and evaluated boronated chitosan/alginate nanoparticles (BCHIALG NPs) as a localized mucoadhesive drug delivery system for cervical cancer. Boronated chitosan (BCHI) was synthesized by incorporating 4-carboxyphenylboronic acid onto chitosan (CHI), and boronated chitosan/alginate nanoparticles (BCHIALG NPs) with varying polymer ratios were prepared using an ionic gelation method. The physical properties, drug loading capacity/encapsulation efficiency, mucoadhesive properties, and in vitro drug release profile of the nanoparticles were evaluated. The BCHIALG NPs exhibited a size of less than 390 nm and demonstrated high drug encapsulation efficiency (98.1 - 99.8%) and loading capacity (326.9 - 332.7 μg/mg). Remarkably, the BCHIALG NPs containing 0.03% boronated chitosan and 0.07% alginate showed superior mucoadhesive capability compared to CHIALG NPs, providing sustained drug release and they showed the most promising results as a transmucosal drug delivery system for hydrophobic drugs like paclitaxel (PTX). To the best of our knowledge, this is the first report investigating BCHIALG NPs for cervical drug delivery. The new mucoadhesive paclitaxel formulation could offer an innovative strategy for improving cervical cancer treatment.

Hydrogel-Forming Microneedles with Applications in Oral Diseases Management

Controlled drug delivery in the oral cavity poses challenges such as bacterial contamination, saliva dilution, and inactivation by salivary enzymes upon ingestion. Microneedles offer a location-specific, minimally invasive, and retentive approach. Hydrogel-forming microneedles (HFMs) have emerged for dental diagnostics and therapeutics. HFMs penetrate the stratum corneum, undergo swelling upon contact, secure attachment, and enable sustained transdermal or transmucosal drug delivery. Commonly employed polymers such as polyvinyl alcohol (PVA) and polyvinyl pyrrolidone are crosslinked with tartaric acid or its derivatives while incorporating therapeutic agents. Microneedle patches provide suture-free and painless drug delivery to keratinized or non-keratinized mucosa, facilitating site-specific treatment and patient compliance. This review comprehensively discusses HFMs’ applications in dentistry such as local anesthesia, oral ulcer management, periodontal treatment, etc., encompassing animal experiments, clinical trials, and their fundamental impact and limitations, for example, restricted drug carrying capacity and, until now, a low number of dental clinical trial reports. The review explores the advantages and future perspectives of HFMs for oral drug delivery.

Localized Drug Delivery Systems: An Update on Treatment Options for Head and Neck Squamous Cell Carcinomas.

Head and neck squamous cell carcinoma (HNSCC) is one of the most common cancers in the world, with surgery, radiotherapy, chemotherapy, and immunotherapy being the primary treatment modalities. The treatment for HNSCC has evolved over time, due to which the prognosis has improved drastically. Despite the varied treatment options, major challenges persist. HNSCC chemotherapeutic and immunotherapeutic drugs are usually administered systemically, which could affect the patient's quality of life due to the associated side effects. Moreover, the systemic administration of salivary stimulating agents for the treatment of radiation-induced xerostomia is associated with toxicities. Localized drug delivery systems (LDDS) are gaining importance, as they have the potential to provide non-invasive, patient-friendly alternatives to cancer therapy with reduced dose-limiting toxicities. LDDSs involve directly delivering a drug to the tissue or organ affected by the disease. Some of the common localized routes of administration include the transdermal and transmucosal drug delivery system (DDSs). This review will attempt to explore the different treatment options using LDDSs for the treatment of HNSCC and radiotherapy-induced damage and their potential to provide a better experience for patients, as well as the obstacles that need to be addressed to render them successful.

Tumbler‐Inspired Microneedle Containing Robots: Achieving Rapid Self‐Orientation and Peristalsis‐Resistant Adhesion for Colonic Administration

AbstractMicroneedle containing miniature robots offer a promising route for gastrointestinal administration since their capability of transmucosal delivery and controllable drug release. However, many challenges still lie ahead such as the intricate control modes, destitute systematic theory of the locomotion and adhesion behaviors, failure due to peristalsis and fluid flow, and risk of ileus. Herein, an untethered microneedle containing robots is designed for specific colonic administration, which can dispense with control systems, achieve fast self‐orientation and adhesion onto the mucosa (&lt;0.6 s), against physiology of peristalsis, and show low risks of obstruction. Further, the detachable layer between the microneedle and the robots can degrade under a time of 6 min, which ensures safely discharge under a small, excreted force of 20 mN induced by fluid flow. Through the optimism of microneedles, different drug release times can be achieved including 14 min, 2 days, 4 days, and 30 days, respectively. The in vivo experiments also demonstrate the effectiveness and feasibility of the robots. These robots can serve as a versatile platform to treat diseases such as chronic inflammation and cancer of the colon to minimize invasive surgical intervention and patient suffering.

Lidocaine-loaded dissolving microneedle for safe local anesthesia on oral mucosa for dental procedure

ABSTRACT Background Lidocaine has been widely used as a short-acting local anesthetic agent to reduce the pain caused by needle insertion. Dissolving microneedles (DMNs), which are minimally invasive, can effectively deliver drugs by overcoming the oral mucosal barrier and relieving patient discomfort. Methods Lidocaine solution prepared by mixing lidocaine-HCl and hyaluronic acid was used to fabricate oral lidocaine HCl-encapsulated DMNs (oral Li-DMNs) via centrifugal lithography. The dissolution, penetration ability, and local transmucosal drug delivery of oral Li-DMNs into the oral mucosa were evaluated in porcine jaws. Pharmacokinetic analysis and safety assessment were performed using rabbits. Results The insertion depth of the oral Li-DMNs satisfies the safety standard. The oral Li-DMNs were completely dissolved after 3 min of application. The local transmucosal drug delivery, pharmacokinetic, and safety evaluations showed that the oral Li-DMNs can obtain a local anesthesia effect at a relatively lower dose, and there was no oral mucosal irritation in rabbits. Conclusions A novel and safe oral Li-DMNs have potential applications in large animals and clinical trials and would possibly enter the anesthesia market.

Mucus-penetrating nanovesicles encapsulating a novel anti-inflammatory recipe as a transmucosal remedy: Herbal extract preparation, synergistic combination, and niosomal encapsulation

IntroductionMucositis is the oxidation and inflammation of mucosal tissues. Transmucosal delivery can be applicable with herbal plant extracts providing anti-inflammatory activity. Thus, this research aimed to formulate an anti-inflammatory remedy from extracts obtained from the Indian gooseberry (IGB) and sappanwood heartwood (SPW) for encapsulation as mucus-penetrating nanovesicles. MethodsA suitable method was determined by maximizing antioxidant activity (AOA) and total phenolic content (TPC); the synergistic recipe was AOA and anti-inflammatory activity (AIA). The niosomal suspensions prepared by the ethanol injection method were optimized with the goal of high encapsulation efficiency and small particle size. The mucus-penetrating property was assessed by using modified Franz diffusion cells. ResultsSoxhlet extraction was the most suitable method for preparing effective extracts that could rapidly provide a high extraction yield without hindering AOA and TPC. IGB and SPW were effective in AOA and AIA, respectively. Thus, an increase in SPW in the remedies raised AIA but not AOA. Despite a synergism in the AOA of all recipes, the AIA was specifically synergistic in herbal remedy 1 (HR1). It could diminish the cytotoxic effect of SPW. The niosomal suspensions containing Span60, Tween80, and cholesterol could provide nanoparticles with a high encapsulation efficiency and large particle sizes, in which the incorporation of poloxamer 407 caused a decrease in mucus penetration upon altering the diffusion mechanism. ConclusionThis research pioneered the utilization of the recipe formulated from IGB and SPW. The novel anti-inflammatory recipe developed with mucus-penetrating drug delivery is applicable for treating mucositis.