Mucoadhesive Films Research Articles

Functionality and Acceptance of the EsoCap System-A Novel Film-Based Drug Delivery Technology: Results of an In Vivo Study.

There are no methods for specific local application of active substances to the mucosa of the esophagus to treat eosinophilic esophagitis or other esophageal diseases. This publication describes the principal in vivo functionality and acceptance of a novel modular drug delivery concept, called EsoCap system, by 12 healthy volunteers. For the first time, the EsoCap system enables targeted placement on the esophageal mucosa of a mucoadhesive polymer film. Acceptance was determined by means of a standardized questionnaire after administration and functionality of the device by MRI scans. Two different setups of the EsoCap system were tested: one setup with a density of 0.4 g/cm3 and one with a density of 1.0 g/cm3. Acceptability of the dosage form was also confirmed in addition to functionality, by measuring the applied film length. It was found that acceptance of the variant with the higher density was significantly better. This novel drug delivery technology could enable a targeted, local and long-lasting therapy of the esophagus for the first time, depending on the polymer film used.

Formulation, Optimization, and In-Vitro Evaluation of Hyaluronic Acid Buccal Films Containing Benzydamine Hydrochloride

Aim: Mucoadhesive buccal films provide drug delivery for both local and systemic circulation with increased patient compliance. The objective of this study was to develop a buccal film containing benzydamine hydrochloride (BNZ) by using hyaluronic acid (HA) as a film-forming agent and glycerin (Gly) as a plasticizer for the anti-inflammatory effect on the mucosal ulcer. Material and Methods: The effects of different concentrations of HA and Gly on responses were analyzed using 23 factorial design. The HA and Gly ratio were selected as independent factors, and work of mucoadhesion, tensile strength, elongation at break, and contact angle values were chosen as dependent factors. Nine different film formulations were prepared at constant BNZ concentration (0.15%) by solvent casting method. Mechanical and mucoadhesion properties of film formulations were evaluated, and also contact angles were calculated. The BNZ release profiles were evaluated in simulated saliva solution (pH 6.8). Results: All film formulations were successfully prepared by solvent casting method. Increasing HA concentration from 0.5 to 2 % raised the mechanical and mucoadhesion properties of film formulations. Although the addition of Gly decreased the tensile strength values, it increased the elongation at break values about ten times. All formulations released more than 60 % BNZ in 60 mins. Conclusion: It is concluded that HA oral mucoadhesive film formulations containing BNZ are promising for treating oral ulcers.

Development of Mucoadhesive Buccal Film for Rizatriptan: In Vitro and In Vivo Evaluation.

The reduced therapeutic efficacy of rizatriptan in migraine treatment is primarily due to low oral bioavailability and extensive first pass metabolism. The purpose of this investigation was to optimize the thin mucoadhesive buccal film of rizatriptan and assess the practicability of its development as a potential substitute for conventional migraine treatment. Buccal films (FR1–FR10) were fabricated by a conventional solvent casting method utilizing a combination of polymers (Proloc, hydroxypropyl methylcellulose and Eudragit RS 100). Drug-loaded buccal films (F1–F4) were examined for mechanical, mucoadhesive, swelling and release characteristics. In vivo pharmacokinetics parameters of selected buccal film (F1) in rabbits were compared to oral administration. Films F1–F4 displayed optimal physicomechanical properties including mucoadhesive strength, which can prolong the buccal residence time. A biphasic, complete and higher drug release was seen in films F1 and F4, which followed Weibull model kinetics. The optimized film, F1, exhibited significantly higher (p < 0.005) rizatriptan buccal flux (71.94 ± 8.26 µg/cm2/h) with a short lag time. Film features suggested the drug particles were in an amorphous form, compatible with the polymers used and had an appropriate surface morphology suitable for buccal application. Pharmacokinetic data indicated a significantly higher rizatriptan plasma level (p < 0.005) and Cmax (p < 0.0001) upon buccal film application as compared to oral solution. The observed AUC0–12h (994.86 ± 95.79 ng.h/mL) in buccal treatment was two-fold higher (p < 0.0001) than the control, and the relative bioavailability judged was 245%. This investigation demonstrates the prospective of buccal films as a viable and alternative approach for effective rizatriptan delivery.

Formulation, design and characterization of mucoadhesive buccal film – a systematic review

Formulation, design and characterization of mucoadhesive buccal film – a systematic review

Effect of Doxycycline Microencapsulation on Buccal Films: Stability, Mucoadhesion and In Vitro Drug Release.

The aim of this work was to stabilize doxycycline in mucoadhesive buccal films at room temperature (25 °C). Since doxycycline is susceptible to degradation such as oxidation and epimerization, tablets are currently the only formulation that can keep the drug fully stable at room temperature, while liquid formulations are limited to refrigerated conditions (4 °C). In this study, the aim was to make formulations containing subclinical (antibiotic) doxycycline concentration that can act as matrix metalloproteinase inhibitors (MMPI) and can be stored at temperatures such as 25 °C. Here, doxycycline was complexed with excipients using three techniques and entrapped into microparticles that were stored at 4 °C, 25 °C and 40 °C. Effect of addition of precomplexed doxycycline microparticles on films: stability mucoadhesion capacity, tensile strength, swelling index and in vitro release was studied. The complexation efficiency between drug-excipients, microparticles and films was studied using Fourier-transform infrared spectroscopy (FTIR) and differential scanning calorimetry (DSC). Two of the films were found to be stable at 4 °C but the film containing microparticle composed of precomplexed doxycycline with β-cyclodextrin, MgCl2, sodium thiosulfate, HPMC and Eudragit® RS 12.5 was found to be stable at 25 °C until 26 weeks. The addition of microparticles to the films was found to reduce the mucoadhesive capacity, peak detachment force, tensile strength and elasticity, but improved the stability at room temperature.

Formulation and Optimization of Sodium Alginate Polymer Film as a Buccal Mucoadhesive Drug Delivery System Containing Cetirizine Dihydrochloride.

Currently, pharmaceutical companies are working on innovative methods, processes and products. Oral mucoadhesive systems, such as tablets, gels, and polymer films, are among these possible products. Oral mucoadhesive systems possess many advantages, including the possibility to be applied in swallowing problems. The present study focused on formulating buccal mucoadhesive polymer films and investigating the physical and physical–chemical properties of films. Sodium alginate (SA) and hydroxypropyl methylcellulose (HPMC) were used as film-forming agents, glycerol (GLY) was added as a plasticizer, and cetirizine dihydrochloride (CTZ) was used as an active pharmaceutical ingredient (API). The polymer films were prepared at room temperature with the solvent casting method by mixed two-level and three-level factorial designs. The thickness, tensile strength (hardness), mucoadhesivity, surface free energy (SFE), FTIR, and Raman spectra, as well as the dissolution of the prepared films, were investigated. The investigations showed that GLY can reduce the mucoadhesivity of films, and CTZ can increase the tensile strength of films. The distribution of CTZ proved to be homogeneous in the films. The API could dissolve completely from all the films. We can conclude that polymer films with 1% and 3% GLY concentrations are appropriate to be formulated for application on the buccal mucosa as a drug delivery system.

MUCOADHESIVE BUCCAL FILMS: A NOVEL APPROACH FOR THE DELIVERY OF ANTI-HYPERTENSIVE DRUGS

The buccal drug delivery system is a prominent route of administration for drug delivery through the buccal mucosa. It is rich in blood supply with more surface area for rapid absorption as well as provides direct entry of drugs from the site of application into the systemic circulation through the jugular vein. Buccal drug delivery systems consist of various approaches such as lozenges, wafers, gels, microparticles, patches or films from which mucoadhesive buccal film is an attractive dosage form in terms of flexibility and high systemic bioavailability. Since most of the antihypertensive drugs show first-pass metabolism which leads to less oral bioavailability generally up to 20–50%. Thus, incorporation of antihypertensive drugs in mucoadhesive buccal films using mucoadhesive polymers can provide higher systemic bioavailability. The films can be formulated using various techniques such as solvent casting method and hot extrusion melt method. These films can be evaluated based on various characteristics to determine their efficacy and performance such as tensile strength, mucoadhesion residence time, and kinetic release data analysis. They have various advantages over conventional solid oral dosage forms, hence are preferable for the preparation of antihypertensive drug-loaded buccal films. Mucoadhesive buccal films of antihypertensive drugs can also provide controlled drug delivery with enhanced bioavailability.

The Role of Purported Mucoprotectants in Dealing with Irritable Bowel Syndrome, Functional Diarrhea, and Other Chronic Diarrheal Disorders in Adults.

Chronic diarrhea is a frequent presenting symptom, both in primary care medicine and in specialized gastroenterology units. It is estimated that more than 5% of the global population suffers from chronic diarrhea. and that about 40% of these subjects are older than 60 years. The clinician is frequently faced with the need to decide which is the best therapeutic approach for these patients. While the origin of chronic diarrhea is diverse, impairment of intestinal barrier function, dysbiosis. and mucosal micro-inflammation are being increasingly recognized as underlying phenomena characterizing a variety of chronic diarrheal diseases. In addition to current pharmacological therapies, there is growing interest in alternative products such as mucoprotectants, which form a mucoadhesive film over the epithelium to reduce and protect against the development of altered intestinal permeability, dysbiosis, and mucosal micro-inflammation. This manuscript focuses on chronic diarrhea in adults, and we will review recent evidence on the ability of these natural compounds to improve symptoms associated with chronic diarrhea and to exert protective effects for the intestinal barrier.

A mussel-inspired film for adhesion to wet buccal tissue and efficient buccal drug delivery

Administration of drugs via the buccal route has attracted much attention in recent years. However, developing systems with satisfactory adhesion under wet conditions and adequate drug bioavailability still remains a challenge. Here, we propose a mussel-inspired mucoadhesive film. Ex vivo models show that this film can achieve strong adhesion to wet buccal tissues (up to 38.72 ± 10.94 kPa). We also demonstrate that the adhesion mechanism of this film relies on both physical association and covalent bonding between the film and mucus. Additionally, the film with incorporated polydopamine nanoparticles shows superior advantages for transport across the mucosal barrier, with improved drug bioavailability (~3.5-fold greater than observed with oral delivery) and therapeutic efficacy in oral mucositis models (~6.0-fold improvement in wound closure at day 5 compared with that observed with no treatment). We anticipate that this platform might aid the development of tissue adhesives and inspire the design of nanoparticle-based buccal delivery systems.

Mucoadhesive Gelatin Buccal Films with Propranolol Hydrochloride: Evaluation of Mechanical, Mucoadhesive, and Biopharmaceutical Properties.

This study processes and characterizes propranolol hydrochloride/gelatin mucoadhesive buccal films. Two types of gelatin are used: Gelatin from porcine skin, type A (GA), and gelatin from bovine skin (GB). The influence of gelatin type on mechanical, mucoadhesive, and biopharmaceutical characteristics of buccal films is evaluated. Fourier-Transfer infrared spectroscopy (FTIR) and differential scanning calorimetry (DSC) analysis show that GA with propranolol hydrochloride (PRH) in the film (GAP) formed a physical mixture, whereas GB with PRH (GBP) form a compound-complex. Results of mechanical testing (tensile test, hardness) revealed that GAP films exhibit higher elastic modulus, tensile strength, and hardness. A mucoahesion test shows that GBP has higher adhesion strength, while GAP shows higher work of adhesion. Both in vitro release study and in silico simulation indicated that processed films can provide effective drug transport through the buccal mucosa. In silico simulation shows improved bioavailability from buccal films, in comparison to the immediate-release tablets—indicating that the therapeutic drug dose can be markedly reduced.

FORMULA OPTIMIZATION AND IN VITRO RELEASE KINETIC STUDIES OF DILTIAZEM HYDROCHLORIDE MUCOADHESIVE BILAYER BUCCAL FILM

Objective: This research aims to determine the amount of hydroxypropyl methylcellulose (HPMC) and chitosan, which can produce the optimum buccal film formula and to determine the release kinetics of diltiazem hydrochloride in vitro.&#x0D; Methods: The film was prepared by the solvent casting method. The formula's optimization was carried out using factorial design, which was processed using Design Expert 11.0.0 software, while the release kinetics was analyzed using the DDSolver program.&#x0D; Results: The optimization results show that HPMC and chitosan (30 mg: 10 mg) is the amount of polymer that can produce the optimum formula. The buccal film formula has a swelling index of 2.92, a mucoadhesive strength of 64.40 gF, and a mucoadhesive residence time of 464 min. In vitro release study showed 97.64% release of Diltiazem hydrochloride after 480 min. The release kinetic’s of diltiazem hydrochloride follow the Korsmeyer Peppas model.&#x0D; Conclusion: Thus, it can be concluded that the prepared formulation of the buccal mucoadhesive film can be a delivery system for diltiazem hydrochloride.

Optimization of Hydroxy Propyl Methyl Cellulose and Carbomer In Diltiazem Hydrochloride Mucoadhesive Buccal Film

Diltiazem hydrochloride (HCl) is a category of calcium channel blocker used as an antihypertensive agent. Diltiazem HCl is a low bioavailable drug due to high first-pass metabolism and a short half-life (3-5 hours); hence mucoadhesive buccal film was made to overcome this weakness. Bioavailability of Diltiazem HCl increase if the buccal preparations can contact the mucosa for a sufficient time. Therefore, in this study, two polymers are combined to obtain good film characteristics, especially residence time and mucoadhesive strength. This study was aimed to optimize Hydroxy Propyl Methyl Cellulose (HPMC) and Carbomer's amount in Diltiazem HCl mucoadhesive buccal film. The formulas were prepared by the solvent casting method and optimized with design expert software. The release kinetics and mechanism were evaluated using DDSolver program. The optimum amount of polymer obtained from optimization was 40 mg of HPMC and 10 mg of Carbomer. The optimum formula's swelling index was 4.18. The mucoadhesive strength was 53.07 gF, and the mucoadhesive residence time was 529.33 min. The FTIR spectra showed there was no interaction between Diltiazem HCl and other excipients. Thus it did not disturb the therapeutic effect. Based on the DDSolver statistical parameters and curve-fitting, the dissolution model of Diltiazem HCl from buccal mucoadhesive film follows Korsmeyer-Peppas. The release exponent (n) is 0.55, which shows a non-fickian/anomalous diffusion release mechanism. These mechanisms represent drug release controlled by a combination of diffusion and erosion.

Optimasi Hidroksipropil Metilselulosa dan Polivinil Pirolidon dalam Sediaan Mucoadhesive Buccal Film Diltiazem Hidroklorida

Diltiazem HCl is a class of benzodiazepine calcium channel blockers used to treat angina pectoris, arrhythmias, and hypertension. Diltiazem HCl improves first-pass metabolism, a short half time of 3-5 hours, and bioavailability of diltiazem for oral administration of about 40%. Mucoadhesive buccal film diltiazem HCl releases the drug to the buccal mucosa, so the first pass metabolism can be avoided because of its absorption through the venous system that flows from the cheek. This study aimed to study HPMC polymers and polyvinyl pyrrolidone (PVP) polymers on swelling index, residence time, mucoadhesive strength of mucoadhesive buccal film diltiazem HCl, FTIR, and drug release. The prepared film was evaluated for swelling index, mucoadhesive strength, and mucoadhesive residence time. The optimal amount for HPMC was 35 mg, and PVP was 15 mg. The combination of polymers with this amount can produce a swelling index was 3,00, mucoadhesive strength was 41,87 gF, and mucoadhesive residence time was 330,66. FTIR test indicated that there was no interaction between active function clusters of Diltiazem HCl and other excipients. The release of the optimum formula in the 360th minute was about 97.847%, following in the zero-order release model and Higuchi.

Películas mucoadhesivas de quitosano para la liberación sostenida de nistatina en la cavidad bucal

La candidiasis de orofaringe es la enfermedad micótica más prevalente a nivel mundial. Las formulaciones del fármaco de elección para su tratamiento cuentan con un tiempo de residencia y biodisponibilidad bajos en el sitio de la infección. El objetivo de este trabajo fue preparar y caracterizar films con capacidad mucoadhesiva de quitosano y ácido poligalacturónico por la técnica “evaporación del disolvente” conteniendo nistatina como un sistema de liberación sostenida en la cavidad bucal. Las películas obtenidas fueron caracterizadas para determinar sus características morfológicas, capacidad de adherencia, grado de hinchamiento y perfil de liberación del fármaco. La morfología de los films fue determinada por microscopía electrónica de barrido y la interacción entre los polímeros fue determinada por espectroscopía infrarroja, análisis termogravimétrico y calorimetría de escaneo diferencial, adicionalmente se determinó su actividad antimicrobiana contra dos especies de Candida. Las películas obtenidas mostraron capacidad de mucoadhesión y una liberación sostenida del fármaco explicada por el modelo de Korsemeyer-Peppas, también mostraron una actividad antimicrobiana significativa. Estos hallazgos sugieren que las películas con base en quitosano son un posible sistema de liberación de nistatina para la cavidad bucal.

MUCOADHESIVE POLYMERIC FILMS OF ACYCLOVIR PRONIOSOMES FOR BUCCAL ADMINISTRATION

Objective: The aim of the present work was to formulate and evaluate proniosomes of the poorly soluble drug, acyclovir incorporated in mucoadhesive polymeric films for improved buccal mucosal permeability of the drug while achieving prolonged release.&#x0D; Methods: Acyclovir was formulated as proniosomes using Span 60 and cholesterol. The prepared proniosomes were loaded into mucoadhesive polymeric films prepared with varying quantities of carbopol 934P and HPMC K15M. The proniosome incorporated films were evaluated for physicomechanical characters, mucoadhesion, swelling index, drug content, in vitro drug release and ex vivo permeation through porcine buccal mucosa.&#x0D; Results: Hydration of the proniosomes produced spherical vesicles or niosomes, which was confirmed by Scanning Electron Microscopy. The optimized formulation selected on the basis of vesicle size, entrapment efficiency PDI, Zetz potential and in vitro drug release was selected for incorporation into mucoadhesive polymeric films. All the films showed excellent physicomechanical characters. Formulations with higher proportions of carbopol produced slower in vitro drug release. The kinetics of release of drug from all the formulations appeared to be zero-order based on their regression coefficient values. Comparative evaluation of ex vivo permeation from niosomal and non-niosomal films indicated that the former demonstrated improved mucosal permeation and drug release was also sustained for the 8 h period.&#x0D; Conclusion: Mucoadhesive films impregnated with acyclovir loaded proniosomes could be a potential approach for buccal delivery of acyclovir for improving its absorption and bioavailability.

Characterization of Insulin Mucoadhesive Buccal Films: Spectroscopic Analysis and In Vivo Evaluation

Insulin mucoadhesive buccal films (MBF) are a noninvasive insulin delivery system that offers an advantageous alternative route of administration to subcutaneous injection. One major concern in the formulation of insulin MBF is the preservation of an insulin secondary structure in the presence of the other film components. Buccal films were formulated using chitosan, glycerin, and L-arginine. The MBF-forming solutions (MBF-FS) and the films (MBF) were examined for their chemical and structural stability and for their in vivo activity. Enzyme-Linked Immunosorbent Assay (ELISA) of the insulin-loaded MBF showed that each individualized unit dose was at least loaded with 80% of the insulin theoretical dose. Results of Synchrotron Radiation Circular Dichroism (SRCD) measurements revealed that MBF-FS retained the α-helices and β–sheets conformations of insulin. Fourier transform infrared (FTIR)-microspectroscopy (FTIR-MS) examination of insulin MBF revealed the protective action of L-arginine on insulin structure by interacting with chitosan and minimizing the formation of an unordered structure and β-strand. A blood glucose-lowering effect of insulin MBF was observed in comparison with subcutaneous (S.C) injection using a rat model. As a result; chitosan-based MBFs were formulated and characterized using SRCD and FTIR-MS techniques. Furthermore, the results of in vivo testing suggested the MBFs as a promising delivery system for insulin.

Efficacy and safety of plant-based therapy on recurrent aphthous stomatitis and oral mucositis in the past decade: a systematic review

Oral mucosal inflammation is one of the oral diseases causing pain and reducing the quality of human life. The types of oral mucosal inflammation that commonly found were recurrent aphthous stomatitis (RAS) and oral mucositis (OM). Anti-inflammatory drugs, both synthetic and plant-based, have been used to treat RAS and OM. Plant-based drugs have been attracted the attention of some researchers to minimize the side effects of synthetic drugs. However, a comprehensive review addressing the use of plant-based drugs for RAS and OM therapy, including drug formulation and species of plant, has not yet been reported. Here, we reported the article review of 9 publications derived from the databases of PubMed, ScienceDirect, Cochrane Library, and other additional relevant works, in order to find the effectiveness and safety of plant-based drugs for RAS and OM therapy. This review was written by following the PRISMA guidelines, and the risk of bias of the articles was evaluated using the Oxford Quality Scoring System. It was found that the effective and safe drugs for RAS therapy contained acemannan from Aloe vera and curcumin from Curcuma longa, both in an oral gel formulation. For OM therapy, drugs contained curcumin from Curcuma longa; licorice from Glycyrrhiza glabra; Aloe vera and black mulberry from Morus nigra, in soft tablet, mouthwash solution or mucoadhesive film formulation. In conclusion, the most effective and safest plant-based therapy for RAS is Acemannan 0.5% in oral gel, whereas for OM is Licorice root extract 0.18 mg in mucoadhesive film.

Preparation and evaluation of mucoadhesive bio-flexy films from Cocos nucifera biopolymer using Tiagabine moiety

Preparation and evaluation of mucoadhesive bio-flexy films from <i> Cocos nucifera </i> biopolymer using Tiagabine moiety

Quality by Design-driven investigation of the mechanical properties of mucoadhesive films for needleless anesthetics administration

Objectives: To systematically evaluate the effects of hydroxypropyl methyl cellulose (HPMC) type (E5LV, E15LV, and K100LV); plasticizer type (glycerol and mannitol), plasticizer loading (0.12 and 0.24% w/w); and loading of prilocaine and lidocaine hydrochlorides combined at 1:1 ratio (0 and 47 mg/cm2) in the mechanical properties of buccal films. Methods: A quality by design (QbD) approach based on a full factorial design (3 x 23) and complementarily multivariate statistical tools i.e., principal component analysis (PCA), response surface methodology (RSM), and correlation matrix were used in this pursuit. The thickness, elongation at break, tensile strength, force at break, and Young`s modulus of the anesthetic buccal films obtained by solvent casting were assessed. Results: The QbD, PCA and RSM altogether demonstrated that all studied formulation variables, mainly the drug loading, affect the mechanical properties of the films at different significance levels. The multivariate analysis yielded the modelling of elongation at break, tensile strength, and force at break, which significantly correlated with each other. The drugs exerted a synergic plasticizing effect on the films, and the use of HPMC K100 LV (with greater hydroxypropyl substitution degree and viscosity) and mannitol favored their elasticity and resistance. Furthermore, the majority of the films fulfilled the requirements for buccal administration due to their softness and mechanical resistance. Conclusion: Mannitol is suitable plasticizer for manufacturing HPMC anesthetic buccal films with improved mechanical properties. These results are a step forward in the rational development of formulations for the replacement of needles in dentistry

Improved Bioavailability of Montelukast through a Novel Oral Mucoadhesive Film in Humans and Mice

The leukotriene receptor antagonist Montelukast (MTK) is an approved medication for the treatment of asthma and allergic rhinitis. The existing marketed tablet forms of MTK exhibit inconsistent uptake and bioavailability, which partially explains the presence of a significant proportion of MTK low- and non-responders in the population. Besides that, tablets are suboptimal formulations for patients suffering from dysphagia, for example, seen in patients with neurodegenerative diseases such as Alzheimer’s disease, a disease with increasing interest in repurposing of MTK. This, and the need for an improved bioavailability, triggered us to reformulate MTK. Our aim was to develop a mucoadhesive MTK film with good safety and improved pharmacological features, i.e., an improved bioavailability profile in humans as well as in a mouse model of Alzheimer’s disease. We tested dissolution of the MTK mucoadhesive film and assessed pharmacoexposure and kinetics after acute and chronic oral application in mice. Furthermore, we performed a Phase I analysis in humans, which included a comparison with the marketed tablet form as well as a quantitative analysis of the MTK levels in the cerebrospinal fluid. The novel MTK film demonstrated significantly improved bioavailability compared to the marketed tablet in the clinical Phase 1a study. Furthermore, there were measurable amounts of MTK present in the cerebrospinal fluid (CSF). In mice, MTK was detected in serum and CSF after acute and chronic exposure in a dose-dependent manner. The mucoadhesive film of MTK represents a promising alternative for the tablet delivery. The oral film might lower the non-responder rate in patients with asthma and might be an interesting product for repurposing of MTK in other diseases. As we demonstrate Blood-Brain-Barrier (BBB) penetrance in a preclinical model, as well as in a clinical study, the oral film of MTK might find its use as a therapeutic for acute and chronic neurodegenerative diseases such as dementias and stroke.