Mucoadhesive Drug Delivery Systems: Applications, Challenge and Future Perspectives

A special issue of Pharmaceutics (ISSN 1999-4923). This special issue belongs to the section "Drug Delivery and Controlled Release".

Deadline for manuscript submissions: closed (30 April 2021) | Viewed by 19902

Special Issue Editors

Departament of Drugs and Medicines, São Paulo State University—UNESP, Rodovia Araraquara Jaú, km 1, 14800-903 Araraquara, São Paulo, Brazil
Interests: mucoadhesion; targeted delivery; lipid-based nanocarriers; drug delivery systems; polymeric systems; nanotechnology

Special Issue Information

Dear Colleagues,

The efficiency of mucoadhesive drug delivery systems is related not only to their ability to adhere to mucus over a period, but also to the ability to modify the release of the drug and the pattern of biological interaction. It is possible, in this way, to outline mucoadhesive systems in the most varied dosage forms, since the adhesion property depends on the characteristics of the material used in its preparation and the mucus. The mucoadhesion process results from the attachment between a mucoadhesive carrier system and mucus glycoproteins via physical and/or chemical interactions. As a result, the increase in contact time between the formulation and the mucosa obtained through these interactions contributes to reduce in the treatment time and frequency of applications.

Recognizing the importance and growing interest in mucoadhesive drug delivery systmes, we would like to invite you to contribute a short communication, full article or review to this issue, entitled: “Mucoadhesive drug delivery systems: applications, challenge and future perspectives”. This special edition deals with different aspects related to mucoadhesion and will include articles describing the mechanisms, preparation, and characterization of drug delivery systems with mucoadhesive properties and their latest developments in this topic.

Prof. Dr. Marlus Chorilli
Prof. Dr. Maria Palmira Daflon Gremião
Guest Editors

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Keywords

  • mucoadhesion
  • mucoadhesive polymers
  • targeted-delivery
  • controlled drug release
  • active targeting

Published Papers (7 papers)

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Research

16 pages, 13087 KiB  
Article
Orodispersible Film Loaded with Enterococcus faecium CRL183 Presents Anti-Candida albicans Biofilm Activity In Vitro
by Virgínia Barreto Lordello, Andréia Bagliotti Meneguin, Sarah Raquel de Annunzio, Maria Pía Taranto, Marlus Chorilli, Carla Raquel Fontana and Daniela Cardoso Umbelino Cavallini
Pharmaceutics 2021, 13(7), 998; https://doi.org/10.3390/pharmaceutics13070998 - 30 Jun 2021
Cited by 11 | Viewed by 3161
Abstract
Background: Probiotic bacteria have been emerging as a trustworthy choice for the prevention and treatment of Candida spp. infections. This study aimed to develop and characterize an orodispersible film (ODF) for delivering the potentially probiotic Enterococcus faecium CRL 183 into the oral cavity, [...] Read more.
Background: Probiotic bacteria have been emerging as a trustworthy choice for the prevention and treatment of Candida spp. infections. This study aimed to develop and characterize an orodispersible film (ODF) for delivering the potentially probiotic Enterococcus faecium CRL 183 into the oral cavity, evaluating its in vitro antifungal activity against Candida albicans. Methods and Results: The ODF was composed by carboxymethylcellulose, gelatin, and potato starch, and its physical, chemical, and mechanical properties were studied. The probiotic resistance and viability during processing and storage were evaluated as well as its in vitro antifungal activity against C. albicans. The ODFs were thin, resistant, and flexible, with neutral pH and microbiologically safe. The probiotic resisted the ODF obtaining process, demonstrating high viability (>9 log10 CFU·g−1), up to 90 days of storage at room temperature. The Probiotic Film promoted 68.9% of reduction in fungal early biofilm and 91.2% in its mature biofilm compared to the group stimulated with the control film. Those results were confirmed through SEM images. Conclusion: The probiotic ODF developed is a promising strategy to prevent oral candidiasis, since it permits the local probiotic delivery, which in turn was able to reduce C. albicans biofilm formation. Full article
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16 pages, 2255 KiB  
Article
Development of Mucoadhesive Buccal Film for Rizatriptan: In Vitro and In Vivo Evaluation
by Anroop B. Nair, Jigar Shah, Shery Jacob, Bandar E. Al-Dhubiab, Vimal Patel, Nagaraja Sreeharsha and Pottathil Shinu
Pharmaceutics 2021, 13(5), 728; https://doi.org/10.3390/pharmaceutics13050728 - 15 May 2021
Cited by 27 | Viewed by 4073
Abstract
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 [...] Read more.
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. Full article
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13 pages, 2494 KiB  
Article
Resistivity Technique for the Evaluation of the Integrity of Buccal and Esophageal Epithelium Mucosa for In Vitro Permeation Studies: Swine Buccal and Esophageal Mucosa Barrier Models
by Jaiza Samara Macena de Araújo, Maria Cristina Volpato, Bruno Vilela Muniz, Gabriela Gama Augusto Xavier, Claudia Cristina Maia Martinelli, Renata Fonseca Vianna Lopez, Francisco Carlos Groppo and Michelle Franz-Montan
Pharmaceutics 2021, 13(5), 643; https://doi.org/10.3390/pharmaceutics13050643 - 30 Apr 2021
Cited by 6 | Viewed by 2006
Abstract
Permeation assays are important for the development of topical formulations applied on buccal mucosa. Swine buccal and esophageal epithelia are usually used as barriers for these assays, while frozen epithelia have been used to optimize the experimental setup. However, there is no consensus [...] Read more.
Permeation assays are important for the development of topical formulations applied on buccal mucosa. Swine buccal and esophageal epithelia are usually used as barriers for these assays, while frozen epithelia have been used to optimize the experimental setup. However, there is no consensus on these methods. In transdermal studies, barrier integrity has been evaluated by measuring electrical resistance (ER) across the skin, which has been demonstrated to be a simple, fast, safe, and cost-effective method. Therefore, the aims here were to investigate whether ER might also be an effective method to evaluate buccal and esophageal epithelium mucosa integrity for in vitro permeation studies, and to establish a cut-off ER value for each epithelium mucosa model. We further investigated whether buccal epithelium could be substituted by esophageal epithelium in transbuccal permeation studies, and whether their permeability and integrity were affected by freezing at −20 °C for 3 weeks. Fresh and frozen swine buccal and esophageal epithelia were mounted in Franz diffusion cells and were then submitted to ER measurement. Permeation assays were performed using lidocaine hydrochloride as a hydrophilic drug model. ER was shown to be a reliable method for evaluating esophageal and buccal epithelia. The esophageal epithelium presented higher permeability compared to the buccal epithelium. For both epithelia, freezing and storage led to decreased electrical resistivity and increased permeability. We conclude that ER may be safely used to confirm tissue integrity when it is equal to or above 3 kΩ for fresh esophageal mucosa, but not for buccal epithelium mucosa. However, the use of esophageal epithelium in in vitro transmucosal studies could overestimate the absorption of hydrophilic drugs. In addition, fresh samples are recommended for these experiments, especially when hydrophilic drugs are involved. Full article
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17 pages, 3633 KiB  
Article
Ionic Cross-Linking as a Strategy to Modulate the Properties of Oral Mucoadhesive Microparticles Based on Polysaccharide Blends
by Fernanda Isadora Boni, Beatriz S. F. Cury, Natália Noronha Ferreira and Maria Palmira Daflon Gremião
Pharmaceutics 2021, 13(3), 407; https://doi.org/10.3390/pharmaceutics13030407 - 19 Mar 2021
Cited by 6 | Viewed by 1663
Abstract
Polymer blends of gellan gum (GG)/retrograded starch(RS) and GG/pectin (P) were cross-linked with calcium, aluminum, or both to prepare mucoadhesive microparticles as oral carriers of drugs or nano systems. Cross-linking with different cations promoted different effects on each blend, which can potentially be [...] Read more.
Polymer blends of gellan gum (GG)/retrograded starch(RS) and GG/pectin (P) were cross-linked with calcium, aluminum, or both to prepare mucoadhesive microparticles as oral carriers of drugs or nano systems. Cross-linking with different cations promoted different effects on each blend, which can potentially be explored as novel strategies for modulating physical–chemical and mucoadhesive properties of microparticles. Particles exhibited spherical shapes, diameters from 888 to 1764 µm, and span index values lower than 0.5. Blends of GG:P cross-linked with aluminum resulted in smaller particles than those obtained by calcium cross-linking. GG:RS particles exhibited larger sizes, but cross-linking this blend with calcium promoted diameter reduction. The uptake rates of acid medium were lower than phosphate buffer (pH 6.8), especially GG:RS based particles cross-linked with calcium. On the other hand, particles based on GG:P cross-linked with calcium absorbed the highest volume of acid medium. The percentage of systems erosion was higher in acid medium, but apparently occurred in the outermost layer of the particle. In pH 6.8, erosion was lower, but caused expressive swelling of the matrixes. Calcium cross-linking of GG:RS promoted a significantly reduction on enzymatic degradation at both pH 1.2 and 6.8, which is a promising feature that can provide drug protection against premature degradation in the stomach. In contrast, GG:P microparticles cross-linked with calcium suffered high degradation at both pH values, an advantageous feature for quickly releasing drugs at different sites of the gastrointestinal tract. The high mucoadhesive ability of the microparticles was evidenced at both pH values, and the Freundlich parameters indicated stronger particle–mucin interactions at pH 6.8. Full article
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26 pages, 6389 KiB  
Article
Amoxicillin and Clarithromycin Mucoadhesive Delivery System for Helicobacter pylori Infection in a Mouse Model: Characterization, Pharmacokinetics, and Efficacy
by Isabel Villegas, María Ángeles Rosillo, Catalina Alarcón-de-la-Lastra, Victoria Vázquez-Román, Maria Llorente, Susana Sánchez, Ana Gloria Gil, Pilar Alcalde, Esther González, Elisabet Rosell, Carles Nieto and Francisco Fernandez-Campos
Pharmaceutics 2021, 13(2), 153; https://doi.org/10.3390/pharmaceutics13020153 - 24 Jan 2021
Cited by 5 | Viewed by 2343
Abstract
Helicobacter pylori is the main pathogen responsible for gastric ulcers and a predisposing factor of stomach cancer. Although current treatment is usually successful, it requires high doses and frequent administration. An innovative mucoadhesive system (Mucolast®) loaded with amoxicillin and clarithromycin is [...] Read more.
Helicobacter pylori is the main pathogen responsible for gastric ulcers and a predisposing factor of stomach cancer. Although current treatment is usually successful, it requires high doses and frequent administration. An innovative mucoadhesive system (Mucolast®) loaded with amoxicillin and clarithromycin is proposed to improve the efficacy of treatment against H. pylori. The drug product was optimized based on its viscoelastic properties to obtain long-term stability of the vehicle. The drug release mechanisms were different for both antibiotics based on their solubilization status. A systemic and stomach pharmacokinetic profile was obtained after three different doses were administered to mice, obtaining similar systemic exposure levels but an increase in drug concentration in the stomach. The efficacy results in mice infected with H. pylori also demonstrated the superiority of the antibiotics when administered in Mucolast®, as shown by the bacterial count in stomach tissue and under histopathological and biochemical evaluation. The proposed treatment was efficacious and safe and is presented as a realistic alternative to current treatment options to improve patient compliance and to reduce bacterial resistance. Full article
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26 pages, 4820 KiB  
Article
Mucoadhesive Poloxamer-Based Hydrogels for the Release of HP-β-CD-Complexed Dexamethasone in the Treatment of Buccal Diseases
by Raul Diaz-Salmeron, Balthazar Toussaint, Nicolas Huang, Etienne Bourgeois Ducournau, Gabriel Alviset, Sophie Goulay Dufaÿ, Hervé Hillaireau, Amélie Dufaÿ Wojcicki and Vincent Boudy
Pharmaceutics 2021, 13(1), 117; https://doi.org/10.3390/pharmaceutics13010117 - 18 Jan 2021
Cited by 15 | Viewed by 3379
Abstract
Oral lichen planus (OLP) is an ongoing and chronic inflammatory disease affecting the mucous membrane of the oral cavity. Currently, the treatment of choice consists in the direct application into the buccal cavity of semisolid formulations containing a corticosteroid molecule to decrease inflammatory [...] Read more.
Oral lichen planus (OLP) is an ongoing and chronic inflammatory disease affecting the mucous membrane of the oral cavity. Currently, the treatment of choice consists in the direct application into the buccal cavity of semisolid formulations containing a corticosteroid molecule to decrease inflammatory signs and symptoms. However, this administration route has shown various disadvantages limiting its clinical use and efficacy. Indeed, the frequency of application and the incorrect use of the preparation may lead to a poor efficacy and limit the treatment compliance. Furthermore, the saliva clearance and the mechanical stress present in the buccal cavity also involve a decrease in the mucosal exposure to the drug. In this context, the design of a new pharmaceutical formulation, containing a steroidal anti-inflammatory, mucoadhesive, sprayable and exhibiting a sustained and controlled release seems to be suitable to overcome the main limitations of the existing pharmaceutical dosage forms. The present work reports the formulation, optimization and evaluation of the mucoadhesive and release properties of a poloxamer 407 thermosensitive hydrogel containing a poorly water-soluble corticosteroid, dexamethasone acetate (DMA), threaded into hydroxypropyl-beta-cyclodextrin (HP-β-CD) molecules. Firstly, physicochemical properties were assessed to ensure suitable complexation of DMA into HP-β-CD cavities. Then, rheological properties, in the presence and absence of various mucoadhesive agents, were determined and optimized. The hydration ratio (0.218–0.191), the poloxamer 407 (15–17 wt%) percentage and liquid-cyclodextrin state were optimized as a function of the gelation transition temperature, viscoelastic behavior and dynamic flow viscosity. Deformation and resistance properties were evaluated in the presence of various mucoadhesive compounds, being the sodium alginate and xanthan gum the most suitable to improve adhesion and mucoadhesion properties. Xanthan gum was shown as the best agent prolonging the hydrogel retention time up to 45 min. Furthermore, xanthan gum has been found as a relevant polymer matrix controlling drug release by diffusion and swelling processes in order to achieve therapeutic concentration for prolonged periods of time. Full article
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22 pages, 3512 KiB  
Article
Design of Mucoadhesive Nanostructured Polyelectrolyte Complexes Based on Chitosan and Hypromellose Phthalate for Metronidazole Delivery Intended to the Treatment of Helicobacter pylori Infections
by Maurício Palmeira Chaves de Souza, Nathalia Helena de Mattos, Liliane Neves Pedreiro, Fernanda Isadora Boni, Matheus Aparecido dos Santos Ramos, Taís Maria Bauab, Maria Palmira Daflon Gremião and Marlus Chorilli
Pharmaceutics 2020, 12(12), 1211; https://doi.org/10.3390/pharmaceutics12121211 - 14 Dec 2020
Cited by 4 | Viewed by 1860
Abstract
Metronidazole (MT) is an important drug available for Helicobacter pylori infection treatment. However, in the past few years, this drug has presented effective reduction for infection control, one of the most important reasons is attributed to the reduction of retention time in the [...] Read more.
Metronidazole (MT) is an important drug available for Helicobacter pylori infection treatment. However, in the past few years, this drug has presented effective reduction for infection control, one of the most important reasons is attributed to the reduction of retention time in the stomach environment. Mucoadhesive nanostructured polyelectrolyte complexes (nano PECs) based on chitosan (CS) and hypromellose phthalate (HP) were rationally developed using a full factorial design (21 × 21 × 31), for the incorporation of MT based on the enhancement of the antimicrobial potential against active Helicobacter pylori, in the stomach. Different mass ratios of CS:HP (w/w) were tested, reaching the most promising ratios of 1:0.1, 1:0.5, and 1:1, and two methods of polymers addition (pouring-I and drip-II) were also evaluated. From method I, the obtained particles presented a diameter in the range of 811–1293 nm (Z-average) and a polydispersity index (PDI) between 0.47 and 0.88. By method II, there was a significant reduction in diameter and PDI to 553–739 nm and 0.23 at 0.34, respectively. The drug incorporation also resulted in a reduction in the diameter and PDI of the nano PECs. All samples showed positive zeta potential, about 20 mV, and a high percentage of MT incorporation (±95%). The method factor presented a greater influence on the nano PECs characteristics. Interactions in the system constituents were indicated by the FTIR data. Nano PECs mucoadhesiveness was observed and the composition and charge density were responsible for this phenomenon. MT dissolution evaluation showed the similarity of the dissolution profiles of free and loaded MT, in which almost 100% of the drug was in the simulated gastric medium in 120 min of testing. The in vitro antimicrobial potential against H. pylori of loaded nano PECs were measured and the minimum inhibitory concentration observed for free MT was >2000 µg/mL, while for the incorporated MT lower values were observed, showing an increase in the encapsulated MT activity. Full article
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