Advances in Mucoadhesive Polymers and Formulations for Transmucosal Drug Delivery

A special issue of Polymers (ISSN 2073-4360).

Deadline for manuscript submissions: closed (15 January 2018) | Viewed by 85193

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Special Issue Information

Dear Colleagues,

It is my pleasure to invite you to contribute to this Special Issue focused on the advances in mucoadhesive polymers and formulations. Mucoadhesion, defined as the ability of materials to stick to mucosal tissues in the human body, has attracted substantial interest over the last few decades. The number of publications reporting the use of various polymeric systems for designing various dosage forms for transmucosal drug delivery is growing continuously. There is also a strong interest in mucoadhesion in food, dental care and cosmetic formulations. Mucoadhesive formulations reported so far range from simple use of water-soluble polymers or their mixtures to functionalised materials bearing specific “adhesive” chemical moieties. The aim of this Special Issue is to present recent advances in the area of mucoadhesive polymers and formulations.

This Special Issue invites original papers and reviews reporting on recent progress in the following areas:

·        Design of novel mucoadhesive polymers
·        Formulation of polymeric dosage forms for transmucosal drug delivery
·        Methods of in vitro and in vivo testing of mucoadhesive dosage forms
·        Studies of mucoadhesive interactions involving polymers

Prof. Vitaliy Khutoryanskiy
Guest Editor

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Keywords

  • Mucoadhesion
  • Mucosal membranes
  • Mucoadhesive polymers
  • Transmucosal drug delivery
  • Mucins
  • Thiols
  • Retention

Published Papers (11 papers)

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Research

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13 pages, 1605 KiB  
Article
Comparative Study of Ex Vivo Transmucosal Permeation of Pioglitazone Nanoparticles for the Treatment of Alzheimer’s Disease
by Marcelle Silva-Abreu, Lupe Carolina Espinoza, Lyda Halbaut, Marta Espina, María Luisa García and Ana Cristina Calpena
Polymers 2018, 10(3), 316; https://doi.org/10.3390/polym10030316 - 14 Mar 2018
Cited by 34 | Viewed by 5362
Abstract
Pioglitazone has been reported in the literature to have a substantial role in the improvement of overall cognition in a mouse model. With this in mind, the aim of this study was to determine the most efficacious route for the administration of Pioglitazone [...] Read more.
Pioglitazone has been reported in the literature to have a substantial role in the improvement of overall cognition in a mouse model. With this in mind, the aim of this study was to determine the most efficacious route for the administration of Pioglitazone nanoparticles (PGZ-NPs) in order to promote drug delivery to the brain for the treatment of Alzheimer’s disease. PGZ-loaded NPs were developed by the solvent displacement method. Parameters such as mean size, polydispersity index, zeta potential, encapsulation efficacy, rheological behavior, and short-term stability were evaluated. Ex vivo permeation studies were then carried out using buccal, sublingual, nasal, and intestinal mucosa. PGZ-NPs with a size around of 160 nm showed high permeability in all mucosae. However, the permeation and prediction parameters revealed that lag-time and vehicle/tissue partition coefficient of nasal mucosa were significantly lower than other studied mucosae, while the diffusion coefficient and theoretical steady-state plasma concentration of the drug were higher, providing biopharmaceutical results that reveal more favorable PGZ permeation through the nasal mucosa. The results suggest that nasal mucosa represents an attractive and non-invasive pathway for PGZ-NPs administration to the brain since the drug permeation was demonstrated to be more favorable in this tissue. Full article
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19 pages, 3359 KiB  
Article
Assessing Mucoadhesion in Polymer Gels: The Effect of Method Type and Instrument Variables
by Jéssica Bassi da Silva, Sabrina Barbosa de Souza Ferreira, Adriano Valim Reis, Michael Thomas Cook and Marcos Luciano Bruschi
Polymers 2018, 10(3), 254; https://doi.org/10.3390/polym10030254 - 01 Mar 2018
Cited by 66 | Viewed by 7640
Abstract
The process of mucoadhesion has been widely studied using a wide variety of methods, which are influenced by instrumental variables and experiment design, making the comparison between the results of different studies difficult. The aim of this work was to standardize the conditions [...] Read more.
The process of mucoadhesion has been widely studied using a wide variety of methods, which are influenced by instrumental variables and experiment design, making the comparison between the results of different studies difficult. The aim of this work was to standardize the conditions of the detachment test and the rheological methods of mucoadhesion assessment for semisolids, and introduce a texture profile analysis (TPA) method. A factorial design was developed to suggest standard conditions for performing the detachment force method. To evaluate the method, binary polymeric systems were prepared containing poloxamer 407 and Carbopol 971P®, Carbopol 974P®, or Noveon® Polycarbophil. The mucoadhesion of systems was evaluated, and the reproducibility of these measurements investigated. This detachment force method was demonstrated to be reproduceable, and gave different adhesion when mucin disk or ex vivo oral mucosa was used. The factorial design demonstrated that all evaluated parameters had an effect on measurements of mucoadhesive force, but the same was not observed for the work of adhesion. It was suggested that the work of adhesion is a more appropriate metric for evaluating mucoadhesion. Oscillatory rheology was more capable of investigating adhesive interactions than flow rheology. TPA method was demonstrated to be reproducible and can evaluate the adhesiveness interaction parameter. This investigation demonstrates the need for standardized methods to evaluate mucoadhesion and makes suggestions for a standard study design. Full article
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13 pages, 1408 KiB  
Article
Formulation of Carbopol®/Poly(2-ethyl-2-oxazoline)s Mucoadhesive Tablets for Buccal Delivery of Hydrocortisone
by Leire Ruiz-Rubio, María Luz Alonso, Leyre Pérez-Álvarez, Rosa Maria Alonso, Jose Luis Vilas and Vitaliy V. Khutoryanskiy
Polymers 2018, 10(2), 175; https://doi.org/10.3390/polym10020175 - 11 Feb 2018
Cited by 28 | Viewed by 7092
Abstract
Poly(2-ethyl-2-oxazoline) has become an excellent alternative to the use of poly(ethylene glycol) in pharmaceutical formulations due to its valuable physicochemical and biological properties. This work presents a formulation of poorly-water soluble drug, hydrocortisone, using interpolymer complexes and physical blends of poly(2-ethyl-2-oxazoline)s and two [...] Read more.
Poly(2-ethyl-2-oxazoline) has become an excellent alternative to the use of poly(ethylene glycol) in pharmaceutical formulations due to its valuable physicochemical and biological properties. This work presents a formulation of poorly-water soluble drug, hydrocortisone, using interpolymer complexes and physical blends of poly(2-ethyl-2-oxazoline)s and two Carbopols® (Carbopol 974 and Carbopol 971) for oromucosal administration. The swelling, hydrocortisone release and mucoadhesive properties of a series of tablet formulations obtained by combination of different Carbopols with poly(2-ethyl-2-oxazoline)s of different molecular weights have been evaluated in vitro. Full article
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16 pages, 2473 KiB  
Article
Production and Characterization of a Clotrimazole Liposphere Gel for Candidiasis Treatment
by Elisabetta Esposito, Maddalena Sguizzato, Christian Bories, Claudio Nastruzzi and Rita Cortesi
Polymers 2018, 10(2), 160; https://doi.org/10.3390/polym10020160 - 08 Feb 2018
Cited by 13 | Viewed by 4865
Abstract
This study describes the design and characterization of a liposphere gel containing clotrimazole for the treatment of Candida albicans. Lipospheres were produced by the melt-dispersion technique, using a lipid phase constituted of stearic triglyceride in a mixture with caprylic/capric triglyceride or an [...] Read more.
This study describes the design and characterization of a liposphere gel containing clotrimazole for the treatment of Candida albicans. Lipospheres were produced by the melt-dispersion technique, using a lipid phase constituted of stearic triglyceride in a mixture with caprylic/capric triglyceride or an alkyl lactate derivative. The latter component was added to improve the action of clotrimazole against candida. The liposphere morphology and dimensional distribution were evaluated by scanning electron microscopy. Clotrimazole release kinetics was investigated by an in vitro dialysis method. An anticandidal activity study was conducted on the lipospheres. To obtain formulations with suitable viscosity for vaginal application, the lipospheres were added to a xanthan gum gel. The rheological properties, spreadability, leakage, and adhesion of the liposphere gel were investigated. Clotrimazole encapsulation was always over 85% w/w. The anticandidal study demonstrated that the encapsulation of clotrimazole in lipospheres increased its activity against Candida albicans, especially in the presence of the alkyl lactate derivative in the liposphere matrix. A dialysis method demonstrated that clotrimazole was slowly released from the liposphere gel and that the alkyl lactate derivative further controlled clotrimazole release. Adhesion and leakage tests indicated a prolonged adhesion of the liposphere gel, suggesting its suitability for vaginal application. Full article
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19 pages, 4218 KiB  
Article
Effects of Cyclodextrins (β and γ) and l-Arginine on Stability and Functional Properties of Mucoadhesive Buccal Films Loaded with Omeprazole for Pediatric Patients
by Sajjad Khan and Joshua Boateng
Polymers 2018, 10(2), 157; https://doi.org/10.3390/polym10020157 - 07 Feb 2018
Cited by 17 | Viewed by 4596
Abstract
Omeprazole (OME) is employed for treating ulcer in children, but is unstable and exhibits first pass metabolism via the oral route. This study aimed to stabilize OME within mucoadhesive metolose (MET) films by combining cyclodextrins (CD) and l-arginine (l-arg) as [...] Read more.
Omeprazole (OME) is employed for treating ulcer in children, but is unstable and exhibits first pass metabolism via the oral route. This study aimed to stabilize OME within mucoadhesive metolose (MET) films by combining cyclodextrins (CD) and l-arginine (l-arg) as stabilizing excipients and functionally characterizing for potential delivery via the buccal mucosa of paediatric patients. Polymeric solutions at a concentration of 1% w/w were obtained by dispersing the required weight of metolose in 20% v/v ethanol as solvent at a temperature of 40 °C using polyethylene glycol (PEG 400) (0.5% w/w) as plasticizer. The films were obtained by drying the resulting polymer solutions at in an oven at 40 °C. Textural (tensile and mucoadhesion) properties, physical form (differential scanning calorimetry (DSC), X-ray diffraction (XRD) and Fourier transform infrared (FTIR) spectroscopy), residual moisture content (thermogravimetric analysis (TGA)) and surface morphology (scanning electron microscopy (SEM)) were investigated. Optimized formulations containing OME, CDs (β or γ) and l-arg (1:1:1) were selected to investigate the stabilization of the drug. The DSC, XRD, and FTIR showed possible molecular dispersion of OME in metolose film matrix. Plasticized MET films containing OME:βCD:l-arg 1:1:1 were optimum in terms of transparency and ease of handling and therefore further functionally characterized (hydration, mucoadhesion, in vitro drug dissolution and long term stability studies). The optimized formulation showed sustained drug release that was modelled by Korsmeyer–Peppas equation, while the OME showed stability under ambient temperature conditions for 28 days. The optimized OME loaded MET films stabilized with βCD and l-arg have potential for use as paediatric mucoadhesive buccal delivery system, which avoids degradation in the stomach acid as well as first pass metabolism in the liver. Full article
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17 pages, 3237 KiB  
Article
Acrylated Chitosan Nanoparticles with Enhanced Mucoadhesion
by Shaked Eliyahu, Anat Aharon and Havazelet Bianco-Peled
Polymers 2018, 10(2), 106; https://doi.org/10.3390/polym10020106 - 23 Jan 2018
Cited by 20 | Viewed by 5518
Abstract
The aim of this study was to investigate the effect of acrylate modification on the mucoadhesion of chitosan at the nanoscale. Nanoparticles were fabricated from acrylated chitosan (ACS) via ionic gelation with tripolyphosphate and were characterized in terms of size, zeta potential, stability, [...] Read more.
The aim of this study was to investigate the effect of acrylate modification on the mucoadhesion of chitosan at the nanoscale. Nanoparticles were fabricated from acrylated chitosan (ACS) via ionic gelation with tripolyphosphate and were characterized in terms of size, zeta potential, stability, and nanoparticle yield. Chitosan (CS) nanoparticles, serving as a control, were fabricated using the same procedure. The mucoadhesion of the nanoparticles was evaluated using the flow-through method after different incubation periods. The retention percentages of ACS nanoparticles were found to be significantly higher than those of CS nanoparticles, for all studied time intervals. An additional indication for the increased mucoadhesion of ACS nanoparticles was the increase in particle size obtained from the mucin particle method, in which mucin and nanoparticles are mixed at different ratios. NMR data verified the presence of free acrylate groups on the ACS nanoparticles. Thus, the improved mucoadhesion could be due to a Michael-type addition reaction between the nanoparticles and thiol groups present in mucin glycoprotein, in addition to entanglements and hydrogen bonding. Overall, ACS nanoparticles exhibit enhanced mucoadhesion properties as compared to CS nanoparticles and could be used as vehicles for drug delivery systems. Full article
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14 pages, 2479 KiB  
Article
Mucoadhesive Interpolyelectrolyte Complexes for the Buccal Delivery of Clobetasol
by Venera R. Garipova, Chiara G. M. Gennari, Francesca Selmin, Francesco Cilurzo and Rouslan I. Moustafine
Polymers 2018, 10(1), 85; https://doi.org/10.3390/polym10010085 - 17 Jan 2018
Cited by 28 | Viewed by 4614
Abstract
This work aimed to investigate the feasibility to design: (a) a mucoadhesive interpolyelectrolyte complex (IPEC) loaded with clobetasol propionate (CP) intended to treat oral lichen planus and (b) individuate an orodispersible dosage form suitable for its administration. IPECs were synthesized by mixing Eudragit [...] Read more.
This work aimed to investigate the feasibility to design: (a) a mucoadhesive interpolyelectrolyte complex (IPEC) loaded with clobetasol propionate (CP) intended to treat oral lichen planus and (b) individuate an orodispersible dosage form suitable for its administration. IPECs were synthesized by mixing Eudragit® E PO (EPO) and different grades of cross-linked polyacrylate derivatives, in different molar ratios, namely 1:1, 1:2, and 2:1. All IPECs resulted at nanoscale independently of their composition (120–200 nm). Both zeta-potentials (ζ) and mucoadhesive performances were influenced by the ratio between polymers. On the bases of the preliminary data, IPECs made of Polycarbophil and EPO in the 1:2 ratio were loaded with CP. The encapsulation efficiency was up 88% independently of the CP-IPEC ratio. The drug encapsulation caused IPEC destabilization in water, as it was noticed by the increase of ζ values and the formation of aggregates. Oral lyophilisates were prepared by freeze-drying slurries made of placebo or CP loaded IPECs, maltodextrin with a dextrose equivalent 38 and Span®80. The optimized formulation permitted to obtain a fast disintegration upon contact with water reducing the tendency of IPECs to aggregate. Moreover, oral lyophilisates allowed improving the apparent solubility of CP throughout the in vitro release experiment. Full article
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14 pages, 3825 KiB  
Article
Gellan Gum/Pectin Beads Are Safe and Efficient for the Targeted Colonic Delivery of Resveratrol
by Fabíola Garavello Prezotti, Fernanda Isadora Boni, Natália Noronha Ferreira, Daniella De Souza e Silva, Sérgio Paulo Campana-Filho, Andreia Almeida, Teófilo Vasconcelos, Maria Palmira Daflon Gremião, Beatriz Stringhetti Ferreira Cury and Bruno Sarmento
Polymers 2018, 10(1), 50; https://doi.org/10.3390/polym10010050 - 08 Jan 2018
Cited by 42 | Viewed by 5116
Abstract
This work addresses the establishment and characterization of gellan gum:pectin (GG:P) biodegradable mucoadhesive beads intended for the colon-targeted delivery of resveratrol (RES). The impact of the polymer carrier system on the cytotoxicity and permeability of RES was evaluated. Beads of circular shape (circularity [...] Read more.
This work addresses the establishment and characterization of gellan gum:pectin (GG:P) biodegradable mucoadhesive beads intended for the colon-targeted delivery of resveratrol (RES). The impact of the polymer carrier system on the cytotoxicity and permeability of RES was evaluated. Beads of circular shape (circularity index of 0.81) with an average diameter of 914 μm, Span index of 0.29, and RES entrapment efficiency of 76% were developed. In vitro drug release demonstrated that beads were able to reduce release rates in gastric media and control release for up to 48 h at an intestinal pH of 6.8. Weibull’s model correlated better with release data and b parameter (0.79) indicated that the release process was driven by a combination of Fickian diffusion and Case II transport, indicating that both diffusion and swelling/polymer chains relaxation are processes that contribute equally to control drug release rates. Beads and isolated polymers were observed to be safe for Caco-2 and HT29-MTX intestinal cell lines. RES encapsulation into the beads allowed for an expressive reduction of drug permeation in an in vitro triple intestinal model. This feature, associated with low RES release rates in acidic media, can favor targeted drug delivery from the beads in the colon, a promising behavior to improve the local activity of RES. Full article
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8250 KiB  
Article
Preformulation Studies of Furosemide-Loaded Electrospun Nanofibrous Systems for Buccal Administration
by Andrea Kovács, Balázs Démuth, Andrea Meskó and Romána Zelkó
Polymers 2017, 9(12), 643; https://doi.org/10.3390/polym9120643 - 25 Nov 2017
Cited by 10 | Viewed by 4588
Abstract
Furosemide loaded electrospun fibers were prepared for buccal administration, with the aim of improving the oral bioavailability of the poorly soluble and permeable crystalline drug, which can be achieved by the increased solubility and by the circumvention of the intensive first pass metabolism. [...] Read more.
Furosemide loaded electrospun fibers were prepared for buccal administration, with the aim of improving the oral bioavailability of the poorly soluble and permeable crystalline drug, which can be achieved by the increased solubility and by the circumvention of the intensive first pass metabolism. The water soluble hydroxypropyl cellulose (HPC) was chosen as a mucoadhesive polymer. In order to improve the electrospinnability of HPC, poly (vinylpyrrolidone) (PVP) was used. During the experiments, the total polymer concentration was kept constant at 15% (w/w), and only the ratio of the two polymers (HPC-PVP = 5:5, 6:4, 7:3, 8:2, 9:1) was changed. A combination of rheological measurements with scanning electron microscopic morphological images of electrospun samples was applied for the determination of the optimum composition of the gels for fiber formation. The crystalline–amorphous transition of furosemide was tracked by Fourier transform infrared spectroscopy. A correlation was found between the rheological properties of the polymer solutions and their electrospinnability, and the consequent morphology of the resultant samples. With decreasing HPC ratio of the system, a transition from the spray-dried droplets to the randomly oriented fibrous structures was observed. The results enable the determination of the polymer ratio for the formation of applicable quality of electrospun fibers. Full article
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Review

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37 pages, 9874 KiB  
Review
Chitosan and Its Derivatives for Application in Mucoadhesive Drug Delivery Systems
by Twana Mohammed M. Ways, Wing Man Lau and Vitaliy V. Khutoryanskiy
Polymers 2018, 10(3), 267; https://doi.org/10.3390/polym10030267 - 05 Mar 2018
Cited by 501 | Viewed by 23236
Abstract
Mucoadhesive drug delivery systems are desirable as they can increase the residence time of drugs at the site of absorption/action, provide sustained drug release and minimize the degradation of drugs in various body sites. Chitosan is a cationic polysaccharide that exhibits mucoadhesive properties [...] Read more.
Mucoadhesive drug delivery systems are desirable as they can increase the residence time of drugs at the site of absorption/action, provide sustained drug release and minimize the degradation of drugs in various body sites. Chitosan is a cationic polysaccharide that exhibits mucoadhesive properties and it has been widely used in the design of mucoadhesive dosage forms. However, its limited mucoadhesive strength and limited water-solubility at neutral and basic pHs are considered as two major drawbacks of its use. Chemical modification of chitosan has been exploited to tackle these two issues. In this review, we highlight the up-to-date studies involving the synthetic approaches and description of mucoadhesive properties of chitosan and chitosan derivatives. These derivatives include trimethyl chitosan, carboxymethyl chitosan, thiolated chitosan, chitosan-enzyme inhibitors, chitosan-ethylenediaminetetraacetic acid (chitosan-EDTA), half-acetylated chitosan, acrylated chitosan, glycol chitosan, chitosan-catechol, methyl pyrrolidinone-chitosan, cyclodextrin-chitosan and oleoyl-quaternised chitosan. We have particularly focused on the effect of chemical derivatization on the mucoadhesive properties of chitosan. Additionally, other important properties including water-solubility, stability, controlled release, permeation enhancing effect, and in vivo performance are also described. Full article
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16 pages, 1326 KiB  
Review
Thiolated Hyaluronic Acid as Versatile Mucoadhesive Polymer: From the Chemistry Behind to Product Developments—What Are the Capabilities?
by Janine Griesser, Gergely Hetényi and Andreas Bernkop-Schnürch
Polymers 2018, 10(3), 243; https://doi.org/10.3390/polym10030243 - 28 Feb 2018
Cited by 54 | Viewed by 11088
Abstract
Within the last decade, intensive research work has been conducted on thiolated hyaluronic acids (HA-SH). By attaching sulfhydryl ligands onto naturally occurring hyaluronic acid various types of HA-SH can be designed. Due the ability of disulfide bond formation within the polymer itself as [...] Read more.
Within the last decade, intensive research work has been conducted on thiolated hyaluronic acids (HA-SH). By attaching sulfhydryl ligands onto naturally occurring hyaluronic acid various types of HA-SH can be designed. Due the ability of disulfide bond formation within the polymer itself as well as with biological materials, certain properties such as mucoadhesive, gelling, enzyme inhibitory, permeation enhancing and release controlling properties are improved. Besides the application in the field of drug delivery, HA-SH has been investigated as auxiliary material for wound healing. Within this review, the characteristics of novel drug delivery systems based on HA-SH are summarized and the versatility of this polymer for further applications is described by introducing numerous relevant studies in this field. Full article
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