Designing Hydrogels for Controlled Drug Delivery

A special issue of Pharmaceutics (ISSN 1999-4923).

Deadline for manuscript submissions: closed (30 September 2019) | Viewed by 56248

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Guest Editor
Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Arcavacata di Rende, 87036 Cosenza, Italy
Interests: drug delivery systems (DDS); biomaterials; multifunctional carriers; micro- and nano-particles; pro-drugs
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Guest Editor
Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Arcavacata di Rende, 87036 Cosenza, Italy
Interests: drug delivery systems (DDS); biomaterials; multifunctional carriers; micro-and nano-particles; pro-drugs
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Hydrogels have received growing attention in recent years as materials for drug delivery systems (DDS), because they are biocompatible and nontoxic. They consist of three-dimensional, hydrophilic, polymeric networks capable of imbibing large quantities of water or biological fluids, due to the presence of hydrophilic groups, and releasing the drugs entrapped in them through slow diffusion. According to their features, they can be natural or synthetic and classified as neutral or ionic hydrogels, while the network can be made up of linear homopolymers, linear copolymers, and block or graft copolymers. Hydrogels can provide spatial and temporal control over the release of various therapeutic agents, including both small molecules and macromolecular drugs. They possess modulable physical properties and the capability to protect labile drugs from degradation controlling their release. This Special Issue welcomes all topics regarding recent studies on the design, preparation, and performance evaluation of hydrogels for controlled drug delivery.

Prof. Sonia Trombino
Dr. Roberta Cassano
Guest Editors

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Keywords

  • Hydrogels
  • Classification
  • Natural materials
  • Synthetic materials
  • Methods of fabrication
  • Drug delivery
  • Pharmaceutical applications

Published Papers (10 papers)

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Editorial

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3 pages, 165 KiB  
Editorial
Special Issue on Designing Hydrogels for Controlled Drug Delivery: Guest Editors’ Introduction
by Sonia Trombino and Roberta Cassano
Pharmaceutics 2020, 12(1), 57; https://doi.org/10.3390/pharmaceutics12010057 - 10 Jan 2020
Cited by 12 | Viewed by 2424
Abstract
Hydrogels have received growing attention in recent years as materials for drug delivery systems (DDS), because they are biocompatible and nontoxic [...] Full article
(This article belongs to the Special Issue Designing Hydrogels for Controlled Drug Delivery)

Research

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12 pages, 1731 KiB  
Article
Trimethyl Chitosan Hydrogel Nanoparticles for Progesterone Delivery in Neurodegenerative Disorders
by Maria Cristina Cardia, Anna Rosa Carta, Pierluigi Caboni, Anna Maria Maccioni, Sara Erbì, Laura Boi, Maria Cristina Meloni, Francesco Lai and Chiara Sinico
Pharmaceutics 2019, 11(12), 657; https://doi.org/10.3390/pharmaceutics11120657 - 06 Dec 2019
Cited by 27 | Viewed by 3180
Abstract
Progesterone is a sex hormone which shows neuroprotective effects in different neurodegenerative disorders, including Parkinson’s disease, stroke, and Alzheimer’s disease. However, the pharmacokinetic limitations associated with the peripheral administration of this molecule highlight the need for more efficient delivery approaches to increase brain [...] Read more.
Progesterone is a sex hormone which shows neuroprotective effects in different neurodegenerative disorders, including Parkinson’s disease, stroke, and Alzheimer’s disease. However, the pharmacokinetic limitations associated with the peripheral administration of this molecule highlight the need for more efficient delivery approaches to increase brain progesterone levels. Since the nose-to-brain administration of mucoadhesive hydrogel nanoparticles is a non-invasive and convenient strategy for the delivery of therapeutics to the central nervous system, in this work, progesterone-loaded hydrogel nanoparticle formulations have been prepared, characterized, and tested in vivo. Nanoparticles, loaded with different progesterone concentrations, have been obtained by polyelectrolyte complex formation between trimethyl chitosan and sodium alginate, followed by ionotropic gelation with sodium tripolyphosphate as a cross-linking agent. All formulations showed a mean diameter ranging from 200 nm to 236 nm, a polydispersity index smaller than 0.23, and a high progesterone encapsulation efficiency (83–95%). The zeta potential values were all positive and greater than 28 mV, thus ensuring nanoparticles stability against aggregation phenomena as well as interaction with negative sialic residues of the nasal mucosa. Finally, in vivo studies on Sprague–Dawley male rats demonstrated a 5-fold increase in brain progesterone concentrations compared to basal progesterone level after 30 min of hydrogel nanoparticle inhalation. Full article
(This article belongs to the Special Issue Designing Hydrogels for Controlled Drug Delivery)
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15 pages, 2188 KiB  
Article
Impact of Different Mucoadhesive Polymeric Nanoparticles Loaded in Thermosensitive Hydrogels on Transcorneal Administration of 5-Fluorouracil
by Angela Fabiano, Anna Maria Piras, Lorenzo Guazzelli, Barbara Storti, Ranieri Bizzarri and Ylenia Zambito
Pharmaceutics 2019, 11(12), 623; https://doi.org/10.3390/pharmaceutics11120623 - 21 Nov 2019
Cited by 26 | Viewed by 2636
Abstract
In a previous paper a thermosensitive hydrogel formulation based on chitosan or its derivatives (TSOH), containing medicated chitosan nanoparticles (Ch NP) for transcorneal administration of 5-fluorouracil (5-FU) was described. The Ch NP-containing TSOH allowed a time-constant 5-FU concentration in the aqueous for 7 [...] Read more.
In a previous paper a thermosensitive hydrogel formulation based on chitosan or its derivatives (TSOH), containing medicated chitosan nanoparticles (Ch NP) for transcorneal administration of 5-fluorouracil (5-FU) was described. The Ch NP-containing TSOH allowed a time-constant 5-FU concentration in the aqueous for 7 h from instillation. The aim of the present work was to study the impact of the surface characteristics of new NP contained in TSOH on ocular 5-FU bioavailability. The Ch derivatives used to prepare NP were quaternary ammonium-Ch conjugate (QA-Ch), S-protected derivative thereof (QA-Ch-S-pro), and a sulphobutyl chitosan derivative (SB-Ch). All NP types had 300–400 nm size, 16–18% encapsulation efficiency, and retained the entrapped drug for at least 15 h. Drug release from TSOH containing NP based on QA-Ch or QA-Ch-S-pro was virtually equal, whereas with TSOH containing NP based on SB-Ch was significantly slower. Instillation, in rabbit eyes, of NP-containing TSOH based on QA-Ch or SB-Ch led to a plateau in the aqueous concentration vs. time plot in the 1–10 h range with significantly enhanced area under curve (AUC). Negative charges on the NP surface slowed down 5-FU release from TSOH while positive charges increased NP contact with the negatively charged ocular surface. Either results in enhanced ocular bioavailability. Full article
(This article belongs to the Special Issue Designing Hydrogels for Controlled Drug Delivery)
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15 pages, 3639 KiB  
Article
Development of Functionalized Carbon Nano-Onions Reinforced Zein Protein Hydrogel Interfaces for Controlled Drug Release
by Narsimha Mamidi, Aldo González-Ortiz, Irasema Lopez Romo and Enrique V. Barrera
Pharmaceutics 2019, 11(12), 621; https://doi.org/10.3390/pharmaceutics11120621 - 20 Nov 2019
Cited by 49 | Viewed by 3948
Abstract
In the current study, poly 4-mercaptophenyl methacrylate-carbon nano-onions (PMPMA-CNOs = f-CNOs) reinforced natural protein (zein) composites (zein/f-CNOs) are fabricated using the acoustic cavitation technique. The influence of f-CNOs inclusion on the microstructural properties, morphology, mechanical, cytocompatibility, in-vitro degradation, and swelling behavior of the [...] Read more.
In the current study, poly 4-mercaptophenyl methacrylate-carbon nano-onions (PMPMA-CNOs = f-CNOs) reinforced natural protein (zein) composites (zein/f-CNOs) are fabricated using the acoustic cavitation technique. The influence of f-CNOs inclusion on the microstructural properties, morphology, mechanical, cytocompatibility, in-vitro degradation, and swelling behavior of the hydrogels are studied. The tensile results showed that zein/f-CNOs hydrogels fabricated by the acoustic cavitation system exhibited good tensile strength (90.18 MPa), compared with the hydrogels fabricated by the traditional method and only microwave radiation method. It reveals the magnitude of physisorption and degree of colloidal stability of f-CNOs within the zein matrix under acoustic cavitation conditions. The swelling behaviors of hydrogels were also tested and improved results were noticed. The cytotoxicity of hydrogels was tested with osteoblast cells. The results showed good cell viability and cell growth. To explore the efficacy of hydrogels as drug transporters, 5-fluorouracil (5-FU) release was measured under gastric and intestinal pH environment. The results showed pH-responsive sustained drug release over 15 days of study, and pH 7.4 showed a more rapid drug release than pH 2.0 and 4.5. Nonetheless, all the results suggest that zein/f-CNOs hydrogel could be a potential pH-responsive drug transporter for a colon-selective delivery system. Full article
(This article belongs to the Special Issue Designing Hydrogels for Controlled Drug Delivery)
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13 pages, 2026 KiB  
Article
Carbamazepine Gel Formulation as a Sustained Release Epilepsy Medication for Pediatric Use
by Saeid Mezail Mawazi, Sinan Mohammed Abdullah Al-Mahmood, Bappaditya Chatterjee, Hazrina AB. Hadi and Abd Almonem Doolaanea
Pharmaceutics 2019, 11(10), 488; https://doi.org/10.3390/pharmaceutics11100488 - 20 Sep 2019
Cited by 21 | Viewed by 4510
Abstract
This study aimed to develop a carbamazepine (CBZ) sustained release formulation suitable for pediatric use with a lower risk of precipitation. The CBZ was first prepared as sustained release microparticles, and then the microparticles were embedded in alginate beads, and finally, the beads [...] Read more.
This study aimed to develop a carbamazepine (CBZ) sustained release formulation suitable for pediatric use with a lower risk of precipitation. The CBZ was first prepared as sustained release microparticles, and then the microparticles were embedded in alginate beads, and finally, the beads were suspended in a gel vehicle. The microparticles were prepared by a solvent evaporation method utilizing ethyl cellulose as a sustained release polymer and were evaluated for particle size, encapsulation efficiency, and release profile. The beads were fabricated by the dropwise addition of sodium alginate in calcium chloride solution and characterized for size, shape, and release properties. The gel was prepared using iota carrageenan as the gelling agent and evaluated for appearance, syneresis, drug content uniformity, rheology, release profile, and stability. The microparticles exhibited a particle size of 135.01 ± 0.61 µm with a monodisperse distribution and an encapsulation efficiency of 83.89 ± 3.98%. The beads were monodispersed with an average size of 1.4 ± 0.05 mm and a sphericity factor of less than 0.05. The gel was prepared using a 1:1 ratio (gel vehicle to beads) and exhibited no syneresis, good homogeneity, and good shear-thinning properties. The release profile from the beads and from the gel was not significantly affected, maintaining similarity to the tablet form. The gel properties were maintained for one month real time stability, but the accelerated stability showed reduced viscosity and pH with time. In conclusion, CBZ in a gel sustained release dosage form combines the advantages of the suspension form in terms of dosing flexibility, and the advantages of the tablet form in regards to the sustained release profile. This dosage form should be further investigated in vivo in animal models before being considered in clinical trials. Full article
(This article belongs to the Special Issue Designing Hydrogels for Controlled Drug Delivery)
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12 pages, 6969 KiB  
Article
A Mixed Thermosensitive Hydrogel System for Sustained Delivery of Tacrolimus for Immunosuppressive Therapy
by Hsiu-Chao Lin, Madonna Rica Anggelia, Chih-Chi Cheng, Kuan-Lin Ku, Hui-Yun Cheng, Chih-Jen Wen, Aline Yen Ling Wang, Cheng-Hung Lin and I-Ming Chu
Pharmaceutics 2019, 11(8), 413; https://doi.org/10.3390/pharmaceutics11080413 - 14 Aug 2019
Cited by 19 | Viewed by 3765
Abstract
Tacrolimus is an immunosuppressive agent for acute rejection after allotransplantation. However, the low aqueous solubility of tacrolimus poses difficulties in formulating an injection dosage. Polypeptide thermosensitive hydrogels can maintain a sustained release depot to deliver tacrolimus. The copolymers, which consist of poloxamer and [...] Read more.
Tacrolimus is an immunosuppressive agent for acute rejection after allotransplantation. However, the low aqueous solubility of tacrolimus poses difficulties in formulating an injection dosage. Polypeptide thermosensitive hydrogels can maintain a sustained release depot to deliver tacrolimus. The copolymers, which consist of poloxamer and poly(l-alanine) with l-lysine segments at both ends (P–Lys–Ala–PLX), are able to carry tacrolimus in an in situ gelled form with acceptable biocompatibility, biodegradability, and low gelling concentrations from 3 to 7 wt %. By adding Pluronic F-127 to formulate a mixed hydrogel system, the drug release rate can be adjusted to maintain suitable drug levels in animals with transplants. Under this formulation, the in vitro release of tacrolimus was stable for more than 100 days, while in vivo release of tacrolimus in mouse model showed that rejection from skin allotransplantation was prevented for at least three weeks with one single administration. Using these mixed hydrogel systems for sustaining delivery of tacrolimus demonstrates advancement in immunosuppressive therapy. Full article
(This article belongs to the Special Issue Designing Hydrogels for Controlled Drug Delivery)
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21 pages, 3678 KiB  
Article
Preparation and Characterization of Oxidized Inulin Hydrogel for Controlled Drug Delivery
by Franklin Afinjuomo, Paris Fouladian, Ankit Parikh, Thomas G. Barclay, Yunmei Song and Sanjay Garg
Pharmaceutics 2019, 11(7), 356; https://doi.org/10.3390/pharmaceutics11070356 - 22 Jul 2019
Cited by 35 | Viewed by 5314
Abstract
Inulin-based hydrogels are useful carriers for the delivery of drugs in the colon-targeted system and in other biomedical applications. In this project, inulin hydrogels were fabricated by crosslinking oxidized inulin with adipic acid dihydrazide (AAD) without the use of a catalyst or initiator. [...] Read more.
Inulin-based hydrogels are useful carriers for the delivery of drugs in the colon-targeted system and in other biomedical applications. In this project, inulin hydrogels were fabricated by crosslinking oxidized inulin with adipic acid dihydrazide (AAD) without the use of a catalyst or initiator. The physicochemical properties of the obtained hydrogels were further characterized using different techniques, such as swelling experiments, in vitro drug release, degradation, and biocompatibility tests. The crosslinking was confirmed with Fourier transform infrared spectroscopy (FTIR), thermal gravimetric analysis (TGA), and differential scanning calorimetry (DSC). In vitro releases of 5-fluorouracil (5FU) from the various inulin hydrogels was enhanced in acidic conditions (pH 5) compared with physiological pH (pH 7.4). In addition, blank gels did not show any appreciable cytotoxicity, whereas 5FU-loaded hydrogels demonstrated efficacy against HCT116 colon cancer cells, which further confirms the potential use of these delivery platforms for direct targeting of 5-FU to the colon. Full article
(This article belongs to the Special Issue Designing Hydrogels for Controlled Drug Delivery)
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12 pages, 2313 KiB  
Article
Effect of a Cationic Surfactant on Microemulsion Globules and Drug Release from Hydrogel Contact Lenses
by Cesar Torres-Luna, Naiping Hu, Abdollah Koolivand, Xin Fan, Yuli Zhu, Roman Domszy, Jeff Yang, Arthur Yang and Nam Sun Wang
Pharmaceutics 2019, 11(6), 262; https://doi.org/10.3390/pharmaceutics11060262 - 06 Jun 2019
Cited by 26 | Viewed by 4179
Abstract
The present study evaluates the in vitro release of diclofenac sodium (DFNa) from contact lenses based on poly-2-hydroxyethyl methacrylate (pHEMA) hydrogels containing an embedded microemulsion to extend release duration. The oil (ethyl butyrate)-in-water microemulsion systems are prepared with two non-ionic surfactants, Brij 97 [...] Read more.
The present study evaluates the in vitro release of diclofenac sodium (DFNa) from contact lenses based on poly-2-hydroxyethyl methacrylate (pHEMA) hydrogels containing an embedded microemulsion to extend release duration. The oil (ethyl butyrate)-in-water microemulsion systems are prepared with two non-ionic surfactants, Brij 97 or Tween 80, together with a long-alkyl chain cationic surfactant, cetalkonium chloride (CKC). Without CKC, Brij 97 or Tween 80-based microemulsions showed average droplet sizes of 12 nm and 18 nm, respectively. The addition of CKC decreased the average droplet sizes to 2–5 nm for both non-ionic surfactants. Such significant reduction in the average droplet size corresponds to an increase in the DFNa release duration as revealed by the in vitro experiments. Contact lens characterization showed that important properties such as optical transparency and water content of Brij 97-based contact lenses with cationic microemulsions was excellent. However, the optical transparency of the corresponding Tween 80 based contact lenses was unsatisfactory. The results indicate that cationic microemulsion-laden contact lenses can benefit from combinatory effects of microemulsions and cationic surfactant at low CKC weight percentage, e.g., with the release of 70% of the drug in 45, 10, and 7 h for B97-CKC-0.45%, CKC-0.45%, and control lenses, respectively. However, the microemulsion effect on extending DFNa release became negligible at the highest CKC weight percentage (1.8%). Full article
(This article belongs to the Special Issue Designing Hydrogels for Controlled Drug Delivery)
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Review

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17 pages, 1727 KiB  
Review
Poloxamer Hydrogels for Biomedical Applications
by Eleonora Russo and Carla Villa
Pharmaceutics 2019, 11(12), 671; https://doi.org/10.3390/pharmaceutics11120671 - 10 Dec 2019
Cited by 227 | Viewed by 12896
Abstract
This review article focuses on thermoresponsive hydrogels consisting of poloxamers which are of high interest for biomedical application especially in drug delivery for ophthalmic, injectable, transdermal, and vaginal administration. These hydrogels remain fluid at room temperature but become more viscous gel once they [...] Read more.
This review article focuses on thermoresponsive hydrogels consisting of poloxamers which are of high interest for biomedical application especially in drug delivery for ophthalmic, injectable, transdermal, and vaginal administration. These hydrogels remain fluid at room temperature but become more viscous gel once they are exposed to body temperature. In this way, the gelling system remains at the topical level for a long time and the drug release is controlled and prolonged. Poloxamers are synthetic triblock copolymers of poly(ethylene oxide)-b-poly(propylene oxide)-b-poly(ethylene oxide) (PEO-PPO-PEO), also commercially known as Pluronics®, Synperonics® or Lutrol®. The different poloxamers cover a range of liquids, pastes, and solids, with molecular weights and ethylene oxide–propylene oxide weight ratios varying from 1100 to 14,000 and 1:9 to 8:2, respectively. Concentrated aqueous solutions of poloxamers form thermoreversible gels. In recent years this type of gel has arouse interest for tissue engineering. Finally, the use of poloxamers as biosurfactants is evaluated since they are able to form micelles in an aqueous environment above a concentration threshold known as critical micelle concentration (CMC). This property is exploited for drug delivery and different therapeutic applications. Full article
(This article belongs to the Special Issue Designing Hydrogels for Controlled Drug Delivery)
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17 pages, 3903 KiB  
Review
Strategies for Hyaluronic Acid-Based Hydrogel Design in Drug Delivery
by Sonia Trombino, Camilla Servidio, Federica Curcio and Roberta Cassano
Pharmaceutics 2019, 11(8), 407; https://doi.org/10.3390/pharmaceutics11080407 - 12 Aug 2019
Cited by 174 | Viewed by 12265
Abstract
Hyaluronic acid (HA) is a natural, linear, endogenous polysaccharide that plays important physiological and biological roles in the human body. Nowadays, among biopolymers, HA is emerging as an appealing starting material for hydrogels design due to its biocompatibility, native biofunctionality, biodegradability, non-immunogenicity, and [...] Read more.
Hyaluronic acid (HA) is a natural, linear, endogenous polysaccharide that plays important physiological and biological roles in the human body. Nowadays, among biopolymers, HA is emerging as an appealing starting material for hydrogels design due to its biocompatibility, native biofunctionality, biodegradability, non-immunogenicity, and versatility. Since HA is not able to form gels alone, chemical modifications, covalent crosslinking, and gelling agents are always needed in order to obtain HA-based hydrogels. Therefore, in the last decade, different strategies for the design of physical and chemical HA hydrogels have been developed, such as click chemistry reactions, enzymatic and disulfide crosslinking, supramolecular assembly via inclusion complexation, and so on. HA-based hydrogels turn out to be versatile platforms, ranging from static to smart and stimuli-responsive systems, and for these reasons, they are widely investigated for biomedical applications like drug delivery, tissue engineering, regenerative medicine, cell therapy, and diagnostics. Furthermore, the overexpression of HA receptors on various tumor cells makes these platforms promising drug delivery systems for targeted cancer therapy. The aim of the present review is to highlight and discuss recent advances made in the last years on the design of chemical and physical HA-based hydrogels and their application for biomedical purposes, in particular, drug delivery. Notable attention is given to HA hydrogel-based drug delivery systems for targeted therapy of cancer and osteoarthritis. Full article
(This article belongs to the Special Issue Designing Hydrogels for Controlled Drug Delivery)
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