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27 pages, 3978 KiB

Open AccessArticle

Combination of Nanomicellar Technology and In Situ Gelling Polymer as Ocular Drug Delivery System (ODDS) for Cyclosporine-A

by Eleonora Terreni, Erica Zucchetti, Silvia Tampucci, Susi Burgalassi, Daniela Monti and Patrizia Chetoni

Pharmaceutics 2021, 13(2), 192; https://doi.org/10.3390/pharmaceutics13020192 - 01 Feb 2021

Cited by 17 | Viewed by 3382

Abstract

A combination of in situ gelling systems and a loaded drug self-assembling nanomicellar carrier was chosen in this study as a new potential Ocular Drug Delivery System (ODDS) for Cyclosporine-A (CyA), a poorly water-soluble drug. Two non-ionic surfactants (d-α-tocopherol polyethylene glycol succinate, VitE-TPGS [...] Read more.

A combination of in situ gelling systems and a loaded drug self-assembling nanomicellar carrier was chosen in this study as a new potential Ocular Drug Delivery System (ODDS) for Cyclosporine-A (CyA), a poorly water-soluble drug. Two non-ionic surfactants (d-α-tocopherol polyethylene glycol succinate, VitE-TPGS and polyoxyl 40 hydrogenated castor oil, RH-40) were used to produce the nanomicelles. The physical–chemical characterization of the nanomicelles in terms of CyA entrapment (EE%) and loading efficiency (LE%), cloud point (CP), regeneration time (RT), size and polydispersity index (PI) allowed us to select the best combination of surfactant mixture, which showed appropriate stability, high CyA-EE (99.07%), very small and homogeneous dimensions and favored the solubilization of an amount of CyA (0.144% w/w) comparable to that contained in marketed emulsion Ikervis^®. The selected nanomicellar formulation incorporated into optimized ion-sensitive polymeric dispersions of gellan gum (GG-LA: 0.10, 0.15 and 0.20% w/w) able to trigger the sol–gel transition after instillation was characterized from technological (osmolality, pH, gelling capacity, rheological behavior, wettability, TEM and storage stability at 4 and 20 °C) and biopharmaceutical points of view. This new combined approach allowed us to obtain clear aqueous dispersions that were easy to instill and able to form a viscous gel when in contact with the tear fluid, improving CyA ocular bioavailability. Furthermore, this new ODDS prevented CyA transcorneal permeation, exhibited low cytotoxicity and prolonged the CyA resident time in the precorneal area compared to Ikervis^®. Full article

(This article belongs to the Special Issue Gels and in Situ Gelling Formulations for Drug Delivery)

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15 pages, 2852 KiB

Open AccessArticle

DoE-Assisted Development of a Novel Glycosaminoglycan-Based Injectable Formulation for Viscosupplementation

by Marta Cicognani, Silvia Rossi, Gabriele Vecchi, Andrea Maria Giori and Franca Ferrari

Pharmaceutics 2020, 12(7), 681; https://doi.org/10.3390/pharmaceutics12070681 - 20 Jul 2020

Cited by 2 | Viewed by 2798

Abstract

The aim of the present work was the development of a novel glycosaminoglycan (GAG)-based injectable formulation intended for intra-articular administration that should best mimic the healthy synovial fluid. Hyaluronic acid (HA) was chosen among GAG polymers, since it is the most abundant component [...] Read more.

The aim of the present work was the development of a novel glycosaminoglycan (GAG)-based injectable formulation intended for intra-articular administration that should best mimic the healthy synovial fluid. Hyaluronic acid (HA) was chosen among GAG polymers, since it is the most abundant component of the synovial fluid. A DoE (Design of Experiment) approach was used for the development of a formulation containing two HA (very high (VHMW) and low (LMW) molecular weight) grades. The rationale for this choice is that so far, no commercial product based on a single HA grade or even on binary HA mixture possesses optimal viscoelastic properties in comparison with healthy synovial fluid. A full factorial design was chosen to investigate the influence of concentration and relative fraction of the two polymer grades (retained as factors of the model) on formulation functional (viscosity and viscoelastic) properties, which are considered response variables. Thanks to the DoE approach, the composition of the optimized HA formulation was found. The addition to such formulation of an injectable grade fat-free soy phospholipid, which was rich in phosphatidylcholine (PC), resulted in improved lubrication properties. The final HA + PC formulation, packaged in pre-filled sterile syringes, was stable in long-term and accelerated ICH (International Council for Harmonisation) storage conditions. The overall results pointed out the formulation suitability for further steps of pharmaceutical developments, namely for the passage to pilot scale. Full article

(This article belongs to the Special Issue Gels and in Situ Gelling Formulations for Drug Delivery)

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19 pages, 3732 KiB

Open AccessArticle

Dual Network Hydrogels Incorporated with Bone Morphogenic Protein-7-Loaded Hyaluronic Acid Complex Nanoparticles for Inducing Chondrogenic Differentiation of Synovium-Derived Mesenchymal Stem Cells

by Qing Min, Jiaoyan Liu, Yuchen Zhang, Bin Yang, Ying Wan and Jiliang Wu

Pharmaceutics 2020, 12(7), 613; https://doi.org/10.3390/pharmaceutics12070613 - 30 Jun 2020

Cited by 11 | Viewed by 2344

Abstract

Alginate-poloxamer (ALG-POL) copolymer with optimal POL content was synthesized, and it was combined with silk fibroin (SF) for building ALG-POL/SF dual network hydrogels. Hyaluronic acid(HA)/chitosan-poly(dioxanone)(CH-PDO) complex nanoparticles (NPs) with optimized composition and high encapsulation efficiency were employed as a vehicle for loading bone [...] Read more.

Alginate-poloxamer (ALG-POL) copolymer with optimal POL content was synthesized, and it was combined with silk fibroin (SF) for building ALG-POL/SF dual network hydrogels. Hyaluronic acid(HA)/chitosan-poly(dioxanone)(CH-PDO) complex nanoparticles (NPs) with optimized composition and high encapsulation efficiency were employed as a vehicle for loading bone morphogenic protein-7 (BMP-7). BMP-7-loaded HA/CH-PDO NPs were incorporated into ALG-POL/SF hydrogel for constructing composite gels to achieve controlled release of BMP-7. These gels showed thermosensitive sol-gel transitions near physiological temperature and pH; and they were tested to be elastic, tough and strong. Some gels exhibited abilities to administer the BMP-7 release in nearly linear manners for a few weeks. Synovium-derived mesenchymal stem cells (SMSCs) were seeded into optimally fabricated gels for assessing their chondrogenic differentiation potency. Real-time PCR analyses showed that the blank ALG-POL/SF gels were not able to induce the chondrogenic differentiation of SMSCs, whereas SMSCs were detected to significantly express cartilage-related genes once they were seeded in the BMP-7-loaded ALG-POL/SF gel for two weeks. The synthesis of cartilaginous matrix components further confirmed that SMSCs seeded in the BMP-7-loaded ALG-POL/SF gel differentiated toward chondrogenesis. Results suggest that BMP-7-loaded ALG-POL/SF composite gels can function as a promising biomaterial for cartilage tissue engineering applications. Full article

(This article belongs to the Special Issue Gels and in Situ Gelling Formulations for Drug Delivery)

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32 pages, 4354 KiB

Open AccessArticle

Fabrication of Transgelosomes for Enhancing the Ocular Delivery of Acetazolamide: Statistical Optimization, In Vitro Characterization, and In Vivo Study

by Eman A. Mazyed and Abdelaziz E. Abdelaziz

Pharmaceutics 2020, 12(5), 465; https://doi.org/10.3390/pharmaceutics12050465 - 20 May 2020

Cited by 34 | Viewed by 3563

Abstract

Acetazolamide (ACZ) is a potent carbonic anhydrase inhibitor that is used for the treatment of glaucoma. Its oral administration causes various undesirable side effects. This study aimed to formulate transgelosomes (TGS) for enhancing the ocular delivery of ACZ. ACZ-loaded transfersomes were formulated by [...] Read more.

Acetazolamide (ACZ) is a potent carbonic anhydrase inhibitor that is used for the treatment of glaucoma. Its oral administration causes various undesirable side effects. This study aimed to formulate transgelosomes (TGS) for enhancing the ocular delivery of ACZ. ACZ-loaded transfersomes were formulated by the ethanol injection method, using phosphatidylcholine (PC) and different edge activators, including Tween 80, Span 60, and Cremophor RH 40. The effects of the ratio of lipid to surfactant and type of surfactant on % drug released after 8 h (Q_8h) and entrapment efficiency (EE%) were investigated by using Design-Expert software. The optimized formula was formulated as TGS, using poloxamers as gelling agents. In vitro and in vivo characterization of ACZ-loaded TGS was performed. According to optimization study, F8 had the highest desirability value and was chosen as the optimized formula for preparing TGS. F8 appeared as spherical elastic nanovesicles with Q_8h of 93.01 ± 3.76% and EE% of 84.44 ± 2.82. Compared to a free drug, TGS exhibited more prolonged drug release of 71.28 ± 0.46% after 8 h, higher ex vivo permeation of 66.82 ± 1.11% after 8 h and a significant lowering of intraocular pressure (IOP) for 24 h. Therefore, TGS provided a promising technique for improving the corneal delivery of ACZ. Full article

(This article belongs to the Special Issue Gels and in Situ Gelling Formulations for Drug Delivery)

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18 pages, 1782 KiB

Open AccessArticle

An In Situ Gelling System for the Local Treatment of Inflammatory Bowel Disease (IBD). The Loading of Maqui (Aristotelia chilensis) Berry Extract as an Antioxidant and Anti-Inflammatory Agent

by Marika Tenci, Silvia Rossi, Valentina Giannino, Barbara Vigani, Giuseppina Sandri, Maria Cristina Bonferoni, Maria Daglia, Luigi Maria Longo, Cristina Macelloni and Franca Ferrari

Pharmaceutics 2019, 11(11), 611; https://doi.org/10.3390/pharmaceutics11110611 - 14 Nov 2019

Cited by 16 | Viewed by 3511

Abstract

The aim of the present work was the development of an innovative in situ gelling system, to be applied on the mucosa of the distal colon via rectal route. The system consisted of three polymers having different functions: gellan (GG), able to jellify [...] Read more.

The aim of the present work was the development of an innovative in situ gelling system, to be applied on the mucosa of the distal colon via rectal route. The system consisted of three polymers having different functions: gellan (GG), able to jellify in presence of ions; methylcellulose (MC), a thermosensitive polymer with a gelation temperature close to 50 °C; and hydroxypropylcellulose (HPC), a mucoadhesive polymer. The three polymers were able to act synergistically, increasing the permanence of the vehicle on the mucosa and forming a protective gel layer. A DoE approach, “simplex centroid mixture design,” was used to identify the optimal quantitative composition of the vehicle. The response variables considered were: vehicle viscosity at room temperature; increase in vehicle viscosity on increasing temperature (from room to physiological value) and upon dilution with simulated colonic fluid (SCF); and viscoelastic behavior, thixotropic area, and mucoadhesion properties of the gel formed at 37 °C upon dilution in SCF. The optimized vehicle was loaded with maqui berry extract (MBE), known for its antioxidant and anti-inflammatory properties. MBE loading (0.5% w/w) into the vehicle improved rheological and mucoadhesive properties of the formulation. Both MBE and the optimized vehicle were not cytotoxic towards human fibroblasts and Caco-2 cells. Moreover, the optimized vehicle did not affect MBE antioxidant properties. Full article

(This article belongs to the Special Issue Gels and in Situ Gelling Formulations for Drug Delivery)

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17 pages, 3907 KiB

Open AccessArticle

Enhanced Treatment Effects of Tilmicosin Against Staphylococcus aureus Cow Mastitis by Self-Assembly Sodium Alginate-Chitosan Nanogel

by Kaixiang Zhou, Xiaofang Wang, Dongmei Chen, Yuanyuan Yuan, Shuge Wang, Chao Li, Yuanyuan Yan, Qianying Liu, Liwei Shao, Lingli Huang, Zonghui Yuan and Shuyu Xie

Pharmaceutics 2019, 11(10), 524; https://doi.org/10.3390/pharmaceutics11100524 - 12 Oct 2019

Cited by 36 | Viewed by 4882

Abstract

The Staphylococcus aureus (S. aureus) cow mastitis causes great losses to the cow industry. In order to improve the treatment effect of tilmicosin against cow mastitis, the combination of solid lipid nanoparticle (SLN) technology with in situ hydrogel technology was used [...] Read more.

The Staphylococcus aureus (S. aureus) cow mastitis causes great losses to the cow industry. In order to improve the treatment effect of tilmicosin against cow mastitis, the combination of solid lipid nanoparticle (SLN) technology with in situ hydrogel technology was used to prepare the self-assembly tilmicosin nanogel (TIL-nanogel). The physicochemical characteristics, in vitro release, antibacterial activity and in vivo treatment efficacy of TIL-SLNs and TIL-nanogel were studied, respectively. The results showed the loading capacity (LC), encapsulation efficiency (EE), size, zeta potential and poly dispersion index (PDI) of TIL-nanogel were 23.33 ± 0.77%, 67.89 ± 3.01%, 431.57 ± 12.87 nm, 8.3 ± 0.06 mv and, 0.424 ± 0.032, respectively. The TIL-nanogel showed stronger sustained release in vitro than TIL-SLNs and commercial injection. The cure rate of half dosage and normal dosage of TIL-nanogel was 58.3% and 75.0%, which was higher than that of commercial injection (50.0%) at normal dosage. The results suggest that the treatment dosage of tilmicosin for cow mastitis could be reduced by TIL-nanogel. The novel TIL-nanogel will be beneficial by decreasing the usage of tilmicosin and the treatment costs of cow mastitis. Full article

(This article belongs to the Special Issue Gels and in Situ Gelling Formulations for Drug Delivery)

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17 pages, 2305 KiB

Open AccessArticle

Development of a Mucoadhesive In Situ Gelling Formulation for the Delivery of Lactobacillus gasseri into Vaginal Cavity

by Barbara Vigani, Angela Faccendini, Silvia Rossi, Giuseppina Sandri, Maria Cristina Bonferoni, Pietro Grisoli and Franca Ferrari

Pharmaceutics 2019, 11(10), 511; https://doi.org/10.3390/pharmaceutics11100511 - 03 Oct 2019

Cited by 26 | Viewed by 3422

Abstract

Local administration of vaginal probiotics, especially lactobacilli, has been recently proposed as an effective prevention strategy against candidosis recurrences, which affect 40–50% of women. In this context, the aim of the present work was the development of a mucoadhesive in situ gelling formulation [...] Read more.

Local administration of vaginal probiotics, especially lactobacilli, has been recently proposed as an effective prevention strategy against candidosis recurrences, which affect 40–50% of women. In this context, the aim of the present work was the development of a mucoadhesive in situ gelling formulation for the vaginal administration of Lactobacillus gasseri. Mixtures of poloxamer 407 (P407) and methylcellulose (MC), two thermosensitive polymers, were prepared and subjected to rheological analyses for the assessment of their sol/gel transition temperature. The association of P407 (15% w/w) with MC (1.5% w/w) produced an increase in gelation extent at 37 °C even after dilution in simulated vaginal fluid (SVF). The presence of 0.5% w/w pectin (PEC) produced a reduction of vehicle pH and viscosity at 25 °C that is the vehicle resistance to flow during administration. The presence of a low concentration of xyloglucan (XYL) (0.25% w/w) increases the mucoadhesive properties and the capability to gelify at 37 °C of the formulation after dilution with SVF. A three-component (P407/MC/PEC; 3cM) and a four-component (P407/MC/PEC/XYL; 4cM) mixture were selected as promising candidates for the delivery of L. gasseri to the vaginal cavity. They were able to preserve L. gasseri viability and were cytocompatible towards the HeLa cell line. Full article

(This article belongs to the Special Issue Gels and in Situ Gelling Formulations for Drug Delivery)

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Review

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29 pages, 2298 KiB

Open AccessReview

Recent Advances in the Development of In Situ Gelling Drug Delivery Systems for Non-Parenteral Administration Routes

by Barbara Vigani, Silvia Rossi, Giuseppina Sandri, Maria Cristina Bonferoni, Carla M. Caramella and Franca Ferrari

Pharmaceutics 2020, 12(9), 859; https://doi.org/10.3390/pharmaceutics12090859 - 10 Sep 2020

Cited by 87 | Viewed by 7585

Abstract

In situ gelling drug delivery systems have gained enormous attention over the last decade. They are in a sol-state before administration, and they are capable of forming gels in response to different endogenous stimuli, such as temperature increase, pH change and the presence [...] Read more.

In situ gelling drug delivery systems have gained enormous attention over the last decade. They are in a sol-state before administration, and they are capable of forming gels in response to different endogenous stimuli, such as temperature increase, pH change and the presence of ions. Such systems can be administered through different routes, to achieve local or systemic drug delivery and can also be successfully used as vehicles for drug-loaded nano- and microparticles. Natural, synthetic and/or semi-synthetic polymers with in situ gelling behavior can be used alone, or in combination, for the preparation of such systems; the association with mucoadhesive polymers is highly desirable in order to further prolong the residence time at the site of action/absorption. In situ gelling systems include also solid polymeric formulations, generally obtained by freeze-drying, which, after contact with biological fluids, undergo a fast hydration with the formation of a gel able to release the drug loaded in a controlled manner. This review provides an overview of the in situ gelling drug delivery systems developed in the last 10 years for non-parenteral administration routes, such as ocular, nasal, buccal, gastrointestinal, vaginal and intravesical ones, with a special focus on formulation composition, polymer gelation mechanism and in vitro release studies. Full article

(This article belongs to the Special Issue Gels and in Situ Gelling Formulations for Drug Delivery)

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