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Cyclodextrins in Drug Formulation and Delivery

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

Deadline for manuscript submissions: closed (20 October 2018) | Viewed by 62833

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Dr. Francesca Maestrelli

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Department of Chemistry, University of Florence, Via Schiff 6, Sesto Fiorentino, 50019 Florence, Italy
Interests: cyclodextrins; drug delivery systems; drug-in-cyclodextrins-in-colloidal systems; microparticulate systems
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Dr. Marzia Cirri

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Department of Chemistry, University of Florence, Via Schiff 6, Sesto Fiorentino, 50019 Florence, Italy
Interests: cyclodextrins; drug delivery systems; drug-in-cyclodextrin-in-nanolipid carriers; oral administration; pediatric formulations; topical delivery
Special Issues, Collections and Topics in MDPI journals

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Dear Colleagues,

Cyclodextrins (CDs) are cyclic oligosaccharides which are able to form inclusion complexes with a variety of hydrophobic guest molecules, and are mainly utilized in the pharmaceutical field to enhance the water solubility and dissolution rate of poorly-soluble drugs, to mask unpleasant taste or odor, improve the stability of the included host molecules from hydrolysis or enzymatic degradation in the gastric environment, and reduce local drug irritation phenomena. Vice versa, hydrophobic cyclodextrins could represent suitable carriers for obtaining slow-dissolving profiles of soluble drugs. The addition of small amounts of some hydrophilic polymers and the application of different solid dispersion preparation methods can significantly increase the CD solubilising and complexing abilities through the formation of ternary drug–CD–hydrophilic polymer complexes.

Cyclodextrins can be successfully applied to improve drug entrapment and drug release and permeation properties from several kinds of conventional or less-conventional drug delivery systems, thus simultaneously exploiting both cyclodextrin complexation and drug delivery systems properties.

Prof. Francesca Maestrelli
Dr. Marzia Cirri
Guest Editors

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Keywords

cyclodextrins complexation
cyclodextrins in solid dispersions
drug-in-cyclodextrins-in-colloidal systems
drug-in cyclodextrin-in nanolipid carriers
improved stability
enhanced bioavailability
sustained release

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Published Papers (9 papers)

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Research

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17 pages, 3044 KB

Open AccessArticle

In Vitro Enhanced Skin Permeation and Retention of Imiquimod Loaded in β-Cyclodextrin Nanosponge Hydrogel

by Monica Argenziano, Adam Haimhoffer, Chiara Bastiancich, László Jicsinszky, Fabrizio Caldera, Francesco Trotta, Sara Scutera, Daniela Alotto, Mara Fumagalli, Tiziana Musso, Carlotta Castagnoli and Roberta Cavalli

Pharmaceutics 2019, 11(3), 138; https://doi.org/10.3390/pharmaceutics11030138 - 20 Mar 2019

Cited by 75 | Viewed by 6746

Abstract

Imiquimod (IMQ) is an immune response modifier clinically used for the treatment of various topical diseases. However, its poor aqueous solubility and skin penetration capability make the topical delivery of IMQ a challenging task. This work aims at developing a nanomedicine-based topical formulation, carrying IMQ to control the scarring process for the treatment of aberrant wounds. For this purpose, IMQ was loaded in β-cyclodextrin-based nanosponges and dispersed in a hydrogel suitable for dermal application. The formulation was characterized in vitro and compared with IMQ inclusion complexes, with (2-hydroxy)propyl β-cyclodextrin(HPβCD) and carboxymethyl β-cyclodextrin (CMβCD) showing enhanced penetration properties. The hydrogel containing IMQ-loaded nanosponges could act as a drug reservoir and guarantee the sustained release of IMQ through the skin. A greater inhibitory effect on fibroblast proliferation was observed for IMQ loaded in nanosponges compared to the other formulations. Full article

(This article belongs to the Special Issue Cyclodextrins in Drug Formulation and Delivery)

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17 pages, 1687 KB

Open AccessArticle

Combined Approach of Cyclodextrin Complexationand Nanostructured Lipid Carriers for the Development of a Pediatric Liquid Oral Dosage Form of Hydrochlorothiazide

by Marzia Cirri, Francesca Maestrelli, Paola Mura, Carla Ghelardini and Lorenzo Di Cesare Mannelli

Pharmaceutics 2018, 10(4), 287; https://doi.org/10.3390/pharmaceutics10040287 - 19 Dec 2018

Cited by 22 | Viewed by 4452

Abstract

The development of specific and age-appropriate pediatric formulations is essential to assure that all children and their care-givers can easily access to safe and effective dosage forms. The need for developing specific pediatric medicinal products has been highlighted by the European Medicines Agency. The aim of this study was to investigate the effectiveness of combining the advantages of both cyclodextrin (CD) complexation and loading into nanostructured lipid carriers (NLC), to obtain a liquid oral pediatric formulation of hydrochlorothiazide (HCT), endowed with safety, dosage accuracy, good stability and therapeutic efficacy. Equimolar drug combinations as physical mixture (P.M.) or coground product (GR) with hydroxypropyl-β-cyclodextrin (HPβCD) or sulfobutylether-β-cyclodextrin (SBEβCD) were loaded into NLC, then characterized for particle size, homogeneity, Zeta potential, entrapment efficiency, gastric and storage stability. The presence of HPβCD allowed higher entrapment efficacy than NLC loaded with the plain drug, and enabled, in the case of GR systems a complete and sustained drug release, attributable to the wetting and solubilising properties of HPβCD toward HCT. In vivo studies on rats proved the superior therapeutic effectiveness of HCT-in HPβCD-in NLC formulations compared to the corresponding free HCT-loaded NLC, thus confirming the successfulness of the proposed approach in the development of an efficacious liquid oral formulation of the drug. Full article

(This article belongs to the Special Issue Cyclodextrins in Drug Formulation and Delivery)

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14 pages, 3127 KB

Open AccessArticle

Enhanced Dissolution and Oral Bioavailability of Cyclosporine A: Microspheres Based on αβ-Cyclodextrins Polymers

by Malika Lahiani-Skiba, Francois Hallouard, Frederic Bounoure, Nicolas Milon, Youness Karrout and Mohamed Skiba

Pharmaceutics 2018, 10(4), 285; https://doi.org/10.3390/pharmaceutics10040285 - 18 Dec 2018

Cited by 19 | Viewed by 7082

Abstract

Cyclosporine (CsA) has a selective property of suppressing various T-lymphocyte functions. This is of utmost importance in preventing allograft rejection by several organ transplantations, as well as in the treatment of systemic and local autoimmune disorders. However, the poor water solubility of CsA can be a major hurdle for its absorption into the blood stream, which leads to low bioavailability and thus less efficacy. The aim of this study was to prepare, characterize, and evaluate in vitro as well as in vivo, the potential of the innovative CsA drug delivery system. The latter contains CsA in spherical amorphous solid dispersion (SASD) which is embedded in an original α-cyclodextrin and β-cyclodextrin polymer mixture (Poly-αβ-CD) as a multifunctional amorphous carrier. The new developed SASD formulation showed that CsA was molecularly dispersed in αβ-cyclodextrins in an amorphous form, as was confirmed by physicochemical characterization studies. Interestingly, the peptide secondary structure, and thus, the drug activity was not impacted by the preparation of SASD as was shown by circular dichroism. Furthermore, the in vitro CsA release profile kinetics was almost identical to the commercially available product Neoral^®. This study presents the first in vivo proof-of-concept for a novel drug delivery system based on Poly-αβ-CD containing CsA, with SASD allowing for increased bioavailibility. The pharmacokinetic parameters of cyclosporine A from the spherical spray-dried dispersion formulation was demonstrated in a “rat” animal model. For comparison, the commercially available Neoral® was studied. Importantly, the pharmacokinetic parameters were improved by extending T_max from 2 to 3 h after the oral administration in rats, and eventually preventing the enterohepatic circulation. All these results clearly demonstrate the improved pharmacokinetic parameters and enhanced bioavailability of CsA in the new developed drug delivery system. These data demonstrated the superiority of the newly developed Poly-αβ-CD formulation for oral administration of the poorly soluble CsA in vivo without altering its secondary structure. Poly-αβ-CD can be a very useful tool for the oral administration of poorly water-soluble drugs. Full article

(This article belongs to the Special Issue Cyclodextrins in Drug Formulation and Delivery)

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27 pages, 7469 KB

Open AccessArticle

Novel Findings about Double-Loaded Curcumin-in-HPβcyclodextrin-in Liposomes: Effects on the Lipid Bilayer and Drug Release

by Ana-María Fernández-Romero, Francesca Maestrelli, Paola Angela Mura, Antonio María Rabasco and María Luisa González-Rodríguez

Pharmaceutics 2018, 10(4), 256; https://doi.org/10.3390/pharmaceutics10040256 - 3 Dec 2018

Cited by 42 | Viewed by 6372

Abstract

In this study, the encapsulation of curcumin (Cur) in “drug-in-cyclodextrin-in-liposomes (DCL)” by following the double-loading technique (DL) was proposed, giving rise to DCL–DL. The aim was to analyze the effect of cyclodextrin (CD) on the physicochemical, stability, and drug-release properties of liposomes. After selecting didodecyldimethylammonium bromide (DDAB) as the cationic lipid, DCL–DL was formulated by adding 2-hydroxypropyl-α/β/γ-CD (HPβCD)–Cur complexes into the aqueous phase. A competitive effect of cholesterol (Cho) for the CD cavity was found, so cholesteryl hemisuccinate (Chems) was used. The optimal composition of the DCL–DL bilayer was obtained by applying Taguchi methodology and regression analysis. Vesicles showed a lower drug encapsulation efficiency compared to conventional liposomes (CL) and CL containing HPβCD in the aqueous phase. However, the presence of HPβCD significantly increased vesicle deformability and Cur antioxidant activity over time. In addition, drug release profiles showed a sustained release after an initial burst effect, fitting to the Korsmeyer-Peppas kinetic model. Moreover, a direct correlation between the area under the curve (AUC) of dissolution profiles and flexibility of liposomes was obtained. It can be concluded that these “drug-in-cyclodextrin-in-deformable” liposomes in the presence of HPβCD may be a promising carrier for increasing the entrapment efficiency and stability of Cur without compromising the integrity of the liposome bilayer. Full article

(This article belongs to the Special Issue Cyclodextrins in Drug Formulation and Delivery)

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16 pages, 6502 KB

Open AccessArticle

Investigation of Combined Cyclodextrin and Hydrogel Formulation for Ocular Delivery of Dexamethasone Acetate by Means of Experimental Designs

by Roseline Mazet, Luc Choisnard, Delphine Levilly, Denis Wouessidjewe and Annabelle Gèze

Pharmaceutics 2018, 10(4), 249; https://doi.org/10.3390/pharmaceutics10040249 - 1 Dec 2018

Cited by 26 | Viewed by 4888

Abstract

Dexamethasone acetate (DXMa) has proven its efficiency to treat corneal inflammation, without a great propensity to increase intraocular pressure. Unfortunately, its poor aqueous solubility, associated with a rapid precorneal elimination, results in a low drug bioavailability and a low penetration after topical ocular administration. The main objective of this study was to improve the apparent aqueous solubility of DXMa using cyclodextrins. First, hydroxypropyl-β-CD (HPβCD) and hydroxypropyl-γ-CD (HPγCD) were used to enhance DXMa concentration in aqueous solution. The β and γ HPCD derivatives allowed the increase of the DXMa amount in solution at 25 °C by a factor of 500 and 1500, respectively. Second, with the aim of improving the persistence of the complex solution after instillation in the eye, the formulations of DXMa-based CD solutions with marketed ophthalmic gels (CELLUVISC^®, GEL-LARMES^®, and VISMED^®) were investigated and optimized by means of special cubic mixture designs, allowing the defining of mixed gels loaded with 0.7% (HPβCD) and 2% (HPγCD) DXMa with osmolality within acceptable physiological range. Finally, in vitro drug release assays from the mixed gels were performed and compared with reference eye drops. Similarly to MAXIDEX^® and DEXAFREE^®, in the case of mixed gel containing HPβCD, more than 90% of the drug was released within 2 h, while in mixed gel containing HPγCD, the release of DXMa was partial, reaching ≈60% in 2 h. This difference will have to be further addressed with ex vivo and in vivo ocular delivery experiments. Full article

(This article belongs to the Special Issue Cyclodextrins in Drug Formulation and Delivery)

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10 pages, 1509 KB

Open AccessArticle

Designing a Formulation of the Nootropic Drug Aniracetam Using 2-Hydroxypropyl-β-Cyclodextrin Suitable for Parenteral Administration

by Sebastian D. Goldsmith and Arlene McDowell

Pharmaceutics 2018, 10(4), 240; https://doi.org/10.3390/pharmaceutics10040240 - 18 Nov 2018

Cited by 7 | Viewed by 5552

Abstract

The nootropic drug aniracetam is greatly limited in its application by low aqueous solubility and a poor oral bioavailability. The primary aim of this study was to design a parenteral formulation of aniracetam that can be administered intravenously. Complexation of aniracetam with 2-hydroxypropyl-β-cyclodextrin (HP-β-CD) was investigated as a strategy to enhance solubility. A phase solubility analysis was performed to quantify the extent of improvement. An 819% increase in the solubility of aniracetam was obtained, reaching 36.44 mg/mL. This marked increase enables aniracetam to exist in an aqueous solvent at levels sufficient for parenteral dosing. A stability test was then devised using a design of experiment approach. The aniracetam-HP-β-CD formulation was subjected to different relative humidity and temperature and cyclodextrin concentrations over a 12-week period. Key changes in FTIR vibrational frequencies suggest the benzene moiety of aniracetam was introduced into the hydrophobic cavity of HP-β-CD. These results are highly supportive of the formation of a predictable 1:1 molar stoichiometric inclusion complex, explaining the improvement seen in physiochemical properties of aniracetam following formulation with HP-β-CD. This novel formulation of aniracetam suitable for parenteral administration will have utility in future studies to further elucidate the pharmacokinetics of this drug. Full article

(This article belongs to the Special Issue Cyclodextrins in Drug Formulation and Delivery)

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18 pages, 3970 KB

Open AccessArticle

Preparation and Characterization of Spherical Amorphous Solid Dispersion with Amphotericin B

by Lyes Mehenni, Malika Lahiani-Skiba, Guy Ladam, François Hallouard and Mohamed Skiba

Pharmaceutics 2018, 10(4), 235; https://doi.org/10.3390/pharmaceutics10040235 - 16 Nov 2018

Cited by 40 | Viewed by 6735

Abstract

In the present study, new polymer microspheres of amphotericin B (AmB) were prepared by a spray drying technique using cyclodextrin polymers (Poly-CD) to improve the solubility and dissolution of AmB, to prevent in vivo toxic AmB aggregations. Formulations were characterized through scanning electron microscopy (SEM), Fourier transform infrared spectroscopy (FT-IR), differential scanning calorimetry (DSC), thermal analysis, Raman spectroscopy, particle size, drug purity test and in vitro release studies. The analysis indicated that the chemical structure of AmB remained unchanged in the amorphous solid dispersion, but the structure was changed from crystalline to amorphous. AmB was completely release from such optimized formulations in dissolution media in 40 min. This work may contribute to a new generation of spherical amorphous solid dispersion using a cyclodextrin polymer, which has implications for the possibility of drug development for oral utilization or as powder aerosols for pulmonary administration. Full article

(This article belongs to the Special Issue Cyclodextrins in Drug Formulation and Delivery)

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18 pages, 3783 KB

Open AccessArticle

Encapsulation of Babchi Oil in Cyclodextrin-Based Nanosponges: Physicochemical Characterization, Photodegradation, and In Vitro Cytotoxicity Studies

by Sunil Kumar, Pooja, Francesco Trotta and Rekha Rao

Pharmaceutics 2018, 10(4), 169; https://doi.org/10.3390/pharmaceutics10040169 - 26 Sep 2018

Cited by 91 | Viewed by 8018

Abstract

Babchi (Psoralea corylifolia) oil is an important essential oil used in several traditional medicines to cure various disorders. This phytotherapeutic agent possesses a number of pharmacological activities including antibacterial, antifungal, antioxidant, anti-inflammatory, immunomodulatory, and antitumor factors. However, volatile nature, poor stability, and solubility of babchi oil (BO) restrict its pharmaceutical applications. Therefore, the aim of the present work was to encapsulate this oil in β-cyclodextrin nanosponges (NS) in order to overcome the above limitations. To fabricate nanosponges, β-cyclodextrin was cross-linked with diphenyl carbonate in different molar ratios viz. 1:2, 1:4, 1:6, 1:8, and 1:10. The blank nanosponges were loaded with BO using the freeze-drying method. The particle size of the BO loaded nanosponges was found to lie between 200 and 500 nm with low polydispersity index. Furthermore, the zeta potential, the Fourier transform infrared spectroscopy, X-ray diffraction, thermal analysis, and electron microscopy were carried out for characterization of BO nanosponges. Results obtained from spectral analysis ascertained the formation of inclusion complexes. Additionally, solubilisation efficiency of BO was checked in distilled water and found enhanced by 4.95 times with optimized β-cyclodextrin nanosponges. The cytotoxicity study was carried out by the MTT assay using HaCaT cell lines. A significant improvement in photo-stability of essential oil was also observed by inclusion innanosponges. Lastly, the optimized formulation was tested for antibacterial activity using Staphylococcus aureus, Pseudomonas aeruginosa, and Escherichia coli. Therefore, encapsulation of BO in nanosponges resulted in efficacious carrier system in terms of solubility, photo-stability, and safety of this oil along with handling benefits. Full article

(This article belongs to the Special Issue Cyclodextrins in Drug Formulation and Delivery)

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Review

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22 pages, 1143 KB

Open AccessFeature PaperReview

Grinding as Solvent-Free Green Chemistry Approach for Cyclodextrin Inclusion Complex Preparation in the Solid State

by Mario Jug and Paola Angela Mura

Pharmaceutics 2018, 10(4), 189; https://doi.org/10.3390/pharmaceutics10040189 - 16 Oct 2018

Cited by 91 | Viewed by 10690

Abstract

Among the different techniques proposed for preparing cyclodextrin inclusion complex in the solid state, mechanochemical activation by grinding appears as a fast, highly efficient, convenient, versatile, sustainable, and eco-friendly solvent-free method. This review is intended to give a systematic overview of the currently available data in this field, highlighting both the advantages as well as the shortcomings of such an approach. The possible mechanisms involved in the inclusion complex formation in the solid state, by grinding, have been illustrated. For each type of applied milling device, the respective process variables have been examined and discussed, together with the characteristics of the obtained products, also in relation with the physicochemical characteristics of both the drug and cyclodextrin subjected to grinding. The critical process parameters were evidenced in order to provide a useful guide for a rational selection of the most suitable conditions for an efficient inclusion complex preparation by grinding, with the final purpose of promoting a wider use of this effective solvent-free cyclodextrin inclusion complex preparation method in the solid state. Full article

(This article belongs to the Special Issue Cyclodextrins in Drug Formulation and Delivery)

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