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Pharmaceutics
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Bioavailability of Topically Applied Drugs
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Bioavailability of Topically Applied Drugs

A special issue of Pharmaceutics (ISSN 1999-4923). This special issue belongs to the section "Physical Pharmacy and Formulation".

Deadline for manuscript submissions: closed (28 February 2021) | Viewed by 37041

Special Issue Editors

Prof. Dr. Patrizia Chetoni

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Guest Editor
Department of Pharmacy, University of Pisa, 56126 Pisa, Italy
Interests: pharmaceutical technology; drug delivery; in vitro and in vivo models; biopharmaceutics; formulation
Special Issues, Collections and Topics in MDPI journals
Dr. Silvia Tampucci

E-Mail Website
Guest Editor
Department of Pharmacy, University of Pisa, 56126 Pisa, Italy
Interests: pharmaceutical technology; drug delivery; in vitro and in vivo models; biopharmaceutics; formulation; skin, eye, nail, buccal and vaginal mucosae
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

One of the main requisites for successful topical therapy is to achieve an optimal drug concentration at the target site in order to minimize systemic side effects and to reduce the required dose to be applied. The improvement of the bioavailability of topically applied drugs represents a great challenge for researchers, as the different structures to be addressed (i.e., skin, eye, nail, buccal and vaginal mucosa) present anatomo-physiological barriers and selective transport mechanisms.

Different drug delivery strategies have been pursued in order to provide selective tissue permeation and distribution, such as the use of new functional materials, the development of nanotechnologies, and the synthesis of new conjugate molecules acting as polymeric pro-drugs. Moreover, the assessment of drug bioavailability with in vitro pharmacokinetic modeling is an important issue, even with the availability of suitable biological models and drug pharmacokinetic studies.

For this Special Issue, we welcome original research or review articles dealing with formulation strategies to improve the bioavailability of topically applied drugs and in vitro/in vivo evaluation.

Prof. Dr. Patrizia Chetoni
Dr. Silvia Tampucci
Guest Editors

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Keywords

  • topical drug delivery
  • skin
  • nail
  • eye
  • vaginal and buccal mucosa
  • mucoadhesion
  • permeation and penetration
  • pharmacokinetic
  • enhancers
  • nanotechnologies

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Published Papers (7 papers)

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Research

13 pages, 1491 KiB  
Article
Studies on Surfactants, Cosurfactants, and Oils for Prospective Use in Formulation of Ketorolac Tromethamine Ophthalmic Nanoemulsions
by Shahla S. Smail, Mowafaq M. Ghareeb, Huner K. Omer, Ali A. Al-Kinani and Raid G. Alany
Pharmaceutics 2021, 13(4), 467; https://doi.org/10.3390/pharmaceutics13040467 - 30 Mar 2021
Cited by 30 | Viewed by 4384
Abstract
Nanoemulsions (NE) are isotropic, dispersions of oil, water, surfactant(s) and cosurfactant(s). A range of components (11 surfactants, nine cosurfactants, and five oils) were investigated as potential excipients for preparation of ketorolac tromethamine (KT) ocular nanoemulsion. Diol cosurfactants were investigated for the effect of [...] Read more.
Nanoemulsions (NE) are isotropic, dispersions of oil, water, surfactant(s) and cosurfactant(s). A range of components (11 surfactants, nine cosurfactants, and five oils) were investigated as potential excipients for preparation of ketorolac tromethamine (KT) ocular nanoemulsion. Diol cosurfactants were investigated for the effect of their carbon chain length and dielectric constant (DEC), Log P, and HLB on saturation solubility of KT. Hen’s Egg Test—ChorioAllantoic Membrane (HET-CAM) assay was used to evaluate conjunctival irritation of selected excipients. Of the investigated surfactants, Tween 60 achieved the highest KT solubility (9.89 ± 0.17 mg/mL), followed by Cremophor RH 40 (9.00 ± 0.21 mg/mL); amongst cosurfactants of interest ethylene glycol yielded the highest KT solubility (36.84 ± 0.40 mg/mL), followed by propylene glycol (26.23 ± 0.82 mg/mL). The solubility of KT in cosurfactants was affected by four molecular descriptors: carbon chain length, DEC, log P and HLB. KT solubility was directly proportional to DEC and the HLB yet, inversely proportional to carbon chain length and log P. All surfactants, except Labrasol ALF, were non-irritant. The majority of cosurfactants were slightly irritant, butylene glycol was a moderate irritant, pentylene and hexylene glycols were strong irritants. These findings will inform experiments aimed at developing NE formulations for ocular administration of KT. Full article
(This article belongs to the Special Issue Bioavailability of Topically Applied Drugs)
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22 pages, 4311 KiB  
Article
Targeting of the Pilosebaceous Follicle by Liquid Crystal Nanocarriers: In Vitro and In Vivo Effects of the Entrapped Minoxidil
by Massimo Fresta, Antonia Mancuso, Maria Chiara Cristiano, Konrad Urbanek, Felisa Cilurzo, Donato Cosco, Michelangelo Iannone and Donatella Paolino
Pharmaceutics 2020, 12(11), 1127; https://doi.org/10.3390/pharmaceutics12111127 - 22 Nov 2020
Cited by 28 | Viewed by 4114
Abstract
The topical administration of active compounds represents an advantageous strategy to reach the various skin components as well as its appendages. Pilosebaceous follicles are skin appendages originating in the deeper skin layers. They are very difficult to target, and hence higher active dosages [...] Read more.
The topical administration of active compounds represents an advantageous strategy to reach the various skin components as well as its appendages. Pilosebaceous follicles are skin appendages originating in the deeper skin layers. They are very difficult to target, and hence higher active dosages are generally required to achieve effective biological responses, thus favoring the rise of side effects. The aim of this work was to design a supramolecular colloidal carrier, i.e., a liquid crystal nanocarrier, for the selective delivery of active compounds into the pilosebaceous follicle. This nanocarrier showed mean sizes of ~80 nm, a good stability, a negative surface charge, and great safety properties. In vitro studies highlighted its ability to contain and release different substances and to successfully permeate the skin. Minoxidil was encapsulated in the nanocarriers and the in vivo biological effect was compared with a conventional dosage form. Minoxidil-loaded liquid crystal nanocarrier was able to selectively reach the pilosebaceous follicle, thus allowing an increased biological effectiveness of the delivered active in terms of biological response, duration of the biological effects, and reduction of collaterals. Our investigation showed that liquid crystal nanocarriers represent a promising device for the treatment of different pilosebaceous follicular impairments/diseases. Full article
(This article belongs to the Special Issue Bioavailability of Topically Applied Drugs)
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10 pages, 719 KiB  
Article
Synthesis and Ex Vivo Trans-Corneal Permeation of Penetratin Analogues as Ophthalmic Carriers: Preliminary Results
by Silvia Pescina, Marina Sala, Maria Carmina Scala, Patrizia Santi, Cristina Padula, Pietro Campiglia, Carmine Ostacolo and Sara Nicoli
Pharmaceutics 2020, 12(8), 728; https://doi.org/10.3390/pharmaceutics12080728 - 3 Aug 2020
Cited by 5 | Viewed by 3131
Abstract
Among enhancing strategies proposed in ocular drug delivery, a rising interest is directed to cell penetrating peptides (CPPs), amino acid short sequences primarily known for their intrinsic ability to cell internalization and, by extension, to cross biological barriers. In fact, CPPs may be [...] Read more.
Among enhancing strategies proposed in ocular drug delivery, a rising interest is directed to cell penetrating peptides (CPPs), amino acid short sequences primarily known for their intrinsic ability to cell internalization and, by extension, to cross biological barriers. In fact, CPPs may be considered as carrier for delivering therapeutic agents across biological membranes, including ocular tissues. Several CPPs have been proposed in ophthalmic delivery, and, among them, penetratin (PNT), a 16-amino acids natural peptide, stands out. Therefore, we describe the synthesis via the mimotopic approach of short fluorescently labeled analogues of both PNT and its reversed sequence PNT-R. Their ability to cross ocular membranes was checked ex vivo using freshly explanted porcine cornea. Furthermore, some sequences were studied by circular dichroism. Despite the hydrophilic nature and the relatively high molecular weight (approx. 1.6 kDa), all analogues showed a not negligible trans-corneal diffusion, indicating a partial preservation of penetration activity, even if no sequences reached the noteworthy ability of PNT. It was not possible to find a correlation between structure and corneal penetration ability, and further studies, exploring peptides distribution within corneal layers, for example using imaging techniques, deserve to be performed to figure out a possible difference in intracellular delivery. Full article
(This article belongs to the Special Issue Bioavailability of Topically Applied Drugs)
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11 pages, 1649 KiB  
Article
In Vitro Skin Retention of Crisaborole after Topical Application
by Adriana Fantini, Anna Demurtas, Sara Nicoli, Cristina Padula, Silvia Pescina and Patrizia Santi
Pharmaceutics 2020, 12(6), 491; https://doi.org/10.3390/pharmaceutics12060491 - 28 May 2020
Cited by 21 | Viewed by 4851
Abstract
Crisaborole, a nonsteroidal phosphodiesterase 4 inhibitor, represents the first nonsteroidal medication approved for the treatment of atopic dermatitis in over a decade. In this work, crisaborole skin permeation and retention was studied in vitro from a 2% ointment using porcine skin as barrier. [...] Read more.
Crisaborole, a nonsteroidal phosphodiesterase 4 inhibitor, represents the first nonsteroidal medication approved for the treatment of atopic dermatitis in over a decade. In this work, crisaborole skin permeation and retention was studied in vitro from a 2% ointment using porcine skin as barrier. Crisaborole was also characterized in terms of thermal behavior, solubility, and logP. Control experiments were performed also on tape stripped skin to clarify the role of stratum corneum in drug partitioning and permeation across the skin. The results obtained indicate that crisaborole accumulates into the skin in considerable amounts after application of a topical lipophilic ointment. Crisaborole shows more affinity for the dermis compared to the epidermis despite its relatively high value of partition coefficient; stratum corneum analysis revealed a low affinity of the drug for this skin layer. Skin penetration across hair follicles or sebaceous glands can be a reason for the high dermis retention and is worth further investigation. The comparison with data obtained from a solution in acetonitrile suggests that the formulation plays a certain role in determining the relative distribution of crisaborole in the skin layers and in the receptor compartment. Full article
(This article belongs to the Special Issue Bioavailability of Topically Applied Drugs)
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14 pages, 2638 KiB  
Article
Development of Gel-in-Oil Emulsions for Khellin Topical Delivery
by Joana Pereira, Rita Gonçalves, Margarida Barreto, Clarisse Dias, Fátima Carvalho, António J. Almeida, Helena Margarida Ribeiro and Joana Marto
Pharmaceutics 2020, 12(5), 398; https://doi.org/10.3390/pharmaceutics12050398 - 26 Apr 2020
Cited by 10 | Viewed by 3896
Abstract
Hypopigmentation is a progressive dermatological condition caused by a reduction in the skin pigment, melanin. Its treatment is considered a challenge due to the lack of a highly efficient single therapy. Currently, the main treatments include photochemotherapy, application of corticosteroids and immunosuppressants, and [...] Read more.
Hypopigmentation is a progressive dermatological condition caused by a reduction in the skin pigment, melanin. Its treatment is considered a challenge due to the lack of a highly efficient single therapy. Currently, the main treatments include photochemotherapy, application of corticosteroids and immunosuppressants, and laser. Khellin-based gel-in-oil emulsions appear as a promising alternative since they ensure a concentration of the drug, a natural furanochromone, at the desired location, skin surface. Khellin promotes repigmentation as it forms a dark colored complex after solar irradiation. The aim of this study was the development and characterization (e.g., rheological behaviour, droplet size, tackiness, adhesion and spreadability) of three topical gel-in-oil emulsions prepared with different emollients, formulated through a cold emulsification process, and suitable for the incorporation of khellin. In vitro studies were performed to evaluate the drug release and permeation profiles across artificial membranes and excised human skin, respectively, using Franz-type vertical diffusion cells. The W/O emulsions developed showed macroscopic appearance, shear-thinning behavior with a mean droplet size from 3.28 to 4.28 μm, suitable for topical application. In vitro studies revealed permeation values of about 1% of khellin across the stratum corneum, making these gel-in-oil emulsions promising for preclinical and clinical studies. The cold process, being an easy and low energy production method, represents an innovative strategy to produce khellin-based gel-in-oil emulsions to treat patients with hypopigmentation. Full article
(This article belongs to the Special Issue Bioavailability of Topically Applied Drugs)
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24 pages, 3973 KiB  
Article
Assembling Surfactants-Mucoadhesive Polymer Nanomicelles (ASMP-Nano) for Ocular Delivery of Cyclosporine-A
by Eleonora Terreni, Patrizia Chetoni, Silvia Tampucci, Susi Burgalassi, Ali Athab Al-kinani, Raid G. Alany and Daniela Monti
Pharmaceutics 2020, 12(3), 253; https://doi.org/10.3390/pharmaceutics12030253 - 11 Mar 2020
Cited by 39 | Viewed by 4399
Abstract
The physiological protective mechanisms of the eye reduce the bioavailability of topically administered drugs above all for those with high molecular weight and /or lipophilic characteristics, such as Cyclosporine A (CyA). The combined strategy based on the association of nanomicelles and mucoadhesive polymer [...] Read more.
The physiological protective mechanisms of the eye reduce the bioavailability of topically administered drugs above all for those with high molecular weight and /or lipophilic characteristics, such as Cyclosporine A (CyA). The combined strategy based on the association of nanomicelles and mucoadhesive polymer seems promising since a limited number of commercial products containing CyA have been recently approved. The scope of this investigation was the design of Assembling Surfactants-Mucoadhesive Polymer Nanomicelles (ASMP-Nano), based on a binary system of two surfactants in combination with hyaluronic acid, and their biopharmaceutical evaluation. The optimisation of the ASMP-Nano in term of the amount of surfactants, CyA-loading and size determined the selection of the clear and stable Nano1HAB-CyA formulation containing 0.105% w/w CyA loaded-nanomicelles with a size of 14.41 nm. The nanostructured system had a protective effect towards epithelial corneal cells with a cell viability of more than 80%. It interacted with cellular barriers favouring the uptake and the accumulation of CyA into the cells as evidenced by fluorescent probe distribution, by hindering CyA permeation through reconstituted corneal epithelial tissue. In pharmacokinetics study on rabbits, the nanomicellar carrier prolonged the CyA retention time in the precorneal area mainly in presence of hyaluronic acid (HA), a mucoadhesive polymer. Full article
(This article belongs to the Special Issue Bioavailability of Topically Applied Drugs)
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19 pages, 1586 KiB  
Article
Evaluation of Formulation Parameters on Permeation of Ibuprofen from Topical Formulations Using Strat-M® Membrane
by Pradeep Kumar Bolla, Bradley A. Clark, Abhishek Juluri, Hanumanth Srikanth Cheruvu and Jwala Renukuntla
Pharmaceutics 2020, 12(2), 151; https://doi.org/10.3390/pharmaceutics12020151 - 13 Feb 2020
Cited by 94 | Viewed by 10626
Abstract
Topical drug delivery is an attractive alternative to conventional methods because of advantages such as non-invasive delivery, by-pass of first pass metabolism, and improved patient compliance. However, several factors such as skin, physicochemical properties of the drug, and vehicle characteristics influence the permeation. [...] Read more.
Topical drug delivery is an attractive alternative to conventional methods because of advantages such as non-invasive delivery, by-pass of first pass metabolism, and improved patient compliance. However, several factors such as skin, physicochemical properties of the drug, and vehicle characteristics influence the permeation. Within a formulation, critical factors such as concentration of drug, physical state of drug in the formulation, and organoleptic properties affect the flux across the skin. The aim of the study was to develop and investigate topical semisolid preparations (creams and gels) with ibuprofen as the model drug and investigate the effect of various formulation parameters on the in-vitro performance across the Strat-M® membrane using flow-through cells. In addition, the physical stability of the developed formulations was investigated by studying viscosity, pH, and appearance. All the formulations developed in the study had appealing appearance with smooth texture and no signs of separation. Viscosity and pH of the formulations were acceptable. Cumulative amount of drug permeated at the end of 24 h was highest for clear gel (3% w/w ibuprofen; F6: 739.6 ± 36.1 µg/cm2) followed by cream with high concentration of ibuprofen in suspended form (5% w/w; F3: 320.8 ± 17.53 µg/cm2), emulgel (3% w/w ibuprofen; F5: 178.5 ± 34.5 µg/cm2), and cream with solubilized ibuprofen (3% w/w; F2A: 163.2 ± 9.36 µg/cm2). Results from this study showed that permeation of ibuprofen was significantly influenced by formulation parameters such as concentration of ibuprofen (3% vs. 5% w/w), physical state of ibuprofen (solubilized vs. suspended), formulation type (cream vs. gel), mucoadhesive agents, and viscosity (high vs. low). Thus, findings from this study indicate that pharmaceutical formulation scientists should explore these critical factors during the early development of any new topical drug product in order to meet pre-determined quality target product profile. Full article
(This article belongs to the Special Issue Bioavailability of Topically Applied Drugs)
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