Pharmaceutics

Editorial

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10 pages, 244 KiB

Open AccessEditorial

Transmucosal Absorption Enhancers in the Drug Delivery Field

by Sam Maher, Luca Casettari and Lisbeth Illum

Pharmaceutics 2019, 11(7), 339; https://doi.org/10.3390/pharmaceutics11070339 - 15 Jul 2019

Cited by 24 | Viewed by 6692

Abstract

Drug delivery systems that safely and consistently improve transport of poorly absorbed compounds across epithelial barriers are highly sought within the drug delivery field. The use of chemical permeation enhancers is one of the simplest and widely tested approaches to improve transmucosal permeability [...] Read more.

Drug delivery systems that safely and consistently improve transport of poorly absorbed compounds across epithelial barriers are highly sought within the drug delivery field. The use of chemical permeation enhancers is one of the simplest and widely tested approaches to improve transmucosal permeability via oral, nasal, buccal, ocular and pulmonary routes. To date, only a small number of permeation enhancers have progressed to clinical trials, and only one product that includes a permeation enhancer has reached the pharmaceutical market. This editorial is an introduction to the special issue entitled Transmucosal Absorption Enhancers in the Drug Delivery Field (https://www.mdpi.com/journal/pharmaceutics/special_issues/transmucosal_absorption_enhancers). The guest editors outline the scope of the issue, reflect on the results and the conclusions of the 19 articles published in the issue and provide an outlook on the use of permeation enhancers in the drug delivery field. Full article

(This article belongs to the Special Issue Transmucosal Absorption Enhancers in the Drug Delivery Field)

Research

Jump to: Editorial, Review

9 pages, 1154 KiB

Open AccessArticle

Delivery of Nanoparticles across the Intestinal Epithelium via the Transferrin Transport Pathway

by Jing M. Yong, Julia Mantaj, Yiyi Cheng and Driton Vllasaliu

Pharmaceutics 2019, 11(7), 298; https://doi.org/10.3390/pharmaceutics11070298 - 26 Jun 2019

Cited by 37 | Viewed by 4732

Abstract

The aim of this study was to probe whether the transferrin (Tf) transport pathway can be exploited for intestinal delivery of nanoparticles. Tf was adsorbed on 100 nm model polystyrene nanoparticles (NP), followed by size characterisation of these systems. Cell uptake of Tf [...] Read more.

The aim of this study was to probe whether the transferrin (Tf) transport pathway can be exploited for intestinal delivery of nanoparticles. Tf was adsorbed on 100 nm model polystyrene nanoparticles (NP), followed by size characterisation of these systems. Cell uptake of Tf and Tf-adsorbed NP was investigated in intestinal epithelial Caco-2 cells cultured on multi-well plates and as differentiated polarised monolayers. Tf-NP demonstrated a remarkably higher cell uptake compared to unmodified NP in both non-polarised (5-fold) and polarised cell monolayers (16-fold difference). Application of soluble Tf significantly attenuated the uptake of Tf-NP. Notably, Tf-NP displayed remarkably higher rate (23-fold) of epithelial transport across Caco-2 monolayers compared to unmodified NP. This study therefore strongly suggests that the Tf transport pathway should be considered as a candidate biological transport route for orally-administered nanomedicines and drugs with poor oral bioavailability. Full article

(This article belongs to the Special Issue Transmucosal Absorption Enhancers in the Drug Delivery Field)

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17 pages, 2674 KiB

Open AccessArticle

Nasal Administration and Plasma Pharmacokinetics of Parathyroid Hormone Peptide PTH 1-34 for the Treatment of Osteoporosis

by Richard G. Pearson, Tahir Masud, Elaine Blackshaw, Andrew Naylor, Michael Hinchcliffe, Kirk Jeffery, Faron Jordan, Anjumn Shabir-Ahmed, Gareth King, Andrew L. Lewis, Lisbeth Illum and Alan C. Perkins

Pharmaceutics 2019, 11(6), 265; https://doi.org/10.3390/pharmaceutics11060265 - 7 Jun 2019

Cited by 25 | Viewed by 5262

Abstract

Nasal delivery of large peptides such as parathyroid 1-34 (PTH 1-34) can benefit from a permeation enhancer to promote absorption across the nasal mucosa into the bloodstream. Previously, we have published an encouraging bioavailability (78%), relative to subcutaneous injection in a small animal [...] Read more.

Nasal delivery of large peptides such as parathyroid 1-34 (PTH 1-34) can benefit from a permeation enhancer to promote absorption across the nasal mucosa into the bloodstream. Previously, we have published an encouraging bioavailability (78%), relative to subcutaneous injection in a small animal preclinical model, for a liquid nasal spray formulation containing the permeation enhancer polyethylene glycol (15)-hydroxystearate (Solutol^® HS15). We report here the plasma pharmacokinetics of PTH 1-34 in healthy human volunteers receiving the liquid nasal spray formulation containing Solutol^® HS15. For comparison, data for a commercially manufactured teriparatide formulation delivered via subcutaneous injection pen are also presented. Tc-99m-DTPA gamma scintigraphy monitored the deposition of the nasal spray in the nasal cavity and clearance via the inferior meatus and nasopharynx. The 50% clearance time was 17.8 min (minimum 10.9, maximum 74.3 min). For PTH 1-34, mean plasma C_max of 5 pg/mL and 253 pg/mL were obtained for the nasal spray and subcutaneous injection respectively; relative bioavailability of the nasal spray was ≤1%. Subsequently, we investigated the pharmacokinetics of the liquid nasal spray formulation as well as a dry powder nasal formulation also containing Solutol^® HS15 in a crossover study in an established ovine model. In this preclinical model, the relative bioavailability of liquid and powder nasal formulations was 1.4% and 1.0% respectively. The absolute bioavailability of subcutaneously administered PTH 1-34 (mean 77%, range 55–108%) in sheep was in agreement with published human data for teriparatide (up to 95%). These findings have important implications in the search for alternative routes of administration of peptides for the treatment of osteoporosis, and in terms of improving translation from animal models to humans. Full article

(This article belongs to the Special Issue Transmucosal Absorption Enhancers in the Drug Delivery Field)

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16 pages, 3312 KiB

Open AccessArticle

Mechanistic Studies on the Absorption-Enhancing Effects of Gemini Surfactant on the Intestinal Absorption of Poorly Absorbed Hydrophilic Drugs in Rats

by Tammam Alama, Kosuke Kusamori, Masaki Morishita, Hidemasa Katsumi, Toshiyasu Sakane and Akira Yamamoto

Pharmaceutics 2019, 11(4), 170; https://doi.org/10.3390/pharmaceutics11040170 - 7 Apr 2019

Cited by 9 | Viewed by 3898

Abstract

Generally, the use of absorption enhancers might be the most effective approaches to ameliorate the enteric absorption of poorly absorbed substances. Among numerous absorption enhancers, we already reported that a gemini surfactant, sodium dilauramidoglutamide lysine (SLG-30) with two hydrophobic and two hydrophilic moieties, [...] Read more.

Generally, the use of absorption enhancers might be the most effective approaches to ameliorate the enteric absorption of poorly absorbed substances. Among numerous absorption enhancers, we already reported that a gemini surfactant, sodium dilauramidoglutamide lysine (SLG-30) with two hydrophobic and two hydrophilic moieties, is a novel and promising adjuvant with a high potency in improving the absorption safely. Here, we examined and elucidated the absorption-improving mechanisms of SLG-30 in the enteric absorption of substances. SLG-30 increased the intestinal absorption of 5(6)-carboxyfluorescein (CF) to a greater level than the typical absorption enhancers, including sodium glycocholate and sodium laurate, as evaluated by an in situ closed-loop method. Furthermore, SLG-30 significantly lowered the fluorescence anisotropy of dansyl chloride (DNS-Cl), suggesting that it might increase the fluidity of protein sections in the intestinal cell membranes. Moreover, SLG-30 significantly lowered the transepithelial-electrical resistance (TEER) values of Caco-2 cells, suggesting that it might open the tight junctions (TJs) between the enteric epithelial cells. Additionally, the levels of claudin-1 and claudin-4 expression decreased in the presence of SLG-30. These outcomes propose that SLG-30 might improve the enteric transport of poorly absorbed substances through both transcellular and paracellular routes. Full article

(This article belongs to the Special Issue Transmucosal Absorption Enhancers in the Drug Delivery Field)

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19 pages, 2932 KiB

Open AccessArticle

Chitosan-Coated Nanoparticles: Effect of Chitosan Molecular Weight on Nasal Transmucosal Delivery

by Franciele Aline Bruinsmann, Stefania Pigana, Tanira Aguirre, Gabriele Dadalt Souto, Gabriela Garrastazu Pereira, Annalisa Bianchera, Laura Tiozzo Fasiolo, Gaia Colombo, Magno Marques, Adriana Raffin Pohlmann, Silvia Stanisçuaski Guterres and Fabio Sonvico

Pharmaceutics 2019, 11(2), 86; https://doi.org/10.3390/pharmaceutics11020086 - 18 Feb 2019

Cited by 94 | Viewed by 8053

Abstract

Drug delivery to the brain represents a challenge, especially in the therapy of central nervous system malignancies. Simvastatin (SVT), as with other statins, has shown potential anticancer properties that are difficult to exploit in the central nervous system (CNS). In the present work [...] Read more.

Drug delivery to the brain represents a challenge, especially in the therapy of central nervous system malignancies. Simvastatin (SVT), as with other statins, has shown potential anticancer properties that are difficult to exploit in the central nervous system (CNS). In the present work the physico–chemical, mucoadhesive, and permeability-enhancing properties of simvastatin-loaded poly-ε-caprolactone nanocapsules coated with chitosan for nose-to-brain administration were investigated. Lipid-core nanocapsules coated with chitosan (LNC_chit) of different molecular weight (MW) were prepared by a novel one-pot technique, and characterized for particle size, surface charge, particle number density, morphology, drug encapsulation efficiency, interaction between surface nanocapsules with mucin, drug release, and permeability across two nasal mucosa models. Results show that all formulations presented adequate particle sizes (below 220 nm), positive surface charge, narrow droplet size distribution (PDI < 0.2), and high encapsulation efficiency. Nanocapsules presented controlled drug release and mucoadhesive properties that are dependent on the MW of the coating chitosan. The results of permeation across the RPMI 2650 human nasal cell line evidenced that LNC_chit increased the permeation of SVT. In particular, the amount of SVT that permeated after 4 hr for nanocapsules coated with low-MW chitosan, high-MW chitosan, and control SVT was 13.9 ± 0.8 μg, 9.2 ± 1.2 µg, and 1.4 ± 0.2 µg, respectively. These results were confirmed by SVT ex vivo permeation across rabbit nasal mucosa. This study highlighted the suitability of LNC_chit as a promising strategy for the administration of simvastatin for a nose-to-brain approach for the therapy of brain tumors. Full article

(This article belongs to the Special Issue Transmucosal Absorption Enhancers in the Drug Delivery Field)

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21 pages, 6117 KiB

Open AccessArticle

Dual Action of the PN159/KLAL/MAP Peptide: Increase of Drug Penetration across Caco-2 Intestinal Barrier Model by Modulation of Tight Junctions and Plasma Membrane Permeability

by Alexandra Bocsik, Ilona Gróf, Lóránd Kiss, Ferenc Ötvös, Ottó Zsíros, Lejla Daruka, Lívia Fülöp, Monika Vastag, Ágnes Kittel, Norbert Imre, Tamás A. Martinek, Csaba Pál, Piroska Szabó-Révész and Mária A. Deli

Pharmaceutics 2019, 11(2), 73; https://doi.org/10.3390/pharmaceutics11020073 - 10 Feb 2019

Cited by 38 | Viewed by 7143

Abstract

The absorption of drugs is limited by the epithelial barriers of the gastrointestinal tract. One of the strategies to improve drug delivery is the modulation of barrier function by the targeted opening of epithelial tight junctions. In our previous study the 18-mer amphiphilic [...] Read more.

The absorption of drugs is limited by the epithelial barriers of the gastrointestinal tract. One of the strategies to improve drug delivery is the modulation of barrier function by the targeted opening of epithelial tight junctions. In our previous study the 18-mer amphiphilic PN159 peptide was found to be an effective tight junction modulator on intestinal epithelial and blood–brain barrier models. PN159, also known as KLAL or MAP, was described to interact with biological membranes as a cell-penetrating peptide. In the present work we demonstrated that the PN159 peptide as a penetration enhancer has a dual action on intestinal epithelial cells. The peptide safely and reversibly enhanced the permeability of Caco-2 monolayers by opening the intercellular junctions. The penetration of dextran molecules with different size and four efflux pump substrate drugs was increased several folds. We identified claudin-4 and -7 junctional proteins by docking studies as potential binding partners and targets of PN159 in the opening of the paracellular pathway. In addition to the tight junction modulator action, the peptide showed cell membrane permeabilizing and antimicrobial effects. This dual action is not general for cell-penetrating peptides (CPPs), since the other three CPPs tested did not show barrier opening effects. Full article

(This article belongs to the Special Issue Transmucosal Absorption Enhancers in the Drug Delivery Field)

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17 pages, 4113 KiB

Open AccessArticle

Chitosan Plus Compound 48/80: Formulation and Preliminary Evaluation as a Hepatitis B Vaccine Adjuvant

by Dulce Bento, Sandra Jesus, Filipa Lebre, Teresa Gonçalves and Olga Borges

Pharmaceutics 2019, 11(2), 72; https://doi.org/10.3390/pharmaceutics11020072 - 9 Feb 2019

Cited by 32 | Viewed by 3898

Abstract

Current vaccine research is mostly based on subunit antigens. Despite the better toxicity profile of these antigens they are often poorly immunogenic, so adjuvant association has been explored as a strategy to obtain a potent vaccine formulation. Recently, mast cell activators were recognized [...] Read more.

Current vaccine research is mostly based on subunit antigens. Despite the better toxicity profile of these antigens they are often poorly immunogenic, so adjuvant association has been explored as a strategy to obtain a potent vaccine formulation. Recently, mast cell activators were recognized as a new class of vaccine adjuvants capable of potentiating mucosal and systemic immune responses. In this study, a co-adjuvanted delivery system was developed and characterized, combining the mast cell activator C48/80 with chitosan nanoparticles (Chi-C48/80 NPs), and the results were compared with plain chitosan nanoparticles. The adsorption of model antigens onto the NP surface as well as the biocompatibility of the system was not affected by the incorporation of C48/80 in the formulation. The stability of the nanoparticles was demonstrated by studying the variation of size and zeta potential at different times, and the ability to be internalized by antigen presenting cells was confirmed by confocal microscopy. Vaccination studies with hepatitis B surface antigen loaded Chi-C48/80 NPs validated the adjuvanticity of the delivery system, demonstrating for the first time a successful association between a mast cell activator and chitosan nanoparticles as a vaccine adjuvant for hepatitis B virus, applied to a nasal vaccination strategy. Full article

(This article belongs to the Special Issue Transmucosal Absorption Enhancers in the Drug Delivery Field)

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17 pages, 4297 KiB

Open AccessArticle

Intestinal Drug Absorption Enhancement by Aloe vera Gel and Whole Leaf Extract: In Vitro Investigations into the Mechanisms of Action

by Anja Haasbroek, Clarissa Willers, Matthew Glyn, Lissinda du Plessis and Josias Hamman

Pharmaceutics 2019, 11(1), 36; https://doi.org/10.3390/pharmaceutics11010036 - 18 Jan 2019

Cited by 22 | Viewed by 6384

Abstract

The co-administration of absorption enhancing agents with macromolecular drugs (e.g., protein and peptide drugs) has been identified as a means to improve the oral bioavailability of these drugs. Absorption-enhancing agents of natural origins have received a great deal of attention due to their [...] Read more.

The co-administration of absorption enhancing agents with macromolecular drugs (e.g., protein and peptide drugs) has been identified as a means to improve the oral bioavailability of these drugs. Absorption-enhancing agents of natural origins have received a great deal of attention due to their sustainable production, in support of green chemistry. In previous studies, certain parts of the Aloe vera leaf (e.g., gel and whole leaf extract) have shown a potential to enhance drug permeation across the intestinal epithelial barrier. The mechanism of the drug-absorption-enhancement action and the capacity for absorption-enhancement of the A. vera gel and whole leaf, were investigated in this study. A clear decrease in transepithelial electrical resistance (TEER) of Caco-2 cell monolayers exposed to A. vera gel and wholeleaf extract, in various concentrations, indicated the opening of tight junctions between the epithelial cells. The transport of Fluorescein isothiocyanate (FITC)-dextran, with a molecular weight of 4 kDa (FD-4), could be enhanced across the Caco-2 cell monolayers, by the A. vera gel and whole-leaf extract, but not the FITC-dextran with larger molecular weights (i.e., 10, 20, and 40 kDa), which indicated a limited drug absorption enhancement capacity, in terms of the molecular size. Accumulation of FD-4 between the Caco-2 cells (and not within the cells), after treatment with the A. vera gel and whole-leaf extract was shown with a confocal laser scanning microscopy (CLSM) imaging, indicating that the paracellular transport of FD-4 occurred after the interaction of the A. vera gel and whole-leaf extract, with the epithelial cell monolayers. Furthermore, changes in the F-actin distribution in the cytoskeleton of the Caco-2 cell monolayers was observed by means of a fluorescence staining, which confirmed tight junction modulation as the mechanism of action for the absorption enhancement effect of the A. vera gel and whole-leaf extract. Full article

(This article belongs to the Special Issue Transmucosal Absorption Enhancers in the Drug Delivery Field)

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16 pages, 4527 KiB

Open AccessArticle

Enhanced Delivery of Imatinib into Vaginal Mucosa via a New Positively Charged Nanocrystal-Loaded in Situ Hydrogel Formulation for Treatment of Cervical Cancer

by Li-qian Ci, Zhi-gang Huang, Feng-mei Lv, Jun Wang, Ling-lin Feng, Feng Sun, Shui-juan Cao, Zhe-peng Liu, Yu Liu, Gang Wei and Wei-yue Lu

Pharmaceutics 2019, 11(1), 15; https://doi.org/10.3390/pharmaceutics11010015 - 4 Jan 2019

Cited by 31 | Viewed by 5537 | Correction

Abstract

The present study was carried out to investigate the potential of cationic functionalization on imatinib nanocrystals to improve the mucoadhesiveness and, thus, delivery to the lesion of cervicovaginal tumors. Amino-group-functionalized imatinib nanocrystals (NC@PDA-NH₂) were prepared with near-spheroid shape, nanoscale size distribution, [...] Read more.

The present study was carried out to investigate the potential of cationic functionalization on imatinib nanocrystals to improve the mucoadhesiveness and, thus, delivery to the lesion of cervicovaginal tumors. Amino-group-functionalized imatinib nanocrystals (NC@PDA-NH₂) were prepared with near-spheroid shape, nanoscale size distribution, positive zeta potential, and relatively high drug content with the aid of the polydopamine-coating technique. Efficient interaction between NC@PDA-NH₂ and mucin was proven by mucin adsorption which was related to the positive zeta-potential value of NC@PDA-NH₂ and the change in the size distribution on mixing of NC@PDA-NH₂ and mucin. Cellular uptake, growth inhibition, and apoptosis induction in cervicovaginal cancer-related cells demonstrated the superiority of NC@PDA-NH₂ over unmodified nanocrystals. For practical intravaginal administration, NC@PDA-NH₂ was dispersed in Pluronic F127-based thermosensitive in situ hydrogel, which showed suitable gelation temperature and sustained-release profiles. In comparison with unmodified nanocrystals, NC@PDA-NH₂ exhibited extended residence on ex vivo murine vaginal mucosa, prolonged in vivo intravaginal residence, and enhanced inhibition on the growth of murine orthotopic cervicovaginal model tumors indicated by smaller tumor size, longer median survival time, and more intratumor apoptosis with negligible mucosal toxicity. In conclusion, cationic functionalization endowed NC@PDA-NH₂ significant mucoadhesiveness and, thus, good potential against cervicovaginal cancer via intravaginal administration. Full article

(This article belongs to the Special Issue Transmucosal Absorption Enhancers in the Drug Delivery Field)

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18 pages, 3459 KiB

Open AccessArticle

N-(2-Hydroxy)-propyl-3-trimethylammonium, O-Mysristoyl Chitosan Enhances the Solubility and Intestinal Permeability of Anticancer Curcumin

by Daniella S. Silva, Danilo M. dos Santos, Andreia Almeida, Leonardo Marchiori, Sérgio P. Campana-Filho, Sidney J. L. Ribeiro and Bruno Sarmento

Pharmaceutics 2018, 10(4), 245; https://doi.org/10.3390/pharmaceutics10040245 - 20 Nov 2018

Cited by 21 | Viewed by 5580

Abstract

An amphiphilic derivative of chitosan containing quaternary ammonium and myristoyl groups, herein named as ammonium myristoyl chitosan (DMCat), was synthesized by reacting glycidyltrimethylammonium chloride (GTMAC) and myristoyl chitosan (DMCh). The success of the modification was confirmed using Fourier-transform infrared spectroscopy (FTIR) and ¹ [...] Read more.

An amphiphilic derivative of chitosan containing quaternary ammonium and myristoyl groups, herein named as ammonium myristoyl chitosan (DMCat), was synthesized by reacting glycidyltrimethylammonium chloride (GTMAC) and myristoyl chitosan (DMCh). The success of the modification was confirmed using Fourier-transform infrared spectroscopy (FTIR) and ¹H nuclear magnetic resonance (NMR) spectroscopy. The average degrees of alkylation and quaternization (

\bar{D Q}

) were determined by using ¹H NMR and conductometric titration. The zeta potential of the micelles was higher than 28 mV while its average size and encapsulation efficiency ranged from 280 nm to 375 nm and 68% to 100%, respectively. The in vitro cytotoxicity of the unloaded and curcumin (CUR)-loaded micelles was tested against Caco-2 and HT29-MTX intestinal epithelial cell lines. The results showed no cytotoxic effect from loaded and unloaded micelles as compared to free CUR. In the permeability test, it was observed that both types of micelles, i.e., DMCh and DMCat, improved CUR permeability. Additionally, higher permeability was verified for both systems in Caco-2/HT29-MTX:Raji B because of the mucoadhesive character of chitosan and its ability to open tight junctions. The results indicated that DMCat micelles, due to the physico-chemical, improved characteristics may be a promising carrier to encapsulate CUR aiming cancer therapy. Full article

(This article belongs to the Special Issue Transmucosal Absorption Enhancers in the Drug Delivery Field)

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20 pages, 3536 KiB

Open AccessArticle

A Tailored Thermosensitive PLGA-PEG-PLGA/Emulsomes Composite for Enhanced Oxcarbazepine Brain Delivery via the Nasal Route

by Ghada M. El-Zaafarany, Mahmoud E. Soliman, Samar Mansour, Marco Cespi, Giovanni Filippo Palmieri, Lisbeth Illum, Luca Casettari and Gehanne A. S. Awad

Pharmaceutics 2018, 10(4), 217; https://doi.org/10.3390/pharmaceutics10040217 - 5 Nov 2018

Cited by 39 | Viewed by 6771

Abstract

The use of nanocarrier delivery systems for direct nose to brain drug delivery shows promise for achieving increased brain drug levels as compared to simple solution systems. An example of such nanocarriers is emulsomes formed from lipid cores surrounded and stabilised by a [...] Read more.

The use of nanocarrier delivery systems for direct nose to brain drug delivery shows promise for achieving increased brain drug levels as compared to simple solution systems. An example of such nanocarriers is emulsomes formed from lipid cores surrounded and stabilised by a corona of phospholipids (PC) and a coating of Tween 80, which combines the properties of both liposomes and emulsions. Oxcarbazepine (OX), an antiepileptic drug, was entrapped in emulsomes and then localized in a poly(lactic acid-co-glycolic acid)-poly(ethylene glycol)-poly(lactic acid-co-glycolic acid) (PLGA-PEG-PLGA) triblock copolymer thermogel. The incorporation of OX emulsomes in thermogels retarded drug release and increased its residence time (MRT) in rats. The OX-emulsome and the OX-emulsome-thermogel formulations showed in vitro sustained drug release of 81.1 and 53.5%, respectively, over a period of 24 h. The pharmacokinetic studies in rats showed transport of OX to the systemic circulation after nasal administration with a higher uptake in the brain tissue in case of OX-emulsomes and highest MRT for OX-emulsomal-thermogels as compared to the IN OX-emulsomes, OX-solution and Trileptal^® suspension. Histopathological examination of nasal tissues showed a mild vascular congestion and moderate inflammatory changes around congested vessels compared to saline control, but lower toxic effect than that reported in case of the drug solution. Full article

(This article belongs to the Special Issue Transmucosal Absorption Enhancers in the Drug Delivery Field)

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15 pages, 3726 KiB

Open AccessArticle

The Role of Combined Penetration Enhancers in Nasal Microspheres on In Vivo Drug Bioavailability

by Giovanna Rassu, Luca Ferraro, Barbara Pavan, Paolo Giunchedi, Elisabetta Gavini and Alessandro Dalpiaz

Pharmaceutics 2018, 10(4), 206; https://doi.org/10.3390/pharmaceutics10040206 - 26 Oct 2018

Cited by 39 | Viewed by 4592

Abstract

Microspheres based on both methyl-β-cyclodextrins and chitosan were prepared by spray-drying as nasal formulations of a model polar drug to analyze, firstly, how the composition of the carrier affects drug permeation across synthetic membranes and, secondly, how it induces systemic or brain delivery [...] Read more.

Microspheres based on both methyl-β-cyclodextrins and chitosan were prepared by spray-drying as nasal formulations of a model polar drug to analyze, firstly, how the composition of the carrier affects drug permeation across synthetic membranes and, secondly, how it induces systemic or brain delivery of the drug. Microparticles with different weight ratios of the two penetration enhancers (10–90, 50–50, 90–10) were characterized with respect to morphology, size, structural composition, water uptake, and the in vitro drug permeation profile. The leader formulation (weight ratio of 50–50) was then nasally administered to rats; systemic and cerebrospinal fluid (CSF) drug concentrations were analyzed by high performance liquid chromatography (HPLC) over time. Microspheres obtained with a single enhancer, methyl-β-cyclodextrins or chitosan, were administered in vivo as a comparison. The in vitro properties of combined microspheres appeared modified with regard to the polymeric matrix ratio. In vivo results suggest that the optimal drug distribution between CSF and bloodstream can be easily obtained by varying the amount of these two penetration enhancers studied in the matrix of nasal microspheres. Full article

(This article belongs to the Special Issue Transmucosal Absorption Enhancers in the Drug Delivery Field)

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21 pages, 4610 KiB

Open AccessArticle

Hydrophobic Amino Acid Tryptophan Shows Promise as a Potential Absorption Enhancer for Oral Delivery of Biopharmaceuticals

by Noriyasu Kamei, Hideyuki Tamiwa, Mari Miyata, Yuta Haruna, Koyo Matsumura, Hideyuki Ogino, Serena Hirano, Kazuhiro Higashiyama and Mariko Takeda-Morishita

Pharmaceutics 2018, 10(4), 182; https://doi.org/10.3390/pharmaceutics10040182 - 10 Oct 2018

Cited by 19 | Viewed by 6638

Abstract

Cell-penetrating peptides (CPPs) have great potential to efficiently deliver drug cargos across cell membranes without cytotoxicity. Cationic arginine and hydrophobic tryptophan have been reported to be key component amino acids for cellular internalization of CPPs. We recently found that l-arginine could increase [...] Read more.

Cell-penetrating peptides (CPPs) have great potential to efficiently deliver drug cargos across cell membranes without cytotoxicity. Cationic arginine and hydrophobic tryptophan have been reported to be key component amino acids for cellular internalization of CPPs. We recently found that l-arginine could increase the oral delivery of insulin in its single amino acid form. Therefore, in the present study, we evaluated the ability of another key amino acid, tryptophan, to enhance the intestinal absorption of biopharmaceuticals. We demonstrated that co-administration with l-tryptophan significantly facilitated the oral and intestinal absorption of the peptide drug insulin administered to rats. Furthermore, l-tryptophan exhibited the ability to greatly enhance the intestinal absorption of other peptide drugs such as glucagon-like peptide-1 (GLP-1), its analog Exendin-4 and macromolecular hydrophilic dextrans with molecular weights ranging from 4000 to 70,000 g/mol. However, no intermolecular interaction between insulin and l-tryptophan was observed and no toxic alterations to epithelial cellular integrity—such as changes to cell membranes, cell viability, or paracellular tight junctions—were found. This suggests that yet to be discovered inherent biological mechanisms are involved in the stimulation of insulin absorption by co-administration with l-tryptophan. These results are the first to demonstrate the significant potential of using the single amino acid l-tryptophan as an effective and versatile bioavailability enhancer for the oral delivery of biopharmaceuticals. Full article

(This article belongs to the Special Issue Transmucosal Absorption Enhancers in the Drug Delivery Field)

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17 pages, 6770 KiB

Open AccessArticle

Probing the Action of Permeation Enhancers Sodium Cholate and N-dodecyl-β-D-maltoside in a Porcine Jejunal Mucosal Explant System

by E. Michael Danielsen and Gert H. Hansen

Pharmaceutics 2018, 10(4), 172; https://doi.org/10.3390/pharmaceutics10040172 - 2 Oct 2018

Cited by 12 | Viewed by 4302

Abstract

The small intestinal epithelium constitutes a major permeability barrier for the oral administration of therapeutic drugs with poor bioavailability, and permeation enhancers (PEs) are required to increase the paracellular and/or transcellular uptake of such drugs. Many PEs act as surfactants by perturbing cell [...] Read more.

The small intestinal epithelium constitutes a major permeability barrier for the oral administration of therapeutic drugs with poor bioavailability, and permeation enhancers (PEs) are required to increase the paracellular and/or transcellular uptake of such drugs. Many PEs act as surfactants by perturbing cell membrane integrity and causing permeabilization by leakage or endocytosis. The aim of the present work was to study the action of sodium cholate (NaC) and N-dodecyl-β-D-maltoside (DDM), using a small intestinal mucosal explant system. At 2 mM, both NaC and DDM caused leakage into the enterocyte cytosol of the fluorescent probe Lucifer Yellow, but they also blocked the constitutive endocytotic pathway from the brush border. In addition, an increased paracellular passage of 3-kDa Texas Red Dextran into the lamina propria was observed. By electron microscopy, both PEs disrupted the hexagonal organization of microvilli of the brush border and led to the apical extrusion of vesicle-like and amorphous cell debris to the lumen. In conclusion, NaC and DDM acted in a multimodal way to increase the permeability of the jejunal epithelium both by paracellular and transcellular mechanisms. However, endocytosis, commonly thought to be an uptake mechanism that may be stimulated by PEs, was not involved in the transcellular process. Full article

(This article belongs to the Special Issue Transmucosal Absorption Enhancers in the Drug Delivery Field)

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18 pages, 2305 KiB

Open AccessArticle

Synthesis, Structure–Activity Relationships and In Vitro Toxicity Profile of Lactose-Based Fatty Acid Monoesters as Possible Drug Permeability Enhancers

by Simone Lucarini, Laura Fagioli, Robert Cavanagh, Wanling Liang, Diego Romano Perinelli, Mario Campana, Snjezana Stolnik, Jenny K. W. Lam, Luca Casettari and Andrea Duranti

Pharmaceutics 2018, 10(3), 81; https://doi.org/10.3390/pharmaceutics10030081 - 3 Jul 2018

Cited by 31 | Viewed by 6611

Abstract

Permeability enhancers are receiving increased attention arising from their ability to increase transepithelial permeability and thus, bioavailability of orally or pulmonary administered biopharmaceutics. Here we present the synthesis and the in vitro assaying of a series of lactose-based non-ionic surfactants, highlighting the relationship [...] Read more.

Permeability enhancers are receiving increased attention arising from their ability to increase transepithelial permeability and thus, bioavailability of orally or pulmonary administered biopharmaceutics. Here we present the synthesis and the in vitro assaying of a series of lactose-based non-ionic surfactants, highlighting the relationship between their structure and biological effect. Using tensiometric measurements the critical micelle concentrations (CMCs) of the surfactants were determined and demonstrate that increasing hydrophobic chain length reduces surfactant CMC. In vitro testing on Caco-2 intestinal and Calu-3 airway epithelia revealed that cytotoxicity, assessed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and lactate dehydrogenase (LDH) release assays, is presented for most of the surfactants at concentrations greater than their CMCs. Further biological study demonstrates that application of cytotoxic concentrations of the surfactants is associated with depolarizing mitochondrial membrane potential, increasing nuclear membrane permeability and activation of effector caspases. It is, therefore, proposed that when applied at cytotoxic levels, the surfactants are inducing apoptosis in both cell lines tested. Importantly, through the culture of epithelial monolayers on Transwell^® supports, the surfactants demonstrate the ability to reversibly modulate transepithelial electrical resistance (TEER), and thus open tight junctions, at non-toxic concentrations, emphasizing their potential application as safe permeability enhancers in vivo. Full article

(This article belongs to the Special Issue Transmucosal Absorption Enhancers in the Drug Delivery Field)

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Review

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33 pages, 5435 KiB

Open AccessReview

Penetration Enhancers in Ocular Drug Delivery

by Roman V. Moiseev, Peter W. J. Morrison, Fraser Steele and Vitaliy V. Khutoryanskiy

Pharmaceutics 2019, 11(7), 321; https://doi.org/10.3390/pharmaceutics11070321 - 9 Jul 2019

Cited by 154 | Viewed by 12596

Abstract

There are more than 100 recognized disorders of the eye. This makes the development of advanced ocular formulations an important topic in pharmaceutical science. One of the ways to improve drug delivery to the eye is the use of penetration enhancers. These are [...] Read more.

There are more than 100 recognized disorders of the eye. This makes the development of advanced ocular formulations an important topic in pharmaceutical science. One of the ways to improve drug delivery to the eye is the use of penetration enhancers. These are defined as compounds capable of enhancing drug permeability across ocular membranes. This review paper provides an overview of anatomical and physiological features of the eye and discusses some common ophthalmological conditions and permeability of ocular membranes. The review also presents the analysis of literature on the use of penetration-enhancing compounds (cyclodextrins, chelating agents, crown ethers, bile acids and bile salts, cell-penetrating peptides, and other amphiphilic compounds) in ocular drug delivery, describing their properties and modes of action. Full article

(This article belongs to the Special Issue Transmucosal Absorption Enhancers in the Drug Delivery Field)

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20 pages, 1450 KiB

Open AccessReview

Strategies to Enhance Drug Absorption via Nasal and Pulmonary Routes

by Maliheh Ghadiri, Paul M. Young and Daniela Traini

Pharmaceutics 2019, 11(3), 113; https://doi.org/10.3390/pharmaceutics11030113 - 11 Mar 2019

Cited by 181 | Viewed by 12462

Abstract

New therapeutic agents such as proteins, peptides, and nucleic acid-based agents are being developed every year, making it vital to find a non-invasive route such as nasal or pulmonary for their administration. However, a major concern for some of these newly developed therapeutic [...] Read more.

New therapeutic agents such as proteins, peptides, and nucleic acid-based agents are being developed every year, making it vital to find a non-invasive route such as nasal or pulmonary for their administration. However, a major concern for some of these newly developed therapeutic agents is their poor absorption. Therefore, absorption enhancers have been investigated to address this major administration problem. This paper describes the basic concepts of transmucosal administration of drugs, and in particular the use of the pulmonary or nasal routes for administration of drugs with poor absorption. Strategies for the exploitation of absorption enhancers for the improvement of pulmonary or nasal administration are discussed, including use of surfactants, cyclodextrins, protease inhibitors, and tight junction modulators, as well as application of carriers such as liposomes and nanoparticles. Full article

(This article belongs to the Special Issue Transmucosal Absorption Enhancers in the Drug Delivery Field)

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21 pages, 1614 KiB

Open AccessReview

Intestinal Permeation Enhancers for Oral Delivery of Macromolecules: A Comparison between Salcaprozate Sodium (SNAC) and Sodium Caprate (C₁₀)

by Caroline Twarog, Sarinj Fattah, Joanne Heade, Sam Maher, Elias Fattal and David J. Brayden

Pharmaceutics 2019, 11(2), 78; https://doi.org/10.3390/pharmaceutics11020078 - 13 Feb 2019

Cited by 157 | Viewed by 26814

Abstract

Salcaprozate sodium (SNAC) and sodium caprate (C₁₀) are two of the most advanced intestinal permeation enhancers (PEs) that have been tested in clinical trials for oral delivery of macromolecules. Their effects on intestinal epithelia were studied for over 30 years, yet [...] Read more.

Salcaprozate sodium (SNAC) and sodium caprate (C₁₀) are two of the most advanced intestinal permeation enhancers (PEs) that have been tested in clinical trials for oral delivery of macromolecules. Their effects on intestinal epithelia were studied for over 30 years, yet there is still debate over their mechanisms of action. C₁₀ acts via openings of epithelial tight junctions and/or membrane perturbation, while for decades SNAC was thought to increase passive transcellular permeation across small intestinal epithelia based on increased lipophilicity arising from non-covalent macromolecule complexation. More recently, an additional mechanism for SNAC associated with a pH-elevating, monomer-inducing, and pepsin-inhibiting effect in the stomach for oral delivery of semaglutide was advocated. Comparing the two surfactants, we found equivocal evidence for discrete mechanisms at the level of epithelial interactions in the small intestine, especially at the high doses used in vivo. Evidence that one agent is more efficacious compared to the other is not convincing, with tablets containing these PEs inducing single-digit highly variable increases in oral bioavailability of payloads in human trials, although this may be adequate for potent macromolecules. Regarding safety, SNAC has generally regarded as safe (GRAS) status and is Food and Drug Administration (FDA)-approved as a medical food (Eligen^®-Vitamin B₁₂, Emisphere, Roseland, NJ, USA), whereas C₁₀ has a long history of use in man, and has food additive status. Evidence for co-absorption of microorganisms in the presence of either SNAC or C₁₀ has not emerged from clinical trials to date, and long-term effects from repeat dosing beyond six months have yet to be assessed. Since there are no obvious scientific reasons to prefer SNAC over C₁₀ in orally delivering a poorly permeable macromolecule, then formulation, manufacturing, and commercial considerations are the key drivers in decision-making. Full article

(This article belongs to the Special Issue Transmucosal Absorption Enhancers in the Drug Delivery Field)

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23 pages, 983 KiB

Open AccessReview

Application of Permeation Enhancers in Oral Delivery of Macromolecules: An Update

by Sam Maher, David J. Brayden, Luca Casettari and Lisbeth Illum

Pharmaceutics 2019, 11(1), 41; https://doi.org/10.3390/pharmaceutics11010041 - 19 Jan 2019

Cited by 123 | Viewed by 11971

Abstract

The application of permeation enhancers (PEs) to improve transport of poorly absorbed active pharmaceutical ingredients across the intestinal epithelium is a widely tested approach. Several hundred compounds have been shown to alter the epithelial barrier, and although the research emphasis has broadened to [...] Read more.

The application of permeation enhancers (PEs) to improve transport of poorly absorbed active pharmaceutical ingredients across the intestinal epithelium is a widely tested approach. Several hundred compounds have been shown to alter the epithelial barrier, and although the research emphasis has broadened to encompass a role for nanoparticle approaches, PEs represent a key constituent of conventional oral formulations that have progressed to clinical testing. In this review, we highlight promising PEs in early development, summarize the current state of the art, and highlight challenges to the translation of PE-based delivery systems into safe and effective oral dosage forms for patients. Full article

(This article belongs to the Special Issue Transmucosal Absorption Enhancers in the Drug Delivery Field)

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46 pages, 2240 KiB

Open AccessReview

Drug Bioavailability Enhancing Agents of Natural Origin (Bioenhancers) that Modulate Drug Membrane Permeation and Pre-Systemic Metabolism

by Bianca Peterson, Morné Weyers, Jan H. Steenekamp, Johan D. Steyn, Chrisna Gouws and Josias H. Hamman

Pharmaceutics 2019, 11(1), 33; https://doi.org/10.3390/pharmaceutics11010033 - 16 Jan 2019

Cited by 71 | Viewed by 9440

Abstract

Many new chemical entities are discovered with high therapeutic potential, however, many of these compounds exhibit unfavorable pharmacokinetic properties due to poor solubility and/or poor membrane permeation characteristics. The latter is mainly due to the lipid-like barrier imposed by epithelial mucosal layers, which [...] Read more.

Many new chemical entities are discovered with high therapeutic potential, however, many of these compounds exhibit unfavorable pharmacokinetic properties due to poor solubility and/or poor membrane permeation characteristics. The latter is mainly due to the lipid-like barrier imposed by epithelial mucosal layers, which have to be crossed by drug molecules in order to exert a therapeutic effect. Another barrier is the pre-systemic metabolic degradation of drug molecules, mainly by cytochrome P450 enzymes located in the intestinal enterocytes and liver hepatocytes. Although the nasal, buccal and pulmonary routes of administration avoid the first-pass effect, they are still dependent on absorption of drug molecules across the mucosal surfaces to achieve systemic drug delivery. Bioenhancers (drug absorption enhancers of natural origin) have been identified that can increase the quantity of unchanged drug that appears in the systemic blood circulation by means of modulating membrane permeation and/or pre-systemic metabolism. The aim of this paper is to provide an overview of natural bioenhancers and their main mechanisms of action for the nasal, buccal, pulmonary and oral routes of drug administration. Poorly bioavailable drugs such as large, hydrophilic therapeutics are often administered by injections. Bioenhancers may potentially be used to benefit patients by making systemic delivery of these poorly bioavailable drugs possible via alternative routes of administration (i.e., oral, nasal, buccal or pulmonary routes of administration) and may also reduce dosages of small molecular drugs and thereby reduce treatment costs. Full article

(This article belongs to the Special Issue Transmucosal Absorption Enhancers in the Drug Delivery Field)

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