Publications by authors named "Yogeshvar N Kalia"

87 Publications

Co-administration of zinc phthalocyanine and quercetin via hybrid nanoparticles for augmented photodynamic therapy.

Nanomedicine 2021 Feb 3:102368. Epub 2021 Feb 3.

Department of Pharmaceutical Technology (Biotechnology), National Institute of Pharmaceutical Education and Research (NIPER), Nagar, Punjab, India; Department of Biotechnology, National Institute of Pharmaceutical Education and Research (NIPER), Nagar, Punjab, India. Electronic address:

The photodynamic anticancer activity of a photosensitizer can be further increased by co-administration of a flavonoid. However, this requires that both molecules must be effectively accumulated at the tumor site. Hence, in order to enhance the activity of zinc phthalocyanine (ZnPc, photosensitizer), it was co-encapsulated with quercetin (QC, flavonoid) in lipid polymer hybrid nanoparticles (LPNs) developed using biodegradable & biocompatible materials and prepared using a single-step nanoprecipitation technique. High stability and cellular uptake, sustained release, inherent fluorescence, of ZnPC were observed after encapsulation in the LPNs, which also showed a higher cytotoxic effect in breast carcinoma cells (MCF-7) compared to photodynamic therapy (PDT) alone. In vivo studies in tumor-bearing Sprague Dawley rats demonstrated that the LPNs were able to deliver ZnPc and QC to the tumor site with minimal systemic toxicity and increased antitumor effect. Overall, the photodynamic effect of ZnPc was synergized by QC. This strategy could be highly beneficial for cancer management in the future while nullifying the side effects of chemotherapy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.nano.2021.102368DOI Listing
February 2021

Iontosomes: Electroresponsive Liposomes for Topical Iontophoretic Delivery of Chemotherapeutics to the Buccal Mucosa.

Pharmaceutics 2021 Jan 11;13(1). Epub 2021 Jan 11.

School of Pharmaceutical Sciences, University of Geneva, CMU-1 Rue Michel Servet, 1211 Geneva, Switzerland.

The targeted local delivery of anticancer therapeutics offers an alternative to systemic chemotherapy for oral cancers not amenable to surgical excision. However, epithelial barrier function can pose a challenge to their passive topical delivery. The charged, deformable liposomes-"iontosomes"-described here are able to overcome the buccal mucosal barrier via a combination of the electrical potential gradient imposed by iontophoresis and their shape-deforming characteristics. Two chemotherapeutic agents with very different physicochemical properties, cisplatin (CDDP) and docetaxel (DTX), were co-encapsulated in cationic iontosomes comprising 1,2-dioleoyl-3-trimethylammonium-propane (DOTAP) and Lipoid-S75. The entrapment of CDDP was improved by formulating it in anionic reverse micelles of dipalmitoyl-sn-glycero-3-phospho-rac-glycerol sodium (DPPG) prior to loading in the iontosomes. Cryo-TEM imaging clearly demonstrated the iontosomes' electroresponsive shape-deformable properties. The in vitro transport study using porcine mucosa indicated that iontosomes did not enter the mucosa without an external driving force. However, anodal iontophoresis resulted in significant amounts of co-encapsulated CDDP and DTX being deposited in the buccal mucosa; e.g., after current application for 10 min, the deposition of CDDP and DTX was 13.54 ± 1.78 and 10.75 ± 1.75 μg/cm cf. 0.20 ± 0.07 and 0.19 ± 0.09 μg/cm for the passive controls-i.e., 67.7- and 56.6-fold increases-without any noticeable increase in their transmucosal permeation. Confocal microscopy confirmed that the iontosomes penetrated the mucosa through the intercellular spaces and that the penetration depth could be controlled by varying the duration of current application. Overall, the results suggest that the combination of topical iontophoresis with a suitable nanocarrier system can be used to deliver multiple "physicochemically incompatible" chemotherapeutics selectively to oral cancers while decreasing the extent of systemic absorption and the associated risk of side effects.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/pharmaceutics13010088DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7826915PMC
January 2021

Using Ex Vivo Porcine Jejunum to Identify Membrane Transporter Substrates: A Screening Tool for Early-Stage Drug Development.

Biomedicines 2020 Sep 10;8(9). Epub 2020 Sep 10.

School of Pharmaceutical Sciences, University of Geneva, Centre Médical Universitaire, 1 rue Michel Servet, 1211 Geneva, Switzerland.

Robust, predictive ex vivo/in vitro models to study intestinal drug absorption by passive and active transport mechanisms are scarce. Membrane transporters can significantly impact drug uptake and transporter-mediated drug-drug interactions can play a pivotal role in determining the drug safety profile. Here, the presence and activity of seven clinically relevant apical/basolateral drug transporters found in human jejunum were tested using ex vivo porcine intestine in a Ussing chamber system. Experiments using known substrates of peptide transporter 1 (PEPT1), organic anion transporting polypeptide (OATP2B1), organic cation transporter 1 (OCT1), P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), multi drug resistance-associated protein 2 and 3 (MRP2 and MRP3), in the absence and presence of potent inhibitors, showed that there was a statistically significant change in apparent intestinal permeability (cm/s) in the presence of the corresponding inhibitor. For MRP2, a transporter reportedly present at relatively low concentration, although did not significantly change in the presence of the inhibitor, substrate deposition () in the intestinal tissue was significantly increased. The activity of the seven transport proteins was successfully demonstrated and the results provided insight into their apical/basolateral localization. In conclusion, the results suggest that studies using the porcine intestine/Ussing chamber system, which could easily be integrated into the drug development process, might enable the early-stage identification of new molecular entities that are substrates of membrane transporters.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/biomedicines8090340DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7555276PMC
September 2020

Tissue Levels of Flurbiprofen in the Rat Plantar Heel after Short-Duration Topical Iontophoresis are Sufficient to Induce Pharmacodynamic Responses to Local Pain Stimuli.

Pharmaceutics 2020 Jun 30;12(7). Epub 2020 Jun 30.

Laboratory for Drug Delivery & Translational Medicine, School of Pharmacy, Nantong University, 19 Qixiu Road, Nantong 226001, Jiangsu Province, China.

The objective of this study was to investigate the topical iontophoresis of flurbiprofen (FBF) as a means to enhance its local bioavailability and thereby provide an improved and targeted treatment of plantar heel pain. Initial in vitro experiments using porcine ear skin investigated iontophoretic transport of FBF under different conditions. Local FBF biodistribution in the rat paw in vivo was compared after topical or oral administration. Efficacy of pain management was investigated using a plantar incisional model by evaluating pharmacodynamic responses to local pain stimuli. The results demonstrated that iontophoresis of FBF significantly increased cutaneous deposition and transdermal permeation of FBF as compared to passive delivery-it also enabled drug input to be controlled by modulation of current density and drug concentration (r > 0.99). Topical iontophoresis of FBF in vivo enabled higher drug levels in skin and muscle in rat plantar aspect and superior pharmacodynamic responses to local pain stimuli, in comparison to oral and passive delivery. In conclusion, short-duration topical iontophoresis of FBF may better help to relieve plantar heel pain than oral or passive administration, which should be of clinical interest.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/pharmaceutics12070608DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7408369PMC
June 2020

Targeted cutaneous delivery of etanercept using Er:YAG fractional laser ablation.

Int J Pharm 2020 Apr 16;580:119234. Epub 2020 Mar 16.

School of Pharmaceutical Sciences, University of Geneva, CMU - 1 Rue Michel Servet 1211, Geneva, Switzerland. Electronic address:

The aim was to investigate the feasibility of using Er:YAG fractional laser ablation to enable topical cutaneous delivery of etanercept (ETA). Preliminary investigations into the effect of fluence on micropore depth, measured by full-field optical coherence tomography, were followed by quantitative experiments to determine ETA delivery and its cutaneous biodistribution from solution and hydrogel formulations. Visualization studies were performed using confocal laser scanning microscopy and an ETA-fluorescein conjugate. Micropore depth was linearly dependent on laser fluence. However, use of a single pulse or "pulse stacking" (i.e. multiple pulses) to apply a given fluence affected pore depth; this was accommodated mathematically by including a "stacking factor". ETA delivery into porated skin from solution and 0.8% Carbopol® formulations was equivalent: increasing ETA content in the gels from 0.5 to 1 and 2% increased ETA delivery linearly (Formulations 7-9: 5.12 ± 0.95 to 7.48 ± 1.45 and 11.2 ± 2.2 µg/cm, respectively; 10% FAA, 89.9 J/cm, 5 ppp); occlusion further increased ETA delivery from Formulation 9 to 23.17 ± 6.62 µg/cm. Cutaneous biodistribution studies demonstrated that ETA was delivered in therapeutically relevant amounts to the epidermis and dermis. Topical laser-assisted delivery of ETA might expand its range of clinical indications to include recalcitrant but not widespread psoriatic plaques (clinical trial underway).
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ijpharm.2020.119234DOI Listing
April 2020

Non-invasive targeted iontophoretic delivery of cetuximab to skin.

Expert Opin Drug Deliv 2020 04 27;17(4):589-602. Epub 2020 Feb 27.

School of Pharmaceutical Sciences, University of Geneva, Geneva, Switzerland.

: Cetuximab (CTX) is a glycosylated anti-EGFR monoclonal antibody of great interest in the treatment of non-melanoma skin cancers. Its intravenous administration is associated with severe side effects. This is the first report on the noninvasive iontophoretic-targeted topical delivery of CTX to skin.: Iontophoretic transport of CTX (0.5 mA/cm) was studied as a function of formulation pH (4, 5.5 and 7) and duration of current application (2, 4 and 8 h). CTX cutaneous biodistribution was determined; electrotransport mechanisms and penetration pathways were investigated.: Electrophoretic mobility measurements of CTX isoforms and co-iontophoresis of acetaminophen at each pH demonstrated that CTX electrotransport was due to electroosmosis: despite an ~8-fold reduction in charge, CTX skin deposition was greater at pH 7 than pH 4 (8.974 ± 1.952 and 0.482 ± 0.165 μg/mm) - consistent with the increased electroosmotic flow at pH 7. Iontophoresis of an Alex488-CTX conjugate showed that skin penetration occurred by the intercellular and follicular routes. Therapeutic concentrations of CTX in the viable epidermis, upper dermis and lower dermis were achieved following iontophoresis for 2, 4 and 8 h, respectively.: The results demonstrate the topical delivery of a 152 kDa monoclonal antibody into skin in a targeted, controlled and entirely noninvasive manner.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/17425247.2020.1731470DOI Listing
April 2020

Ocular Biodistribution of Spironolactone after a Single Intravitreal Injection of a Biodegradable Sustained-Release Polymer in Rats.

Mol Pharm 2020 01 5;17(1):59-69. Epub 2019 Dec 5.

School of Pharmaceutical Sciences , University of Geneva & University of Lausanne , CMU-Rue Michel Servet 1 , 1211 Geneva 4 , Switzerland.

Sustained-release formulations for ocular delivery are of increasing interest given their potential to significantly improve treatment efficacy and patient adherence. The objectives of this study were (i) to develop a sustained-release formulation of spironolactone (SPL) using a biodegradable and injectable polymer, hexyl-substituted poly-lactic acid (hexPLA) and (ii) to investigate the ocular biodistribution and tolerability of SPL and its metabolites in rats in vivo over 1 month following a single intravitreal injection (IVT inj). The concentrations of SPL and its two principal active metabolites, 7α-thiomethylspironolactone and canrenone (CAN), in the different ocular compartments were determined at different time points (3, 7, and 31 days after IVT inj) using a validated ultra-high-performance liquid chromatography-mass spectrometry method. Systemic exposure following a single IVT inj of 5% SPL-hexPLA formulation was evaluated by quantifying SPL and its metabolites in the plasma. Ocular tolerability of the formulation was evaluated using in vivo retinal imaging and histology. In vitro release studies revealed a sustained release of SPL from 5% SPL-hexPLA for up to 65 days. In vivo studies showed that SPL and its metabolites were detected in all ocular tissues at 3 and 7 days post-IVT inj. At 31 days post-IVT inj, SPL and CAN were mainly detected in the retina. These results also highlighted the clearance pathway of SPL and its metabolite involving the anterior and posterior routes in the first week (days 3 and 7), then mainly the posterior segment in the last week (day 31). This study showed that a single IVT inj of 5% SPL-hexPLA in rats enabled sustained delivery of therapeutic amounts of SPL for up to 1 month to the retina without systemic exposure. This formulation may be of interest for the local treatment of diseases involving overactivation of the mineralocorticoid receptor in the chorioretina such as chronic central serous chorioretinopathy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/acs.molpharmaceut.9b00707DOI Listing
January 2020

Cutaneous Biodistribution: A High-Resolution Methodology to Assess Bioequivalence in Topical Skin Delivery.

Pharmaceutics 2019 Sep 18;11(9). Epub 2019 Sep 18.

School of Pharmaceutical Sciences, University of Geneva, CMU-1 rue Michel Servet, 1211 Geneva 4, Switzerland.

A draft guideline from the European Medicines Agency (EMA) highlights the need for methods to assess the quality/equivalence of topical drug formulations. The "cutaneous biodistribution method", which provides insight into a drug's spatial distribution in the epidermis/dermis, was used to compare cutaneous bioavailability of econazole nitrate (ECZ) from a reference medicinal product (RMP) and two approved bioequivalent generic creams under finite dose conditions. Statistically significant differences between the ECZ biodistributions from the RMP/Generics were determined and used with acceptance criteria based on those from the EMA to evaluate bioequivalence. In porcine skin, ECZ deposition in total skin, epidermis, upper and lower dermis from Generic 1 was within the acceptance interval, contrary to Generic 2, which was marginally below it. For human skin, Generic 1 deposition was marginally above the acceptance interval and not bioequivalent. The results were consistent with those using the EMA's acceptance intervals using the ratio of the mean ECZ depositions of Generic 1 and the RMP. Differences identified using this data-rich technique may not translate to observable differences in clinical efficacy; however, generics with non-statistically different biodistributions to the RMP should have a comparable clinical effect. The cutaneous biodistribution method could benchmark the development of topical generic products.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/pharmaceutics11090484DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6781275PMC
September 2019

Using ordered mesoporous silica SBA-15 to limit cutaneous penetration and transdermal permeation of organic UV filters.

Int J Pharm 2019 Oct 19;570:118633. Epub 2019 Aug 19.

School of Pharmaceutical Sciences, University of Geneva & University of Lausanne, Switzerland. Electronic address:

Avobenzone (AVO), oxybenzone (OXY), and octyl methoxycinnamate (OMC), are widely used UV filters. The aim of this study was to investigate the effect of incorporation in mesoporous silica (SBA-15) on their cutaneous deposition and permeation. Stick formulations containing "free" and "incorporated" UV filters (SF1 and SF2, respectively) were prepared and characterized with respect to their physicochemical, thermal, and functional properties. Cutaneous delivery experiments using porcine skin with quantification by UHPLC-MS/MS, demonstrated that skin deposition of AVO and OXY after application of SF2 for 6 and 12 h was significantly lower than that from SF1 at each time-point (Student t-test, p < 0.05): e.g. OXY permeation across the skin was 30-, 12- and 1.5-fold lower after 6, 12 and 24 h, respectively, following application of SF2. Cutaneous biodistribution profiles of AVO and OXY to 800 µm evidenced a significant decrease in the amounts in the viable epidermis and dermis. In contrast, deposition of the more lipophilic OMC was not significantly different (p ˃ 0.05). In vitro photoprotective efficacy results demonstrated that adsorption/entrapment of UV filters enhanced the sun protection factor by 94%. In conclusion, SBA-15, an innovative mesoporous material, increased photoprotection by UV filters while reducing their cutaneous penetration and transdermal permeation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ijpharm.2019.118633DOI Listing
October 2019

Topical iontophoresis of buflomedil hydrochloride increases drug bioavailability in the mucosa: A targeted approach to treat oral submucous fibrosis.

Int J Pharm 2019 Oct 12;569:118610. Epub 2019 Aug 12.

School of Pharmaceutical Sciences, University of Geneva & University of Lausanne, Geneva, Switzerland. Electronic address: https://epgl.unige.ch/molthera.

The aim was to investigate the effect of constant current iontophoresis on the delivery and biodistribution of buflomedil hydrochloride (BUF) in the buccal mucosa. Quantification was by UHPLC-MS/MS; in addition to total delivery, the amounts present in the epithelia and the lamina propria (the target tissue) were also determined. Two-compartment vertical diffusion cells were used to investigate the effect of current density (0.5, 1 and 2 mA/cm), application time (5, 10 and 20 min) and concentration (5, 10 and 20 mM) on iontophoretic delivery of BUF from aqueous solutions. In contrast to passive delivery, iontophoresis for 10 min at 1 mA/cm resulted in statistically equivalent transport from a 20 mM solution and a 2% HEC hydrogel (with equivalent BUF loading; 20 µmol). BUF delivery from the hydrogel using diffusion cells and a new coplanar "side-by-side" set-up was statistically equivalent (304.2 ± 28.9 and 278.2 ± 40.3 µg/cm) - passive delivery was also similar. Iontophoresis (10 min at 1 mA/cm) using a thin film (20 µmol BUF) was superior to the passive control (323.3 ± 5.9 and 24.8 ± 5.9 µg/cm). Concentrations in the LP were ~700-fold > IC to block collagen production, potentially providing a new therapeutic strategy for oral submucous fibrosis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ijpharm.2019.118610DOI Listing
October 2019

Controlled Iontophoretic Delivery and of ARN14140-A Multitarget Compound for Alzheimer's Disease.

Mol Pharm 2019 08 5;16(8):3460-3468. Epub 2019 Jul 5.

School of Pharmaceutical Sciences , University of Geneva and University of Lausanne , Geneva , Switzerland.

ARN14140 is a galantamine-memantine conjugate that acts upon both cholinergic and glutamatergic pathways for better management of Alzheimer's disease. Poor oral bioavailability and pharmacokinetics meant that earlier preclinical studies employed intracerebroventricular injection to administer ARN14140 directly to the brain. The aim of the present study was to evaluate the feasibility of using constant current transdermal iontophoresis for the noninvasive systemic delivery of ARN14140 and to quantify the amounts present in the blood and the brain. Preliminary experiments were performed using porcine skin and validated with human skin. Cumulative ARN14140 permeation across the skin increased linearly with current density and concentration. Delivery efficiency (i.e., fraction of the amount applied that is delivered) reached an exceptional 76.9%. Statistically equivalent delivery was observed after iontophoresis across human and porcine skin. studies in male Wistar rats showed that iontophoretic transport of ARN14140 could be controlled using the current density (426.7 ± 42 and 1118.3 ± 73 nmol/cm at 0.15 and 0.5 mA/cm for 6 h) and demonstrated that transdermal iontophoresis was able to deliver ARN14140 noninvasively to the brain. This is the first report quantifying drug levels in the blood and the brain following transdermal iontophoresis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/acs.molpharmaceut.9b00252DOI Listing
August 2019

Er:YAG fractional laser ablation for cutaneous co-delivery of pentoxifylline and d-α-tocopherol succinate: A new approach for topical treatment of radiation-induced skin fibrosis.

Eur J Pharm Sci 2019 Jul 10;135:22-31. Epub 2019 May 10.

School of Pharmaceutical Sciences, University of Geneva & University of Lausanne, 1211 Geneva, Switzerland. Electronic address:

Radiation induced fibrosis is a common side-effect after radiotherapy. Pentoxifylline is reported to reverse radiation injuries when used in conjunction with D-α-tocopherol. However, pentoxifylline has a short half-life, limited oral bioavailability, and induces several systemic adverse effects. The objective of this study was to investigate the feasibility of using Er:YAG fractional laser ablation to enable simultaneous cutaneous delivery of pentoxifylline and D- α -tocopherol succinate from poly(lactide-co-glycolide) microparticles prepared using the freeze-fracture technique. In vitro release experiments demonstrated the different release profiles of the two molecules, which were influenced by their very different lipophilicities and aqueous solubilities. Experiments were then performed to investigate the effect of laser fluence on pore depth and so determine the pore volume available to host the topically applied microparticles. Application of the pentoxifylline and D-α-tocopherol succinate containing microparticles, prepared with RESOMER® RG 502H, to laser porated skin for 48 h, resulted in simultaneous delivery of pentoxifylline (69.63 ± 6.41 μg/cm; delivery efficiency 46.4%) and D-α-tocopherol succinate (33.25 ± 8.91 μg/cm; delivery efficiency 22.2%). After deposition into the micropores, the poly(lactide-co-glycolide) microparticles containing pentoxifylline and D-α-tocopherol succinate could serve as an intraepidermal depot to enable sustained drug delivery after micropore closure and thereby reduce the need for repeated microporation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ejps.2019.05.007DOI Listing
July 2019

Polymeric micelle nanocarriers for targeted epidermal delivery of the hedgehog pathway inhibitor vismodegib: formulation development and cutaneous biodistribution in human skin.

Expert Opin Drug Deliv 2019 06 26;16(6):667-674. Epub 2019 Apr 26.

a School of Pharmaceutical Sciences , University of Geneva & University of Lausanne , Geneva , Switzerland.

: The aim was to investigate cutaneous delivery and biodistribution of the hedgehog pathway inhibitor, vismodegib (VSD), indicated for basal cell carcinoma (BCC), from polymeric micelle formulations under infinite/finite dose conditions. : VSD-loaded micelles were characterized for drug content, particle size, and shape; a micelle gel was characterized for its rheological behavior. Cutaneous deposition and biodistribution of VSD were determined using porcine and human skin with quantification by UHPLC-MS/MS. : The optimal micelle solution (Z 20-30 nm) increased the aqueous solubility of VSD by >8000-fold; drug content was stable after 4 weeks at 4°C. Application of micelle solution and micelle gel (0.086% w/v) to human skin for 12 h under infinite dose conditions resulted in statistically equivalent VSD deposition (0.62 ± 0.11 and 0.67 ± 0.14 μg/cm, respectively). Cutaneous biodistribution in human skin under infinite (micelle solution and gel) and finite (micelle gel) dose conditions showed that the VSD concentrations obtained in the basal epidermis, at depths of 120-200 μm, were ˃3800- and ˃2300-fold greater than the IC reported for hedgehog signaling pathway inhibition . : Cutaneous delivery of VSD from micelle-based formulations might enable targeted, topical treatment of superficial BCC with minimal risk of systemic exposure.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/17425247.2019.1609449DOI Listing
June 2019

Drug Transport across Porcine Intestine Using an Ussing Chamber System: Regional Differences and the Effect of P-Glycoprotein and CYP3A4 Activity on Drug Absorption.

Pharmaceutics 2019 Mar 21;11(3). Epub 2019 Mar 21.

School of Pharmaceutical Sciences, University of Geneva & University of Lausanne, CMU-1 rue Michel Servet, 1211 Geneva 4, Switzerland.

Drug absorption across viable porcine intestines was investigated using an Ussing chamber system. The apparent permeability coefficients, , were compared to the permeability coefficients determined in humans in vivo, . Eleven drugs from the different Biopharmaceutical Classification System (BCS) categories absorbed by passive diffusion with published values were used to test the system. The initial experiments measured for each drug after application in a Krebs⁻Bicarbonate Ringer (KBR) buffer and in biorelevant media FaSSIF V2 and FeSSIF V2, mimicking fasted and fed states. Strong sigmoidal correlations were observed between and . Differences in the segmental of antipyrine, cimetidine and metoprolol confirmed the discrimination between drug uptake in the duodenum, jejunum and ileum (and colon); the results were in good agreement with human data in vivo. The presence of the P-gp inhibitor verapamil significantly increased across the ileum of the P-gp substrates cimetidine and ranitidine ( < 0.05). Clotrimazole, a potent CYP3A4 inhibitor, significantly increased of the CYP3A4 substrates midazolam, verapamil and tamoxifen and significantly decreased the formation of their main metabolites. In conclusion, the results showed that this is a robust technique to predict passive drug permeability under fasted and fed states, to identify regional differences in drug permeability and to demonstrate the activity of P-gp and CYP3A4.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/pharmaceutics11030139DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6471532PMC
March 2019

Fractional laser ablation for the targeted cutaneous delivery of an anti-CD29 monoclonal antibody - OS2966.

Sci Rep 2019 01 31;9(1):1030. Epub 2019 Jan 31.

School of Pharmaceutical Sciences, University of Geneva & University of Lausanne, Geneva, Switzerland.

Monoclonal antibodies targeting cytokines are administered parenterally for the systemic treatment of severe psoriasis. However, systemic exposure to the biologic increases the risk of side-effects including immunosuppression, whereas only a small fraction of the active molecules actually reaches the target organ, the skin. This preclinical study examines the feasibility of delivering a humanized anti-CD29 monoclonal antibody (OS2966) topically to skin using minimally-invasive fractional laser ablation. This approach would enable the targeted use of a biologic for the treatment of recalcitrant psoriatic plaques in patients with less widespread disease while minimizing the risk of systemic exposure. First, the effect of a wide range of laser poration conditions on skin permeation and deposition of OS2966 was tested in vitro to determine optimal microporation parameters. Subsequently, confocal laser scanning microscopy was employed to visualize the distribution of fluorescently-labelled OS2966 in skin. The results demonstrated that delivery of OS2966 into and across skin was feasible. Above fluences of 35.1 J/cm, skin deposition and permeation were statistically superior to passive delivery reaching values up to 3.7 ± 1.2 µg/cm at the most aggressive condition. Selective targeting of the skin was also possible since ≥70% of the OS2966 was delivered locally to the skin. Although nanogramme quantities were able to permeate across skin, these amounts were orders of magnitude lower than levels seen following subcutaneous or intravenous injection and would result in minimal systemic exposure in vivo. The diffusion of fluorescently-labelled OS2966 into the skin surrounding the pores was clearly higher than in intact skin and demonstrated the feasibility of delivering the antibody at least as deep as the dermo-epithelial junction, a critical border region where inflammatory cells cross to promote disease progression. These preliminary results confirm that fractional laser ablation can be used for the cutaneous delivery of OS2966 and now preclinical/clinical studies are required to demonstrate therapeutic efficacy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41598-018-36966-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6355906PMC
January 2019

Self-assembled mPEG-hexPLA polymeric nanocarriers for the targeted cutaneous delivery of imiquimod.

Eur J Pharm Biopharm 2019 Sep 12;142:553-562. Epub 2019 Jan 12.

School of Pharmaceutical Sciences, University of Geneva & University of Lausanne, Geneva, Switzerland. Electronic address:

mPEG-hexPLA micelles have shown their ability to improve delivery and cutaneous bioavailability of a wide range of poorly water soluble and lipophilic molecules. Although poorly water soluble, imiquimod (IMQ) is only moderately lipophilic and it was decided to investigate whether mPEG-hexPLA polymeric micelles could be used as a drug delivery system for this "less than ideal" candidate for encapsulation. Nanosized IMQ micelles (d = 27 nm) were formulated and characterized. Moreover, the innovative use of size exclusion chromatography allowed the exact drug localization inside the formulation to be determined; it appeared that the use of acetic acid to solubilize IMQ led to a higher IMQ content outside the micelle than inside. IMQ micelles (0.05%) were formulated in a gel using carboxymethyl cellulose (CMC). In vitro application of this formulation to porcine and human skin led to promising delivery results. IMQ deposition in human skin was 1.4 ± 0.4 µg/cm while transdermal permeation was only 79 ± 19 ng/cm: the formulation displayed >17-fold selectivity for cutaneous deposition over transdermal permeation. The optimized 0.05% gel significantly outperformed Aldara® cream (containing 5% IMQ) formulation in terms of delivery efficiency to human skin (2.85 ± 0.74% vs 0.04 ± 0.01%). Despite IMQ being only partially incorporated in the micelles, the biodistribution profile showed that the optimized 0.05% gel delivered as much as 518.2 ± 173.3 ng/cm (1.04 ± 0.35% of the applied dose) to the viable epidermis and 236.4 ± 88.2 ng/cm (0.47 ± 0.18% of the applied dose) to the upper dermis where the target antigen presenting cells reside. In contrast, for Aldara® cream, the delivery efficiencies in those layers were less than 0.02%. The optimal 0.05% gel thus allowed therapeutically relevant drug levels to be achieved in target tissues despite a 100-fold dose reduction.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ejpb.2019.01.008DOI Listing
September 2019

Investigation of Different Iontophoretic Currents Profiles for Short-Term Applications in Cosmetics.

Pharmaceutics 2018 Dec 7;10(4). Epub 2018 Dec 7.

Instrumental Cosmetics, Applied Research, L'Oréal, 94550 Chevilly-Larue, France.

This study aimed at investigating the effect of electrical current profile upon the iontophoretic transport of (i) ascorbic acid (AA) and (ii) ellagic acid (EA), into porcine skin in vitro, and the impact of the physicochemical properties of both actives on their mechanism of transport when formulated in cosmetic compositions. The experiments were performed using a proprietary iontophoretic device containing a roller to apply the formulation. Three current profiles were tested: (i) galvanic direct current (DC), (ii) square unipolar pulse current (SPC), and (iii) galvanic direct current (DC) + pulse current (PC). The skin samples were collected at different sampling points, extracted and analyzed by HPLC. Results suggested that the DC + PC mode for only 5 min was able to significantly increase the delivery of AA from o/w cosmetic compositions. The use of this current profile might improve the skin penetration of AA due to electromigration and passive diffusion, the latter being facilitated by the physical enhancement method. The SPC mode significantly improved the passage of EA in its neutral form from cosmetic o/w formulations by electroosmosis. Tailoring specific electrical current modes considering the ionization state of active ingredients would allow the design of short and personalized cosmetic treatments that significantly improve the penetration efficiency of the active ingredients and possibly reduce the doses applied.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/pharmaceutics10040266DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6321022PMC
December 2018

Strategies for modifying drug residence time and ocular bioavailability to decrease treatment frequency for back of the eye diseases.

Expert Opin Drug Deliv 2019 01 7;16(1):43-57. Epub 2018 Dec 7.

b School of Pharmaceutical Sciences , University of Geneva & University of Lausanne , Geneva , Switzerland.

Introduction: Treating posterior eye diseases has become a major area of focus for pharmaceutical and biotechnology companies. Current standard of care for treating posterior eye diseases relies on administration via intravitreal injection. Although effective, this is not without complications and there is great incentive to develop longer-acting therapeutics and/or sustained release delivery systems. Here, we present an overview of emerging technologies for delivery of biologics to the back of the eye.

Areas Covered: Posterior eye diseases, intravitreal injection, age-related macular degeneration, anti-VEGF, ocular pharmacokinetics, novel technologies to extend half-life, models, translation to the clinic, and hurdles to effective patient care.

Expert Opinion: Posterior eye diseases are a worldwide public health issue. Although anti-VEGF molecules represent a major advance for treating diseases involving choroidal neovascularization, frequent injection can be burdensome for patients and clinicians. There is a need for effective and patient-friendly treatments for posterior eye diseases. Many technologies that enable long-acting delivery to the back of the eye are being evaluated. However, successful development of novel therapies and delivery technologies is hampered by a multitude of factors, including patient education, translatability of / preclinical data to the clinic, and regulatory challenges associated with novel technologies.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/17425247.2019.1553953DOI Listing
January 2019

Controlled non-invasive iontophoretic delivery of triamcinolone acetonide amino acid ester prodrugs into the posterior segment of the eye.

Eur J Pharm Biopharm 2018 Nov 25;132:157-167. Epub 2018 Sep 25.

School of Pharmaceutical Sciences, University of Geneva & University of Lausanne, CMU-1, rue Michel Servet, 1211 Geneva 4, Switzerland. Electronic address:

This study investigated short duration transscleral iontophoretic delivery of four triamcinolone acetonide (TA) amino acid ester prodrugs (TA-AA) (alanine, Ala; arginine, Arg; isoleucine, Ile and lysine, Lys) using whole porcine eyes globes in vitro. Post-iontophoretic biodistribution of TA was quantified by UHPLC-MS/MS in the different ocular compartments (cornea, aqueous humor, sclera, ciliary body, choroid and retinal pigmented epithelium (RPE), neural retina and vitreous humor). Transscleral iontophoresis (3 mA/cm for 10 min) increased total drug delivery of the TA-AA prodrugs by 14-30-fold as compared to passive diffusion. The TA-AA prodrugs had distinct biodistribution profiles - the penetration depth achieved was dependent on their physicochemical properties (e.g. lipophilicity for TA-Ile) and susceptibility to hydrolysis (e.g. TA-Arg). Intraocular drug distribution was also influenced by prodrug binding to melanin (TA-Lys). Interestingly, under conditions of equivalent charge (6 mA/cm for 5 min vs. 1.5 mA/cm for 20 min, i.e. 1.44 C respectively) the longer duration (20 min) at lower current density resulted in ∼6 times more TA delivery into the vitreous humor. Overall, the study provided further evidence of the potential of transscleral iontophoresis for the non-invasive treatment of posterior segment inflammatory diseases.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ejpb.2018.09.020DOI Listing
November 2018

Hyaluronic Acid After Subcutaneous Injection-An Objective Assessment.

Dermatol Surg 2019 01;45(1):108-116

CIDGE International Dermatology Clinic, Geneva, Switzerland.

Background: Hyaluronic acid (HA) fillers are the preferred injectable products for aesthetic correction of skin depressions and restoration of facial volume.

Objective: To investigate the subcutaneous distribution of 3, biophysically distinct, CE-marked and FDA-approved HA fillers.

Materials And Methods: BELB, JUVV, and RESL were injected ex vivo in porcine and human skin. Immediately after injection, the skin samples were snap-frozen, cross-sectioned, and visualized using stereomicroscopy and full-field optical coherence tomography. Images were compared with histological sections after hematoxylin and eosin staining.

Results: Hyaluronic acid fillers were distributed as homogeneous bolus in the ex vivo skin. The injection bulks were found to preserve the fibrous trabecular network, shift the fat lobules, and displace the adjacent adipocyte layers independently of the formulation injected.

Conclusion: For the first time, the subcutaneous injection of 3 HA fillers with markedly different biophysical properties was systematically investigated by complementary visualization techniques. Despite their different properties, no difference in distribution was found after subcutaneous injection. The global preservation of the hypodermis structure observed was consistent with the good tolerability seen in clinical practice after implantation of the HA fillers in the subcutaneous skin layer.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/DSS.0000000000001609DOI Listing
January 2019

Development and validation of a fast and sensitive UHPLC-ESI-MS method for the simultaneous quantification of spironolactone and its metabolites in ocular tissues.

Biomed Chromatogr 2018 Oct 19;32(10):e4287. Epub 2018 Jun 19.

School of Pharmaceutical Sciences, University of Geneva, University of Lausanne, Lausanne, Switzerland.

Glucocorticoids are a mainstay for the treatment of immune-mediated conditions and inflammatory diseases. However, their chronic use causes numerous side-effects including delays in corneal and cutaneous wound healing. This is attributed to off-target agonism of the mineralocorticoid receptor, which can be reduced by co-administration of a mineralocorticoid receptor antagonist such as spironolactone. The aim of this study was to develop a fast, selective and sensitive UHPLC-ESI-MS method for the simultaneous quantification of spironolactone, its active metabolites (7α-thiomethylspironolactone and canrenone), the latter's water-soluble prodrug potassium canrenoate and the synthetic glucocorticoid, dexamethasone, in corneal samples (17α-methyltestosterone served as an internal standard). A one-step extraction procedure using MeOH-H O (1:1) was validated and employed to recover the analytes from the corneal tissue. Extracts were centrifuged and the supernatant analyzed under isocratic conditions. Compounds were detected using selected ion recording mode. The method satisfied US Food and Drug Administration guidelines with respect to selectivity, precision and accuracy and displayed linearity from 5 to 1000 ng/mL for all of the analytes. The lower limit of quantitation of the method was 5 ng/mL, making it sufficiently sensitive for quantification of the analytes in samples from in vivo studies.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/bmc.4287DOI Listing
October 2018

Needle-free cutaneous delivery of living human cells by Er:YAG fractional laser ablation.

Expert Opin Drug Deliv 2018 06 23;15(6):559-566. Epub 2018 May 23.

b School of Pharmaceutical Sciences , University of Geneva & University of Lausanne , Geneva , Switzerland.

Background: Dermatological diseases, including most skin cancers and rare genetic conditions frequently originate in the epidermis. Targeted, topical cell-based therapy is a promising therapeutic strategy. Here, we present the first report demonstrating that fractional laser ablation enables local 'needle-free' intraepidermal delivery of living human cells.

Methods: The cells penetrated porcine ear skin via microchannels created by Er:YAG fractional laser ablation; cell delivery was quantified using a haemocytometer. Cutaneous distribution was confirmed visually by laser scanning confocal microscopy and histological analysis.

Results: Total cell delivery (sum of amounts permeated and deposited) after 24 h increased from 5.7 ± 0.1 x10 to 9.6 ± 1.6 x10 cells/cm when increasing pore density from 300 to 600 pores/cm, - corresponding to 19- and 32-fold increases over the control. At 600 pores/cm, cell deposition was 136-fold greater than cell permeation - the latter most likely due to transport from micropores into appendageal pathways. Production of GFP post-delivery confirmed cell remained viability.

Conclusion: The results demonstrate the feasibility of using controlled laser microporation to achieve local 'needle-free' cutaneous delivery of living human cells to the epidermis and dermis. This raises the possibility of using this technique for targeted new approaches for dermatological therapy in these regions.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/17425247.2018.1472570DOI Listing
June 2018

Hydrogels in three-dimensional dendritic cell (MUTZ-3) culture as a scaffold to mimic human immuno competent subcutaneous tissue.

Int J Pharm 2018 Jun 23;544(1):297-303. Epub 2018 Apr 23.

School of Pharmaceutical Sciences, University of Geneva, University of Lausanne, Centre Médical Universitaire (CMU), Rue Michel-Servet 1, 1211 Geneva 4, Switzerland. Electronic address:

The objective of this study was to develop a 3D cell culture model of the human subcutaneous tissue, allowing the prediction of the immunogenicity of subcutaneously injected therapeutic proteins. Several hydrogels were evaluated as scaffolds to mimic the human subcutaneous tissue in vitro. Cytocompatibility of the hydrogels with the human myelomonocytic cell line (MUTZ-3) was investigated, as well as their influence on cellular phenotype changes. Elastic Young's moduli in compression of the hydrogels were measured by a texture analyser and compared to ex vivo human samples. MUTZ-3 cells were differentiated into dendritic cells before embedding in hydrogels. Agarose at various concentrations (0.5%, 0.35% and 0.25% w/v), Geltrex® matrix and HyStem™ scaffold (1% w/v) displayed a wide range of elastic Young's moduli from 560 kPa to 49 kPa, compared to the reference value of 23 kPa obtained for human tissue. With the exception of HyStem™, good cytocompatibility of hydrogels was shown at the concentrations tested. An optimal combination of MUTZ-3 cells with 0.25% agarose or Geltrex® is suggested.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ijpharm.2018.04.050DOI Listing
June 2018

Simultaneous controlled iontophoretic delivery of pramipexole and rasagiline in vitro and in vivo: Transdermal polypharmacy to treat Parkinson's disease.

Eur J Pharm Biopharm 2018 Jun 22;127:204-212. Epub 2018 Feb 22.

School of Pharmaceutical Sciences, University of Geneva & University of Lausanne, CMU, 1 rue Michel Servet, 1211 Geneva, Switzerland. Electronic address:

Effective treatment of Parkinson's disease (PD) involves administration of therapeutic agents with complementary mechanisms of action in order to replenish, sustain or substitute endogenous dopamine. The objective of this study was to investigate anodal co-iontophoresis of pramipexole (PRAM; dopamine agonist) and rasagiline (RAS; MAO-B inhibitor) in vitro and in vivo. Passive permeation of PRAM and RAS (20 mM each) across porcine skin after 6 h was 15.7 ± 1.9 and 16.0 ± 2.9 µg/cm, respectively. Co-iontophoresis at 0.15, 0.3 and 0.5 mA/cm resulted in statistically significant increases in delivery of PRAM and RAS; at 0.5 mA/cm, cumulative permeation of PRAM and RAS was 613.5 ± 114.6 and 441.1 ± 169.2 µg/cm, respectively - corresponding to 38- and 27-fold increases over passive diffusion. Electromigration was the dominant mechanism for both molecules (>80%) and there was no effect on convective solvent flow. Statistically equivalent delivery was observed with human skin. The co-iontophoretic system showed high delivery efficiency with 29% and 35% of the applied amounts of PRAM and RAS being delivered. Preliminary pharmacokinetics studies in rats confirmed that the input rate in vivo was such that therapeutic amounts of the two drugs could be co-administered to humans by transdermal iontophoresis using reasonably sized patches and moderate current densities.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ejpb.2018.02.031DOI Listing
June 2018

Topical Administration of Spironolactone-Loaded Nanomicelles Prevents Glucocorticoid-Induced Delayed Corneal Wound Healing in Rabbits.

Mol Pharm 2018 03 15;15(3):1192-1202. Epub 2018 Feb 15.

School of Pharmaceutical Sciences , University of Geneva & University of Lausanne , CMU - 1 rue Michel Servet , 1211 Geneva 4 , Switzerland.

The objective was to investigate whether mineralocorticoid receptor antagonism using a novel topical micellar formulation of spironolactone could prevent glucocorticoid-induced delayed corneal wound healing in New Zealand white rabbits. Spironolactone micelles (0.1%, w/v) with a mean number weighted diameter of 20 nm were prepared using a pegylated copolymer (mPEG-dihexPLA) and showed a preliminary stability of at least 12 months at 5 °C. Preclinical studies in New Zealand white rabbits demonstrated that the 0.1% spironolactone micellar formulation was well-tolerated since no reaction was observed in the cornea following multiple daily instillation over 5 days. As expected, the preclinical studies also confirmed that dexamethasone significantly delayed epithelial wound healing as compared to untreated control (percentage re-epithelialization after day 4: 84.6 ± 13.9% versus 99.5 ± 1.0% for the control, p < 0.05). However, the addition of the 0.1% spironolactone micellar formulation significantly improved the extent of re-epithelialization, countering the dexamethasone induced delayed wound healing with a percentage re-epithelialization that was statistically equivalent to the control (96.9 ± 7.3% versus 99.5 ± 1.0%, p > 0.05). The biodistribution study provided insight into the ocular metabolism of spironolactone and hence the relative contributions of the parent molecule and its two principal metabolites, 7α-thiomethylspironolactone and canrenone, to the observed pharmacological effects. Comparison of the efficacies of spironolactone and potassium canrenoate (a water-soluble precursor of canrenone) in overcoming the dexamethasone-induced delayed wound healing confirmed that the former had greater efficacy. The results pointed to the greater potency of 7α-thiomethylspironolactone over canrenone as a mineralocorticoid receptor antagonist, which explained its superior ability in countering the glucocorticoid-induced overactivation that was responsible for the delayed wound healing. In conclusion, the preliminary results supported the above-mentioned hypothesis suggesting that coadministration of mineralocorticoid receptor antagonists to patients under glucocorticoid therapy might prevent the deleterious effects of glucocorticoids on complex corneal wound healing processes.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/acs.molpharmaceut.7b01028DOI Listing
March 2018

Selective delivery of adapalene to the human hair follicle under finite dose conditions using polymeric micelle nanocarriers.

Nanoscale 2018 Jan;10(3):1099-1110

School of Pharmaceutical Sciences, University of Geneva & University of Lausanne, 1 Rue Michel Servet, 1211 Geneva, Switzerland.

Drug delivery systems that target the pilosebaceous unit (PSU) selectively could improve the clinical management of diseases that originate in the hair follicle. The aims of this study were (i) to prepare polymeric micelles using d-α-tocopheryl polyethylene glycol succinate diblock copolymer that incorporated adapalene (ADA), a retinoid indicated for Acne vulgaris, and (ii) to investigate the feasibility of delivering ADA preferentially to the PSU under finite dose conditions - thereby better approximating actual conditions of use by patients. Incorporation of ADA into spherical micelles (d <20 nm) increased aqueous solubility by ∼50 000-fold (from <4 ng mL to 0.2 mg mL). Optimized micelle solution and gel formulations (0.02% ADA) were stable after storage for 4 weeks at 4 °C. Finite dose experiments using full-thickness porcine and human skin revealed that ADA delivery efficiency from micelle solution and gel formulations was equivalent and was >2- and 10-fold higher than that from Differin® gel and Differin® cream (products containing ADA at 0.1% (w/w)). Follicular delivery studies in human skin, using a punch biopsy technique to extract the intact PSU, demonstrated that the micelle solution and gel formulations did indeed enable preferential delivery of ADA to the PSU (4.5- and 3.3-fold higher, respectively, than that to PSU-free skin biopsies). Confocal laser scanning microscopy provided visual corroboration that ADA was uniformly distributed in the hair follicles. In conclusion, the results confirmed that polymeric micelle nanocarriers enabled selective, targeted drug delivery to the PSU under finite dose conditions and so might improve therapy of follicular diseases and decrease off-site side-effects.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1039/c7nr07706hDOI Listing
January 2018

Short-duration ocular iontophoresis of ionizable aciclovir prodrugs: A new approach to treat herpes simplex infections in the anterior and posterior segments of the eye.

Int J Pharm 2018 Jan 2;536(1):292-300. Epub 2017 Dec 2.

School of Pharmaceutical Sciences, University of Geneva & University of Lausanne, CMU, 1 rue Michel Servet, 1211 Geneva 4, Switzerland. Electronic address:

The objective was to investigate (trans)corneal and transscleral iontophoresis of biolabile amino acid ester prodrugs of aciclovir (ACV-X, X = Arg, Gly and Trp) as a means to increase ocular bioavailability of ACV. Prodrugs displayed tissue-dependent susceptibility to hydrolysis. Iontophoresis of ACV-Arg, ACV-Gly and ACV-Trp (5 mM, 0.5 mA/cm) for 5 min followed by 55 min passive diffusion resulted in appreciable corneal deposition (21.5 ± 5.1, 14.1 ± 2.0 and 5.3 ± 0.6 nmol/cm, respectively) and transcorneal permeation (13.9 ± 1.6, 10.9 ± 1.8 and 5.7 ± 0.5 nmol/cm, respectively) of ACV species. In contrast, passive delivery of ACV across porcine cornea after 1 h was < LOQ (i.e. <0.125 nmol/cm). Transscleral permeation of ACV-Arg, ACV-Gly and ACV-Trp (9 mM, 1.25 mA/cm) after iontophoresis for 5 min was 20.4 ± 3.8, 12.3 ± 0.3 and 8.4 ± 0.4 nmol/cm, respectively - far superior to passive delivery which was again < LOQ. Using intact porcine eye globes, 5 min transscleral iontophoresis of ACV-Gly at 3.75 mA/cm resulted in considerable delivery of ACV species to the choroid/retina and vitreous humour (5.7 ± 2.3 and 11.7 ± 3.7 nmol/cm, respectively). Furthermore, the average concentration of ACV species in the whole eyeball (4.5 ± 1.6 nmol/cm) was significantly higher than the IC of ACV against HSV-1 (<0.22 nmol/cm), demonstrating the potential application for the treatment of ocular HSV infections.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ijpharm.2017.11.069DOI Listing
January 2018

Targeted intracorneal delivery-Biodistribution of triamcinolone acetonide following topical iontophoresis of cationic amino acid ester prodrugs.

Int J Pharm 2017 Jun 14;525(1):43-53. Epub 2017 Apr 14.

School of Pharmaceutical Sciences, University of Geneva & University of Lausanne, CMU, 1 rue Michel Servet, 1211 Geneva 4, Switzerland. Electronic address:

The aim was to investigate intracorneal iontophoresis of biolabile triamcinolone acetonide (TA) amino acid ester prodrugs (TA-AA). Arginine and lysine esters of TA (TA-Arg and TA-Lys, respectively) were synthesized and characterized; quantification was performed by HPLC-UV and UHPLC-MS/MS. The aqueous solubility of the prodrugs (at pH 5.5) was ∼1000-fold greater than TA. Anodal iontophoresis (10min at 3mA/cm) of TA-AA was investigated using isolated porcine cornea. Although no statistically significant difference was observed in total intracorneal delivery of TA (468.25±59.70 and 540.85±79.16nmol/cm, for TA-Arg and TA-Lys, respectively), the different susceptibilities of the prodrugs to hydrolysis influenced intracorneal biodistribution. Quantification of TA in twenty-five 40μm thick corneal lamellae revealed significantly deeper penetration of TA following TA-Lys iontophoresis. Its superior resistance to hydrolysis enabled sustained electromigration into the deeper cornea suggesting judicious prodrug selection might enable targeted regioselective drug delivery. The intracorneal biodistribution following anodal iontophoresis of TA-Arg (2.3mM; 10min, 3mA/cm) was visualized by full field optical coherence tomography providing qualitative confirmation of the extensive intracorneal penetration of TA. Short duration iontophoresis of TA-AA prodrugs may improve deep corneal bioavailability and efficacy in vivo, constituting a "single-shot" treatment option for corneal allograft rejection.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ijpharm.2017.04.030DOI Listing
June 2017

Formulation challenges for 21st century topical and transdermal delivery systems.

Expert Opin Drug Deliv 2017 06 30;14(6):705-708. Epub 2017 Mar 30.

a School of Pharmaceutical Sciences , University of Geneva & University of Lausanne , Geneva , Switzerland.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/17425247.2017.1311320DOI Listing
June 2017

Cutaneous iontophoresis of μ-conotoxin CnIIIC-A potent Na1.4 antagonist with analgesic, anaesthetic and myorelaxant properties.

Int J Pharm 2017 Feb 26;518(1-2):59-65. Epub 2016 Dec 26.

School of Pharmaceutical Sciences, University of Geneva & University of Lausanne, 1 Rue Michel-Servet, 1211 Geneva, Switzerland. Electronic address:

Cutaneous iontophoretic delivery of μ-conotoxin CnIIIC (XEP), a potent peptide antagonist of the Na1.4 sodium channel, was investigated using porcine ear skin and validated using human abdominal skin. Initial results demonstrated that cutaneous deposition of XEP following iontophoresis was superior to passive delivery and increased with current density. XEP deposition after iontophoresis at 0.1, 0.3 and 0.5mA/cm for 2h and 4h was 22.4±0.4, 34.5±1.4, 57.4±7.6μg/cm and 30.6±5.4, 53.9±17.2, 90.9±30.8μg/cm, respectively (cf. corresponding passive controls - 9.8±1.1 and 16.9±1.0μg/cm). Moreover, tape-stripping studies showed that XEP was mainly adsorbed on the skin surface when administered passively. Co-iontophoresis of acetaminophen demonstrated that XEP was present in the skin as it significantly reduced convective solvent flow as evidenced by the ∼7-fold decrease in acetaminophen permeation. Shorter duration iontophoresis (15, 30 and 60min) was performed and the effect of current density (0.1, 0.3 and 0.5mA/cm) and concentration (0.1 and 1mM) investigated. Skin deposition of XEP was already quantifiable after iontophoresis for 15min at the lower concentration. There was no statistically significant difference between XEP deposition in porcine and human skin. Confocal laser scanning microscopy enabled post-iontophoretic visualization of FITC-labelled XEP in the epidermis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ijpharm.2016.12.054DOI Listing
February 2017