Characterisation of Drug Delivery Efficacy Using Microstructure-Assisted Application of a Range of APIs

Polymer-based solid microstructures (MSts) have the potential to significantly increase the quantity and range of drugs that can be administered across the skin. MSt arrays are used to demonstrate their capacity to bypass the skin barrier and enhance permeability by creating microchannels through the stratum corneum, in a minimally invasive manner. This study is designed to demonstrate the ability of MSts to exceed the current boundaries for transdermal delivery of compounds with different molecular weights, partition coefficients, acid dissociation constants, melting points, and water solubilities. In vitro permeation of a range of selected molecules, including acetyl salicylic acid (aspirin), galantamine, selegiline hydrochloride (Sel-HCl), insulin, caffeine, hydrocortisone (HC), hydrocortisone 21-hemisuccinate sodium salt (HC-HS) and bovine serum albumin (BSA) has been studied across excised porcine skin with and without poke and patch application of MSts. Permeation of the molecules was monitored using Franz diffusion cells over 24 h. MSts significantly increased the permeation of all selected molecules up to 40 times, compared to topical applications of the molecules without MSts. The greatest increase in permeation was observed for caffeine with 70 ± 8% permeation and the lowest enhancement was observed for HC with a 2.4 ± 1.3% increase in permeation. The highest obtained flux was BSA (8133 ± 1365 μg/cm2/h) and the lowest flux observed for HC (11 ± 4 μg/cm2/h). BSA and HC also showed the highest (16,275 ± 3078 μg) and the lowest (73 ± 47 μg) permeation amount after 24 h respectively. MSt-treated skin exhibits greatly increased permeation. The molecule parameters (size, acid dissociation constant, partition coefficient and solubility)—traditional hurdles associated with passive diffusion through intact skin—are overcome using MSt skin treatment.

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Development and evaluation of a heparin gel for transdermal delivery via laser-generated micropores

Therapeutic Delivery ◽

10.4155/tde-2020-0024 ◽

2021 ◽

Vol 12 (2) ◽

pp. 133-144

Author(s):

Deepal Vora ◽

Yujin Kim ◽

Ajay K Banga

Keyword(s):

Transdermal Delivery ◽

Continuous Intravenous Infusion ◽

In Vitro Permeation ◽

Assisted Delivery ◽

Permeation Studies ◽

Franz Diffusion Cells ◽

Transdermal Route ◽

Poloxamer Gel ◽

Ablative Laser

Aim: Our study investigated the feasibility of transdermal delivery of heparin, an anticoagulant used against venous thromboembolism, as an alternative to intravenous administration. Materials & methods: Skin was pretreated using ablative laser (Precise Laser Epidermal System [P.L.E.A.S.E.®] technology) for enhanced delivery of heparin. In vitro permeation studies using static Franz diffusion cells provided a comparison between delivery from 0.3% w/v heparin-loaded poloxamer gel and solution across untreated and laser-treated dermatomed porcine ear skin. Results: No passive delivery of heparin was observed. Laser-assisted delivery from solution (26.07 ± 1.82 μg/cm2) was higher (p < 0.05) than delivery from heparin gel (11.28 ± 5.32 μg/cm2). However, gel is likely to sustain the delivery over prolonged periods like a maintenance dose via continuous intravenous infusion. Conclusion: Thus, ablative laser pretreatment successfully delivered heparin, establishing the feasibility of delivering hydrophilic macromolecules using the transdermal route.

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Effect of Topical Liposomes Containing Paromomycin Sulfate in the Course of Leishmania major Infection in Susceptible BALB/c Mice

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.01319-08 ◽

2009 ◽

Vol 53 (6) ◽

pp. 2259-2265 ◽

Cited By ~ 46

Author(s):

Mahmoud R. Jaafari ◽

Neda Bavarsad ◽

Bibi Sedigheh Fazly Bazzaz ◽

Afshin Samiei ◽

Dina Soroush ◽

...

Keyword(s):

Leishmania Major ◽

Mouse Skin ◽

Parasite Burden ◽

Lesion Size ◽

Control Group ◽

In Vitro Permeation ◽

Significant Difference ◽

Pm 10 ◽

Franz Diffusion Cells

ABSTRACT The aim of this study was to evaluate the antileishmanial effects of topical liposomal paromomycin sulfate (PM) in Leishmania major-infected BALB/c mice. Liposomes containing 10 or 15% PM (Lip-PM-10 and Lip-PM-15, respectively) were prepared by the fusion method and were characterized for their size and encapsulation efficiency. The penetration of PM from the liposomal PM formulations (LPMFs) through and into skin was evaluated in vitro with Franz diffusion cells fitted with mouse skin at 37°C for 8 h. The in vitro permeation data showed that almost 15% of the LPMFs applied penetrated the mouse skin, and the amount retained in the skin was about 60% for both formulations. The 50% effective doses of Lip-PM-10 and Lip-PM-15 against L. major promastigotes in culture were 65.32 and 59.73 μg/ml, respectively, and those against L. major amastigotes in macrophages were 24.64 and 26.44 μg/ml, respectively. Lip-PM-10 or Lip-PM-15 was used topically twice a day for 4 weeks to treat L. major lesions on BALB/c mice, and the results showed a significantly (P < 0.001) smaller lesion size in the mice in the treated groups than in the mice in the control group, which received either empty liposomes or phosphate-buffered saline (PBS). Eight weeks after the beginning of the treatment, every mouse treated with LPMFs was completely cured. The spleen parasite burden was significantly (P < 0.001) lower in mice treated with Lip-PM-10 or Lip-PM-15 than in mice treated with PBS or control liposomes, but no significant difference was seen between the two groups treated with either Lip-PM-10 or Lip-PM-15. The results suggest that topical liposomal PM may be useful for the treatment of cutaneous leishmaniasis.

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Novel Design Approaches in the Fabrication of Polymeric Microarray Patches via Micromoulding

Micromachines ◽

10.3390/mi11060554 ◽

2020 ◽

Vol 11 (6) ◽

pp. 554 ◽

Cited By ~ 2

Author(s):

Inken Ramöller ◽

Emma McAlister ◽

Abigail Bogan ◽

Ana Cordeiro ◽

Ryan Donnelly

Keyword(s):

Skin Barrier ◽

Systemic Delivery ◽

Porcine Skin ◽

Density Maps ◽

In Vitro Permeation ◽

Wide Range ◽

Significant Difference ◽

Permeation Studies ◽

Novel Design

The focus on novel systems for transdermal delivery of therapeutic agents has increased considerably over recent years, as this administration route comes with many advantages. Polymeric microarray patches (MAPs) are minimally invasive devices that enable systemic delivery of a wide range of drugs by overcoming the outer skin barrier. Conventionally, MAPs fabricated by micromoulding have a low needle density. In this study, the performance of hydrogel-forming MAPs cast using novel industrially manufactured micromoulds with a high needle density (600 needles/0.75 cm2) was compared to that of MAPs obtained using conventional moulds with a lower density (196 needles/0.89 cm2). Surrounding holders for micromoulds were designed for time-efficient fabrication of MAPs. The influence of needle densities on mechanical strength, insertion efficiency and in vitro permeation of ibuprofen sodium (IBU) was analysed. Insertion of both MAPs into an artificial skin model and neonatal porcine skin was comparable. No significant difference was observed in permeation studies of IBU (p > 0.05), with a delivery of 8.7 ± 1.7 mg for low-density and 9.5 ± 0.1 mg for high-density MAPs within 24 h. This highlights the potential of these novel micromoulds for manufacturing polymeric MAPs with a higher needle density for future applications.

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Chromatographic Determination of Thermodynamic Acid Dissociation Constants of Tetracycline Antibiotics and Their Epimers

Journal of Chromatographic Science ◽

10.1093/chromsci/bmz051 ◽

2019 ◽

Vol 57 (8) ◽

pp. 745-750

Author(s):

İlkay Konçe ◽

Ebru Çubuk Demiralay ◽

Hülya Yılmaz Ortak

Keyword(s):

Experimental Data ◽

Dissociation Constant ◽

Binary Mixtures ◽

Dissociation Constants ◽

Reversed Phase ◽

Acid Dissociation ◽

Acid Dissociation Constant ◽

Chromatography Method ◽

Ph Values

Abstract The presented study describes the development of reversed-phase liquid chromatography method using a core-shell particle column with a pentafluorophenyl stationary phase for the dissociation constant (pKa) determination of the tetracycline group antibiotics (tetracycline, oxytetracycline, chlortetracycline) and their epimers (4-epitetracycline, 4-epioxytetracycline, 4-epichlortetracycline). The pH values were measured in the acetonitrile (ACN)–water binary mixtures, used as mobile phases, instead of in water and take into account the effect of the activity coefficients. Thermodynamic acid dissociation constant (pKa1) values of studied antibiotics and their epimers were calculated using retention factor (k) at different mobile phase pH values in studied binary mixtures with ACN percentages of 20, 25, 30 and 35% (v/v). Experimental data were analyzed by using an Origin 7.0 program to fit experimental data to the nonlinear expression derived. From calculated pKa1 values, the aqueous pKa values of studied compounds were calculated by different approaches and these values were compared.

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Synthesis, Molecular Docking, BSA, and in-vitro reactivation study of imidazopyridine oxime against paraoxon inhibited acetylcholinesterase

Medicinal Chemistry ◽

10.2174/1573406417666210208223240 ◽

2021 ◽

Vol 17 ◽

Author(s):

Ashima Thakur ◽

Jayant Patwa ◽

Abha Sharma ◽

Swaran Jeet Flora

Keyword(s):

Molecular Docking ◽

Bovine Serum Albumin ◽

Serum Albumin ◽

In Silico ◽

Bovine Serum ◽

Enzymatic Assay ◽

Acid Dissociation ◽

Acid Dissociation Constant ◽

Spectroscopic Techniques

Aim: To synthesize and evaluate the fused heterocyclic imidazopyridine oxime as a reactivator against paraoxon inhibited acetylcholinesterase. Background: Organophosphorus compounds (OPs) include parathion, malathion, chlorpyrifos, monocrotophos, and diazinon which are commonly used in agriculture for enhancing agricultural productivity via killing crop-damaging pests. However, people may get exposed to OPs pesticides unintentionally/intentionally via ingestion, inhalation or dermal. The current treatment regimen includes reactivator such as mono or bis-pyridinium oximes along with anticholinergic and an anticonvulsant drugs are recommended for the treatment of OP poisoning. Unfortunately, the drawback of the existing reactivator is that owing to the permanent charge present on the pyridinium makes them inefficient to cross the blood-brain barrier (BBB) and reactivate OP-inhibited central nervous system (CNS) acetylcholinesterase. Therefore, there is a need of reactivator that could cross the BBB and reactivate the OP inhibited acetylcholinesterase. Objective: The objectives of the study were synthesis, molecular docking, BSA binding and in-vitro estimation of oximes of various substituted imidazo [1,2-a]pyridine against paraoxon inhibited acetylcholinesterase. Method: The reactivators were synthesized in three steps and characterized using various spectroscopic techniques. Molecular docking study was performed on 2WHP and 3ZLV PDB using Autodock tool. The acid dissociation constant (pKa) of oximes was calculated experimentally and drug-likeness properties of the oximes were calculated In silico using mole inspiration and Swiss ADME software. The binding of oximes with bovine serum albumin (BSA) was also investigated by UV-Vis spectrophotometer. The reactivation potential of the oximes was determined by in vitro enzymatic assay. Result: in-silico study inferred that synthesized molecules fulfilled the parameters that required for a successful CNS drug candidate. Further, in-vitro enzymatic assay indicated reasonable reactivation potential of the oximes against paraoxon-inhibited AChE. The binding of oximes with bovine serum albumin (BSA) revealed static quenching of intrinsic fluorescence of BSA by oxime. The binding constant value and number of binding sites were found 0.24 mol-1 and 1 respectively. Conclusion: The results of study concluded that this scaffold could be used for further designing of more efficient uncharged reactivators.

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Effect of two surfactants on in vitro permeation of butorphanol through horse nasal mucosa

Uniciencia ◽

10.15359/ru.35-2.1 ◽

2021 ◽

Vol 35 (2) ◽

pp. 1-10

Author(s):

María Inés Velloso ◽

Héctor Alfredo Andreeta ◽

María Fabiana Landoni

Keyword(s):

Nasal Mucosa ◽

Tween 80 ◽

Ionic Surfactant ◽

Apparent Permeability ◽

In Vitro Permeation ◽

Apparent Permeability Coefficient ◽

Dose Control ◽

Franz Diffusion Cells ◽

Cetrimonium Bromide

The aim of the present study was to evaluate the effect of two surfactants on in vitro permeation of butorphanol through equine nasal mucosa. Franz diffusion cells and equine nasal mucosa were used. Three formulations were developed based on citric acid, sodium citrate, sodium chloride, and butorphanol tartrate and administered at a 24.4 g cm-3 dose. Control formulation lacked any penetration enhancer. Formulation 1 (F1) had a cationic surfactant (cetrimonium bromide) and formulation 2 (F2) had a non-ionic surfactant (Tween 80). Statistically comparing flux values at the steady state (Jss), apparent permeability coefficient (Kp), and lag-time from control, F1 and F2 for the respiratory region does not show statistically significant differences (α= 0.05). However, statistically significant differences were found on the Jss and Kp, values from control, F1, and F2 in olfactory mucosa. A statistical analysis on the latter showed significant differences between the Jss values of F1 and F2 and between control and F2. Based on this, Tween 80 proved to be a promising excipient in developing intranasal butorphanol formulations in equines since it increases its passage through the nasal mucosa. These results are very promising to continue with the development of intranasal butorphanol formulation in equines.

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In vitro permeation and disposition of niacinamide in silicone and porcine skin of skin barrier-mimetic formulations

International Journal of Pharmaceutics ◽

10.1016/j.ijpharm.2017.01.054 ◽

2017 ◽

Vol 520 (1-2) ◽

pp. 158-162 ◽

Cited By ~ 9

Author(s):

Tasnuva Haque ◽

Majella E. Lane ◽

Bruno C. Sil ◽

Jonathan M. Crowther ◽

David J. Moore

Keyword(s):

Skin Barrier ◽

Porcine Skin ◽

In Vitro Permeation

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Tretinoin-based formulations - influence of concentration and vehicles on skin penetration

Brazilian Journal of Pharmaceutical Sciences ◽

10.1590/s1984-82502015000100009 ◽

2015 ◽

Vol 51 (1) ◽

pp. 85-90 ◽

Cited By ~ 4

Author(s):

Edileia Bagatin ◽

Tais Aleriana Lucon Wagemaker ◽

Nelson dos Reis Aguiar Júnior ◽

Mirela Donato Gianeti ◽

Erika Maria Berardo Gonçalves ◽

...

Keyword(s):

High Performance ◽

Standard Treatment ◽

Skin Penetration ◽

Aqueous Methanol ◽

In Vitro Permeation ◽

Receptor Compartment ◽

Chemical Peeling ◽

Deep Layers ◽

Franz Diffusion Cells

Tretinoin is used in the management of acne and it is part of a gold standard treatment for photoaging. It has also been reported as an agent for superficial chemical peeling in highly concentrated formulations with few considerations about skin penetration. The aim of this study was to evaluate the influence of drug concentration and vehicles currently used on skin penetration of tretinoin. In vitro permeation tests were carried out using Franz diffusion cells fitted with porcine ear skin and 10% aqueous methanol in the receptor compartment. Formulations studied, cream or hydroalcoholic dispersion, containing 0.25%, 1% and 5% of tretinoin were placed in the donor compartment for six hours. Tretinoin concentration in skin layers was measured by high performance liquid chromatography. The largest amount of tretinoin from both vehicles was detected in stratum corneum with significant differences among the three concentrations. The hydroalcoholic dispersion was the best vehicle. Significant amounts of tretinoin were found even in deep layers of epidermis. The formulation with 0.25% tretinoin showed better results when considered the amount of tretinoin on skin in terms of percentage. Finally, skin penetration of tretinoin was influenced by vehicle and concentration of this drug used in formulation.

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EFECTO DE UN SURFACTANTE NO IONICO EN LA PERMEABILIDAD DE BUTORFANOL A TRAVES DE MUCOSA NASAL EQUINA

FAVE Sección Ciencias Veterinarias ◽

10.14409/favecv.v19isuplemento.10945 ◽

2021 ◽

Vol 19 (suplemento) ◽

Author(s):

M I Velloso

Keyword(s):

Intranasal Administration ◽

Tween 80 ◽

Ionic Surfactant ◽

Apparent Permeability ◽

In Vitro Permeation ◽

Equine Medicine ◽

Site Of Action ◽

The Central Nervous System ◽

Franz Diffusion Cells

Implementation of intranasal administration for the delivery of drugs with site of action into the central nervous system, such as butorphanol, became a potential choice in equine medicine. In this study, using Franz-diffusion cells the in vitro permeation rate through respiratory and olfactory equine nasal mucosa of two butorphanol formulations was estimated and compared. Both formulations had the same composition, was the exception for formulation 2, that contained 2, 5 x 10 -4 M of a non-ionic surfactant (tween 80). Butorphanol administered dose was 24, 4 mg/cm2. Plots of the cumulative amounts of butorphanol against time were constructed, where maximum flux values at the steady state (Jss), apparent permeability coefficients (Kp) and lag-time (tlag) were estimated. The Jss and Kp show that permeation of butorphanol through olfactory mucosa is different than respiratory mucosa. Moreover, Jss for formulation 2 was higher than formulation 1 in both anatomical areas, probably for the effect of the surfactant. The present results are promising to carry on with the development of formulation of butorphanol for intranasal administration.

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Resistivity Technique for the Evaluation of the Integrity of Buccal and Esophageal Epithelium Mucosa for In Vitro Permeation Studies: Swine Buccal and Esophageal Mucosa Barrier Models

Pharmaceutics ◽

10.3390/pharmaceutics13050643 ◽

2021 ◽

Vol 13 (5) ◽

pp. 643

Author(s):

Jaiza Samara Macena de Araújo ◽

Maria Cristina Volpato ◽

Bruno Vilela Muniz ◽

Gabriela Gama Augusto Xavier ◽

Claudia Cristina Maia Martinelli ◽

...

Keyword(s):

Cost Effective ◽

Esophageal Mucosa ◽

Buccal Epithelium ◽

Esophageal Epithelium ◽

Hydrophilic Drugs ◽

In Vitro Permeation ◽

Cost Effective Method ◽

Permeation Studies ◽

Franz Diffusion Cells

Permeation assays are important for the development of topical formulations applied on buccal mucosa. Swine buccal and esophageal epithelia are usually used as barriers for these assays, while frozen epithelia have been used to optimize the experimental setup. However, there is no consensus on these methods. In transdermal studies, barrier integrity has been evaluated by measuring electrical resistance (ER) across the skin, which has been demonstrated to be a simple, fast, safe, and cost-effective method. Therefore, the aims here were to investigate whether ER might also be an effective method to evaluate buccal and esophageal epithelium mucosa integrity for in vitro permeation studies, and to establish a cut-off ER value for each epithelium mucosa model. We further investigated whether buccal epithelium could be substituted by esophageal epithelium in transbuccal permeation studies, and whether their permeability and integrity were affected by freezing at −20 °C for 3 weeks. Fresh and frozen swine buccal and esophageal epithelia were mounted in Franz diffusion cells and were then submitted to ER measurement. Permeation assays were performed using lidocaine hydrochloride as a hydrophilic drug model. ER was shown to be a reliable method for evaluating esophageal and buccal epithelia. The esophageal epithelium presented higher permeability compared to the buccal epithelium. For both epithelia, freezing and storage led to decreased electrical resistivity and increased permeability. We conclude that ER may be safely used to confirm tissue integrity when it is equal to or above 3 kΩ for fresh esophageal mucosa, but not for buccal epithelium mucosa. However, the use of esophageal epithelium in in vitro transmucosal studies could overestimate the absorption of hydrophilic drugs. In addition, fresh samples are recommended for these experiments, especially when hydrophilic drugs are involved.

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