Transdermal Delivery Applications Research Articles

Assessing the impact of quaternary ammonium compounds with different stoichiometric ratio on atorvastatin calcium solubility

ABSTRACT Co-crystallisation of atorvastatin calcium (ATC) at different molar ratio with choline chloride (CC) and benzalkonium chloride (BAC) was carried out using the solvent evaporation method in methanol. The solids obtained were characterised by Fourier transform infrared spectroscopy (FT-IR), differential scanning calorimetry (DSC), and powder X-ray diffraction (PXRD). Solubility studies were performed in different media including distilled water, pH 1.2, pH 4.5 and, pH 6.8. PXRD revealed the co-amorphous nature of the developed formulations. FT-IR and DSC confirmed the structural changes and formation of amorphous structures. Results revealed that the solubility increased marginally. ATC-BAC showed the highest drug solubility and a 3.8-fold increase in drug solubility. These comprehensive approaches suggest that the ATC-BAC amorphous system had solubility advantages and it might provide a theoretical basis for its application in transdermal delivery of ATC.

Microneedles and Their Application in Transdermal Delivery of Antihypertensive Drugs-A Review.

One of the most cutting-edge, effective, and least invasive pharmaceutical innovations is the utilization of microneedles (MNs) for drug delivery, patient monitoring, diagnostics, medicine or vaccine delivery, and other medical procedures (e.g., intradermal vaccination, allergy testing, dermatology, and blood sampling). The MN-based system offers many advantages, such as minimal cost, high medical effectiveness, comparatively good safety, and painless drug application. Drug delivery through MNs can possibly be viewed as a viable instrument for various macromolecules (e.g., proteins, peptides, and nucleic acids) that are not efficiently administered through traditional approaches. This review article provides an overview of MN-based research in the transdermal delivery of hypertensive drugs. The critical attributes of microneedles are discussed, including the mechanism of drug release, pharmacokinetics, fabrication techniques, therapeutic applications, and upcoming challenges. Furthermore, the therapeutic perspective and improved bioavailability of hypertensive drugs that are poorly aqueous-soluble are also discussed. This focused review provides an overview of reported studies and the recent progress of MN-based delivery of hypertensive drugs, paving the way for future pharmaceutical uses. As MN-based drug administration bypasses first-pass metabolism and the high variability in drug plasma levels, it has grown significantly more important for systemic therapy. In conclusion, MN-based drug delivery of hypertensive drugs for increasing bioavailability and patient compliance could support a new trend of hypertensive drug delivery and provide an alternative option, overcoming the restrictions of the current dosage forms.

Hollow silicon microneedles, fabricated using combined wet and dry etching techniques, for transdermal delivery and diagnostics

Microneedle-based technologies are the subject of intense research and commercial interest for applications in transdermal delivery and diagnostics, primarily because of their minimally invasive and painless nature, which in turn could lead to increased patient compliance and self-administration. In this paper, a process for the fabrication of arrays of hollow silicon microneedles is described. This method uses just two bulk silicon etches – a front-side wet etch to define the 500 μm tall octagonal needle structure itself, and a rear-side dry etch to create a 50 μm diameter bore through the needle. This reduces the number of etches and process complexity over the approaches described elsewhere. Ex-vivo human skin and a customised applicator were used to demonstrate biomechanical reliability and the feasibility of using these microneedles for both transdermal delivery and diagnostics. Microneedle arrays show no damage even when applied to skin up to 40 times, are capable of delivering several mL of fluid at flowrates of 30 μL/min, and of withdrawing 1 μL of interstitial fluid using capillary action.

A transferosome-loaded bigel for enhanced transdermal delivery and antibacterial activity of vancomycin hydrochloride

Transdermal drug delivery is an attractive route of administration relative to other routes as it offers enhanced therapeutic efficacy. However, due to poor skin permeability of certain drugs, their application in transdermal delivery is limited. The ultra-deformable nature of transferosomes makes them suitable vehicles for transdermal delivery of drugs that have high molecular weights and hydrophilicity. However, their low viscosity, which leads to low contact time on the surface of the skin, has restricted their application in transdermal delivery. Therefore, this study aimed to deliver transferosomes loaded with a highly water-soluble and high molecular weight vancomycin hydrochloride (VCM-HCl) via a bigel for systemic delivery and treatment of microbial infections. VCM-HCl-loaded transferosomal formulations (TNFs) were prepared using a reverse-phase evaporation method and then loaded into a bigel. Both the TNFs and TNFs-loaded bigel (TNF-L-B) were characterized by a range of in vitro and ex vivo techniques. TNFs and TNF-L-B were tested for biosafety via the MTT assay and found to be biosafe. Prepared TNFs had sizes, zeta potential and entrapment efficiency of 63.02 ± 5.34 nm, −20.93 ± 6.13 mV and 84.48 ± 1.22% respectively. VCM-HCl release from TNF-L-B showed a prolonged release profile with 39.76 ± 1.6% after 24hrs when compared to bare VCM-HCl loaded in the bigel (74.81 ± 8.84%). Ex-vivo permeation of prepared TNF-L-B showed a higher permeation flux of 0.56 µg/cm2/h compared to the bare VCM-HCl-loaded bigel of 0.23 µg/cm2/h, indicating superior permeation and bioavailability of the drug. Additionally, the prepared TNF-L-B demonstrated improved antimicrobial activity. The TNF-L-B showed minimum inhibitory concentrations (MIC) of 0.97 μg/ml against Staphylococcus aureus (SA) and 1.95 μg/ml against methicillin-resistant SA (MRSA), which were 2-fold lower MIC values than the bare drug. The time-kill assay showed that both TNFs and TNF-L-B systems caused a 5.6-log reduction (100%) in MRSA compared to bare VCM-HCl after 24 hrs of incubation. Furthermore, as opposed to the bare VCM-HCl solution, the degree of biofilm reduction caused by TNFs (55.72%) and TNF-L-B (34.58%) suggests their dominance in eradicating MRSA biofilm. These findings indicate that TNF-L-B is a promising system for transdermal delivery of hydrophilic and high molecular weight drugs.

Assessment of Finite and Infinite Dose In Vitro Experiments in Transdermal Drug Delivery

Penetration, usually with finite dosing, provides data about the total active amount in the skin and permeation, being the most used methodology, usually with infinite dosing, leads to data about pharmacokinetic parameters. The main objective of this work is to assess if results from permeation, most of them at finite dose, may be equivalent to those from penetration usually at infinite dose. The transdermal behavior of four drugs with different physicochemical properties (diclofenac sodium, ibuprofen, lidocaine, and caffeine) was studied using penetration/finite and kinetic permeation/infinite dose systems using vertical Franz diffusion cells to determine the relationships between permeation and penetration profiles. Good correlation of these two in vitro assays is difficult to find; the influence of their dosage and the proportion of different ionized/unionized compounds due to the pH of the skin layers was demonstrated. Finite and infinite dose regimens have different applications in transdermal delivery. Each approach presents its own advantages and challenges. Pharmaceutical industries are not always clear about the method and the dose to use to determine transdermal drug delivery. Being aware that this study presents results for four actives with different physicochemical properties, it can be concluded that the permeation/infinite results could not be always extrapolated to those of penetration/finite. Differences in hydrophilicity and ionization of drugs can significantly influence the lack of equivalence between the two methodologies. Further investigations in this field are still needed to study the correlation of the two methodologies and the main properties of the drugs that should be taken into account.

Comparative Study of Conventional and Fatty Acid Vesicular Systems – An Overview

: Fatty acid vesicles are suspensions of closed lipid bilayers that are composed of fatty acids and their ionized species which are restricted to a narrow pH range. The fatty acid molecules are oriented in such a way that their hydrocarbon tails are directed toward the membrane interior and the carboxyl groups are in contact with water. Recent innovations provide an opportunity to formulate fatty acid vesicles with distinguishing features such as extension of pH range, insensitivity toward divalent cations, easy alteration in membrane composition, very simple systems in terms of chemical nature and enhanced stability properties. This review contains detail about the present stature of fatty acid vesicles, comparative study of fatty acid vesicles with conventional liposomes, unique features of fatty acid vesicles (dynamicity, stability, matrix effect etc.,) and key evaluation parameters of fatty acid vesicles. Fatty acid vesicles were found to have high penetration capacity, good bio-distribution properties, increased diffusion rate and optimum drug deposition nature than other vesicular forms. They have various applications in transdermal delivery, follicular delivery and in brain targeting drug delivery systems (drugs that are unable to cross blood brain barrier due to high solubility). This review focuses on various researches conducted on fatty acid vesicles with reference to its formulation and evaluation parameters. © 2020 iGlobal Research and Publishing Foundation. All rights reserved.

Polyvinylidene fluoride–Hyaluronic acid wound dressing comprised of ionic liquids for controlled drug delivery and dual therapeutic behavior

To improve the efficacy of transdermal drug delivery systems, the physical and chemical properties of drugs need to be optimized to better penetrate into the stratum corneum and to better diffuse into the epidermis and dermis layers. Accordingly, dual-biological function ionic liquids composed of active pharmaceutical ingredients were synthesized, comprising both analgesic and anti-inflammatory properties, by combining a cation derived from lidocaine and anions derived from hydrophobic nonsteroidal anti-inflammatory drugs. Active pharmaceutical ingredient ionic liquids (API-ILs) were characterized through nuclear magnetic resonance, cytotoxicity assay, and water solubility assay. All properties were compared with those of the original drugs. By converting the analgesic and anti-inflammatory drugs into dual-function API-ILs, their water solubility increased up to 470-fold, without affecting their cytotoxic profile. These API-ILs were incorporated into a bilayer wound dressing composed of a hydrophobic polyvinylidene fluoride (PVDF) membrane to act as a drug reservoir and a biocompatible hyaluronic acid (HA) layer. The prepared bilayer wound dressing was characterized in terms of mechanical properties, membrane drug uptake and drug release behavior, and application in transdermal delivery, demonstrating to have desirable mechanical properties and improved release of API-ILs. The assessment of anti-inflammatory activity through the inhibition of LPS-induced production of nitric oxide and prostaglandin E2 by macrophages revealed that the prepared membranes containing API-ILs are as effective as those with the original drugs. Cell adhesion of fibroblasts on membrane surfaces and cell viability assay confirmed improved the viability and adhesion of fibroblasts on PVDF/HA membranes. Finally, wound healing assay performed with fibroblasts showed that the bilayer membranes containing dual-function API-ILs are not detrimental to wound healing, while displaying increased and controlled drug delivery and dual therapeutic behavior. Statement of significanceThis work shows the preparation and characterization of bilayer wound dressings comprising dual-biological function active pharmaceutical ingredients based on ionic liquids with improved and controlled drug release and dual therapeutic efficiency. By converting analgesic and anti-inflammatory drugs into ionic liquids, their water solubility increases up to 470-fold. The prepared bilayer wound dressing membranes have desirable mechanical properties and improved release of drugs. The prepared membranes comprising ionic liquids display anti-inflammatory activity as effective as those with the original drugs. Cell adhesion of fibroblasts on membrane surfaces and cell viability assays show improved viability and adhesion of fibroblasts on PVDF/HA membranes, being thus of high relevance as effective transdermal drug delivery systems.

Piezoelectric inkjet coating of injection moulded, reservoir-tipped microneedle arrays for transdermal delivery

Coated microneedles have significant potential for use in transdermal delivery applications. In this paper, we describe the fabrication of microneedle master templates using microstereolithography techniques and subsequently use a commercial injection moulding process to replicate these microneedles in biocompatible cyclic olefin polymer (COP) materials. Notably, the 475 μm-tall needle designs feature a shallow pit or reservoir at the tip, thereby providing both a target and holder for incoming droplets that are deposited using a piezoelectric inkjet printer. Using this design, no tilting or rotation of the needle array is required during the filling process. In the preliminary tests reported here, the reservoir is filled with a FITC-labelled dye that acts as a model drug, and ex vivo skin tests are used to verify skin penetration, the transfer of this model drug to the skin and to measure the reliability of the needles themselves. To our knowledge, this is the first time that such an inkjet-filled, reservoir-tipped microneedle has been demonstrated.

Recent Patents and Formulation of Nanopharmaceuticals Using Ultrasonication Technique.

Ultrasound (US) has the ever-rising role in the delivery of therapeutic agents that includes chemotherapeutic agents, proteins, and genetic material. The microbubbles are the cavitating gas bodies that act as the mediators through which the energy of relatively non-interactive pressure waves is accumulated to produce forces that can permeabilize cell membranes and disrupt the vesicles that carry the therapeutic agent. This shows that the microbubbles greatly enhance the delivery of smaller chemical agents, proteins and genetic material. Various databases of online literature and patented reports based on sonication were reviewed. The literature reveals that US-assisted drug delivery is used in the delivery of therapeutic agents into various tissues including vascular, cardiac, tumor, skeletal muscle and fetal tissue. US-assisted delivery of proteins has been studied in the application in transdermal delivery of insulin, hormones and small proteins. Cavitation effect occurring during the sonication reversibly disrupts the stratum corneum structure to allow the transport of the large molecules. Cavitation disrupts the structure of the carrier vesicle and releases the drug. But there still remains a need for better understanding the physics of cavitation of microbubbles and the impact of cavitation on drug-carrying vesicles and cells. Ultrasonic technology has been proven effective at creating encapsulating particles and droplets with specific physical and functional properties. This article provides an overview of the factors influencing ultrasonication and various nanosystems formulated by using this technology.

Formulation Development and In vitro Evaluation of Transdermal Patches of Tramadol HCl

In the present research work an attempt was made to prepare and evaluate the transdermal patches of Tramadol HCl, a centrally acting opiod analgesic drug. Formulations were made by using different ratios of rate controlling polymers like Eudragit RL100, hydroxyl propyl methyl cellulose 6 cps and ethyl cellulose. Poly ethylene glycol 400 is used as plasticizer and Tween 80 as penetration enhancer. The patches were prepared by solvent evaporation technique using liquid paraffin as lubricant. The study examines the influence of polymers ratio on physicochemical properties and drug release potential of transdermal films. In the pre formulation studies, solubility, partition coefficient and melting point were determined to assess its application for transdermal delivery. The FTIR studies confirmed that there is no incompatibility present between drug and excipients. The patches were evaluated for their appearance, weight uniformity, and thickness uniformity, drug content uniformity, folding endurance, invitro diffusion and stability studies. Based on the evaluation studies F10 formulation was optimised. The drug release was extended for 12 hrs showing drug release of 94.19%. The release kinetics data for optimised formulation has revealed that the patch is best fit in to higuchi model with fickian type of diffusion. The optimised formulation was subjected to accelerated stability studies for 6 months and the results found to be stable with respect to drug content, drug release as well as physical changes.

Nanotechnology approaches for pain therapy through transdermal drug delivery.

The paper focuses on the advances in the field of pain treatment by transdermal delivery of specific drugs. Starting from a short description of the skin barrier, the pharmacodynamics and pharmacokinetics including absorption, distribution, action mechanism, metabolism and toxicity, aspects related to the use of pain therapy drugs are further discussed. Most recent results on topical anesthetic agents as well as the methods proved to overcome the skin barrier and to provide efficient delivery of the drug are also discussed. The present review is proposing to summarize the recent literature on the pharmacotherapeutic principles of local anesthetics and non-steroidal anti-inflammatory drugs, generally used to alleviate pain but also the drugs as nanoformulations with potential applications in transdermal delivery. A special attention is given to efficient formulations meant for transdermal penetration enhancement of anesthetics where the drug is encapsulated into macrocyclic molecules (cyclodextrins, cyclodextrin derivatives), liposomes or polymer nanoparticles and hydrogels.

Distinct kinetics of molecular gelation in a confined space and its relation to the structure and property of thin gel films.

Thin films of molecular gels formed in a confined space have potential applications in transdermal delivery, artificial skin, molecular electronics, etc. The microstructures and properties of thin gel films can be significantly different from those of their bulk counterparts. However, so far a comprehensive understanding of the effects of spatial confinement on the molecular gelation kinetics, fiber network structure and related mechanical properties is still lacking. In this work, using rheological techniques, we investigated the effect of one-dimensional confinement on the formation kinetics of fiber networks in the molecular gelation process. Fractal analyses of the kinetic information in terms of an extended Dickinson model enabled us to describe quantitatively the distinct kinetic signature of molecular gelation. The structural features derived from gelation kinetics support well the fractal patterns of the fiber networks acquired by optical and electron microscopy. With the kinetics-structure correlation, we can gain an in-depth understanding of the confinement-induced differences in the structure and consequently the mechanical properties of a model molecular gelling system. Particularly, the confinement induced structural transition, from a three-dimensional, dense and compact spherulitic network composed of highly branched fibers to a quasi-two-dimensional sparse spherulitic network composed of less branched fibers and entangled fibrils at the boundary areas, renders a gel film to become less stiff but more ductile. Our study suggests here a new strategy of engineering the fiber network microstructure to achieve functional gel films with unusual but useful properties.

Structural characterization and in-vivo reliability evaluation of silicon microneedles

This work presents an analysis of the failure mechanisms, structural properties and reliability of wet-etched silicon microneedles, which have wide-ranging applications in transdermal delivery, sensing and diagnostics. For the first time, in-vivo skin insertion forces are measured and the structural properties of individual silicon microneedles are assessed using both compression and shear tests. Compressive failure of this particular microneedle design does not occur because of buckling, but instead is predominantly due to progressive fracture along the relatively weak {111} crystal plane. Compressive and shear failure strengths are experimentally determined to be (2.9 +/- 0.3) GPa and (9.2 +/- 0.2) MPa, respectively. It is also shown that basic mechanical tests that are commonly used in the field of microneedle development may significantly underestimate safety factors for this type of needle due to the unrepresentative nature of the interaction of a rigid surface with the needle tips. Therefore, a new figure-of-merit for the reliability of such microneedles is proposed, which is based on the ratio of material failure strength to peak stress during skin insertion. The distribution of forces over the sharp, conical needle tip during skin penetration leads to a very large safety margin of over 700, and a correspondingly high degree of reliability when applied to in-vivo human tissue.

Development of a novel transdermal patch containing sumatriptan succinate for the treatment of migraine: in vitro and in vivo characterization

The objective of the present study was to develop and evaluate patches containing sumatriptan succinate (SS), and characterized their application in transdermal delivery of SS. An acrylic emulsion pressure sensitive adhesive was chosen (Nikasol), and compared with a hydrophilic acrylic adhesive (HGA). In vitro permeation studies showed that Nikasol was a better adhesive than HGA, due to the greater skin permeability. An increase in transepidermal water loss was observed after application of both types of patches, however, this parameter gradually recovered to baseline, suggesting that the skin damage was reversible. Furthermore, in vivo pharmacokinetic studies indicated that SS was effectively absorbed from Nikasol patch through the skin and associated with relatively greater absolute bioavailability than that of oral administration. Therefore, these findings indicate that our transdermal patch delivery system of SS fabricated from Nikasol is a promising and innovative approach that may increase compliance in patients undergoing treatment for migraine.

Transdermal absorption and stability enhancement of salmon calcitonin by Tat peptide

Context: Highly organized structure of stratum corneum (SC) is the major barrier of the delivery of macromolecules such as proteins and peptides across the skin. Recently, cell penetrating peptides (CPPs) such as HIV1-trans-activating transcriptional (Tat) have been used to enhance the topical delivery of proteins and peptides. Objective: This study aimed to enhance the transdermal absorption and chemical stability of salmon calcitonin (sCT) by co-incubation with Tat. Materials and methods: Tat-sCT mixture at 1:1 molar ratio was prepared. Transdermal absorption and chemical stability of the mixture was evaluated in comparing with free sCT. Results: Tat-sCT mixture gave higher cumulative amounts and fluxes of sCT than free sCT. The maximum percentage of sCT of 58.36 ± 12.33% permeated into the receiving chamber was found in Tat-sCT mixture at 6 h which was 3.50 folds of free sCT. Tat-sCT mixture demonstrated better sCT stability than sCT solution after 1 month storage at 4°C, 25°C and 45°C. Discussion: The positively-charged arginine groups in Tat might be responsible for the binding of peptide complexes to negatively charged cell surfaces by electrostatic interactions and also the translocation of sCT through the excised skin. Conclusion: This study demonstrated the enhancements of transdermal absorption and stability of sCT by Tat peptide with potential for further application in transdermal delivery of other therapeutic peptides.

The Effect of Penetration Enhancers on Permeation Kinetics of Nitrendipine in Two Different Skin Models

The purpose of this research was to evaluate the effect of penetration enhancers on permeation kinetics of nitrendipine (NTP) through two different skin models. The permeation profile and related kinetics parameters such as activity parameter, diffusion parameter, lag time, relative activity parameter and relative diffusion parameter of NTP was determined in presence of some novel and widely accepted permeation enhancers. Among all the more pronounced enhancing effect was obtained with oleic acid (OA) as it presented the highest permeability coefficient. The enhancement was found to be increased in the following order: Dimethyl sulphoxide (DMSO)<Isopropyl myristate (IPM)<Sodium lauryl sulphate (SLS)<Tween 20 (T20)<Myristic acid (MA)<Lauric acid (LA)<Capric acid (CA)<Tween 80 (T80)<Span 80 (S80)<Thyme oil (TO)<Palmarosa oil (PA)<Petitlgrain oil (PT)<Basil oil (BO)<Oleic acid (OA). The increase in drug permeation was attributed mainly to the decrease in diffusion path length. Essential oils and surfactant (span 80) have shown relative activity parameter (Kr value) well above unity and relative diffusion parameter (Dr value) almost equal or less than unity, which would be attributed to gradual increase in membrane permeability leading to higher permeation. Oleic acid is effective for augmenting skin permeation of NTP, with potential application in transdermal delivery of the drug.

Effects of Solvents on Skin Permeation of Formoterol Fumarate

Effects of various chemicals applied as penetration enhancers on the permeation of formoterol fumarate (FF) across excised rat skin were investigated. Remarkable enhancement was noted with terpenes, fatty acid esters, and higher alcohols, whereas no significant influence was observed in the case of lower alcohols, pyrrolidones, and amines. At high concentration, a cineole/N-methyl-2-pyrrolidone (NMP) mixed solvent system slightly enhanced the skin permeation of FF compared with cineole alone, and a l-menthol/NMP mixed solvent system caused significant further increase. Maximum skin permeation of FF was seen when the ratio of l-menthol/NMP was 60/40 w/w. From the present results, l-menthol/NMP and isopropyl myristate (IPM)/NMP mixed solvent systems can be considered effective for augmenting skin permeation of FF, with potential applications in transdermal delivery of the drug.

Pharmacokinetic Considerations in the Use of Newer Transdermal Formulations

This review addresses the pharmacokinetics and pharmacodynamics of transdermally delivered drugs. The systemic input of drugs via the skin has attracted considerable interest over the past 15 years. The early promise of the administration route has, to some extent, been realised with the approval and successful launching of transdermal formulations of hyoscine (scopolamine), glyceryl trinitrate (nitroglycerin), clonidine and oestradiol. The further application of transdermal delivery, however, will require additional effort. While other molecules (e.g. testosterone, fentanyl, nicotine) may ultimately be administered in this way, important questions pertaining to pharmacology (tolerance), toxicity (irritation, sensitisation) and dose sufficiency (penetration enhancement) remain. These problems are illustrated using information which has been published in the literature. Overall, while the enthusiasm for attraction and benefits of transdermal delivery remain evident, it is clear that future successes will demand a heightened level of commitment and skill from the pharmaceutical scientist.