Candidate For Transdermal Drug Delivery Research Articles

Metformin HCl-loaded transethosomal gel; development, characterization, and antidiabetic potential evaluation in the diabetes-induced rat model

Herein we designed, optimized, and characterized the Metformin Hydrochloride Transethosomes (MTF-TES) and incorporate them into Chitosan gel to develop Metformin Hydrochloride loaded Transethosomal gel (MTF-TES gel) that provides a sustained release, improved transdermal flux and improved antidiabetic response of MTF. Design Expert® software (Ver. 12, Stat-Ease, USA) was applied for the statistical optimization of MTF-TES. The formulation with Mean Particle Size Distribution (MPSD) of 165.4 ± 2.3 nm, Zeta Potential (ZP) of −21.2 ± 1.9 mV, Polydispersity Index (PDI) of 0.169 ± 0.033, and MTF percent Entrapment Efficiency (%EE) of 89.76 ± 4.12 was considered to be optimized. To check the chemical incompatibility among the MTF and other formulation components, Fourier Transform Infrared (FTIR) spectroscopy was performed and demonstrated with no chemical interaction. Surface morphology, uniformity, and segregation were evaluated through Transmission Electron Microscopy (TEM). It was revealed that the nanoparticles were spherical and round in form with intact borders. The fabricated MTF-TES has shown sustained release followed by a more pronounced effect in MTF-TES gel as compared to the plain MTF solution (MTFS) at a pH of 7.4. The MTF-TES has shown enhanced permeation followed by MTF-TES gel as compared to the MTFS at a pH of 7.4. In vivo antidiabetic assay was performed and results have shown improved antidiabetic potential of the MTF-TES gel, in contrast to MTF-gel. Conclusively, MTF-TES is a promising anti-diabetic candidate for transdermal drug delivery that can provide sustained MTF release and enhanced antidiabetic effect.

Exploration of curcumin-incorporated dual anionic alginate-quince seed gum films for transdermal drug delivery

The idea of combining bioextracted polymers for wound healing applications has emerged in hopes of developing highly flexible and mechanically stable hydrogel films with controlled drug delivery, biocompatibility, and high collagen deposition. In the present research, polysaccharide films composed of Alginate and Quince Seed Gum (QSG) were fabricated by ionic crosslinking, and their potential for curcumin delivery and wound healing were examined. In this regard, microstructure, mechanical properties, thermal stability, physiochemical properties, and biocompatibility of films with three different QSG amounts (25 %, 50 %, and 75 %) were studied. Because of the optimum properties of 25 % QSG films like better transparency (Opacity = 6.1 %), higher flexibility (Elongation = 28.9 %), less water solubility (Water solubility = 66.6 %), proper absorbance (Swelling degree = >600 %), and suitable biocompatibility (Cell viability = >85 %), they were used for drug delivery examination. Curcumin administration through films with and without stearic acid modification was investigated. Stearic Acid (SA) modified samples demonstrated superior compatibility between hydrophobic drug and hydrophilic film. Stearic acid-modified film could prolong the curcumin release up to 48 h and showed increased collagen synthesis and TGF-β expression, making it an excellent candidate for transdermal drug delivery and wound healing applications.

Physicochemical In vivo Anti-Inflammatory effect of Tablet containing Fenoprofen

Fenoprofen, a potent nonsteroidal anti-inflammatory drug, is widely used for relief of pain in patients suffering from rheumatic diseases, migraine, sore throat and primary dysmenorrheal. However, this drug has many gastrointestinal side effects produced by its oral administration, such as gastric bleeding and peptic ulcer. These effects were responsible for non-compliance among patients, which ultimately results in treatment failure. The physicochemical properties of Fenoprofen, make it a suitable candidate for transdermal drug delivery, which can overcome the drawbacks of oral administration. In this sense, tablets have been proved to increase the cutaneous absorption of lipophilic drugs when compared to conventional drug delivery systems. The carrageenan test is highly sensitive to nonsteroidal anti-inflammatory drugs and has long been accepted as a useful model to determine the anti-inflammatory effects of natural products. In the present study the anti-inflammatory activity of Fenoprofen and superdisintegrant was investigated by experimental carrageenan animal model. In our study, the induction of carrageenan in the rat hind paw started off the vascular phase of inflammation which was characterized by temporary vasoconstriction and vasodilatation that generated an increase in the size of the edema for all groups.

A Brief Review on Topical Gels as Drug Delivery System

The method of applying prescription dosage forms to the skin for direct treatment of a cutaneous disorder is known as a topical drug delivery system. Topical gels are semisolid dosage forms in which a liquid phase is constrained within a three-dimensional polymeric matrix derived from natural or semi-synthetic sources with high physical or chemical cross-linking. Because of their intermediate behavior between solid and liquid materials, topical gels are an excellent candidate for transdermal drug delivery. Clinical evidence indicates that topical gel is a safe and effective treatment choice for the management of skin-related diseases, especially when used for local action to avoid the side effects of other conventional dosage forms. Gels, cream, ointment, and paste are the most commonly used semi-solid formulations for topical drug delivery. Gels are colloids in which the liquid medium has thickened to the extent that it behaves like a solid. Since topical gel formulations are less greasy and can be quickly removed from the skin, they offer better drug delivery. In comparison to cream, ointment, and paste, gel formulations have improved application properties and consistency. This article aims to review the principles and recent developments in topical gels, including classification, methods of preparation, applications, and so on.

Effects of solvents and penetration enhancers on transdermal delivery of thymoquinone: permeability and skin deposition study

Thymoquinone (TQ) is a quinone-based phytochemical that was first identified in 1963 in Nigella sativa (black cumin seed) by El-Dakhakhany. Based on the ideal characteristics of transdermal delivery, TQ is potentially an attractive candidate for transdermal drug delivery. The aim of this study was to investigate the feasibility of transdermal delivery of TQ and to assess the effect of an ethanol and propylene glycol donor solvent system along with various compositions of receptor solvents. The effects of penetration enhancers on the in vitro skin permeation and TQ skin absorption were studied using human cadaver skin in Franz diffusion cells. The permeation of saturated solutions of TQ was investigated with 5% v/v of each of the following enhancers: Azone (laurocapram), Transcutol® P (Tc), oleic acid, ethanol, Polysorbate 80 (Tween 80), and N-methyl-pyrrolidone (NMP). The results indicated that Azone, oleic acid, and Tc were able to provide adequate TQ flux and may be the agents of choice for use in a novel transdermal formulation of TQ. These penetration enhancers were also able to generate TQ reservoirs in the skin that may be useful to provide sustained release of TQ from the stratum corneum over longer periods of time.

Electrospun curcumin loaded poly(lactic acid) nanofiber mat on the flexible crosslinked PVA/PEG membrane film: Characterization and in vitro release kinetic study

Herein, a biodegradable and biocompatible composite comprising of support membrane based on crosslinked PVA/PEG film and curcumin loaded electrospun poly(lactic acid) (PLA) nanofiber mat is introduced. The membrane film was prepared from PVA/PEG blend followed by crosslinking with an optimum amount of citric acid, 15 wt.%. After then, PLA solutions with different curcumin content, 0-11 wt.%, were electrospinned on the prepared membrane substrate. The prepared film showed high water absorption, water vapor transmission rate and superior mechanical properties with improved elastic modulus, tensile strength and with an elongation of around 320 % with respect to the non-crosslinked one. Also, the scanning electron microscopy was revealed uniformly dispersed pores throughout the membrane film with a nearly narrow in size distribution centered at 36 μm. As well, a nanostructure porous morphology was found for the electrospun fibrous curcumin loaded PLA from the scanning electron microscopy micrographs and the average fiber diameter was decreased with curcumin content. In vitro drug release from the prepared flexible composite into the vertical diffusion cell was recorded by the measuring curcuminoids content using high performance liquid chromatography and drug release kinetic evaluations were revealed that the release pattern of all prepared samples, containing different content of curcumin, well fitted to the Higuchi’s model signifying diffusion-controlled release mechanism. As well, the determined release rate at the second release stages, i.e. steady state flux (J), was varied from 0.31 to 43.53 μg·cm-2·h-1 with increasing drug content from 1 to 11 wt.%. Regarding this results, this flexible composite by providing the moist environment along with miraculous healing properties of curcumin, can be potential candidate for transdermal drug delivery.

Transdermal delivery of dimethyl fumarate for Alzheimer’s disease: Effect of penetration enhancers

Dimethyl fumarate (DMF) is an orally administered drug with neuroprotective and immunomodulatory activities. It has potential uses in the treatment of neurodegenerative diseases such as Alzheimer’s disease (AD). The objective of this study was to investigate the feasibility of transdermal delivery of DMF by studying the effect of different penetration enhancers on the skin permeation of DMF. The permeation of saturated DMF solutions was investigated in propylene glycol (PG) with varying concentrations of each of the following enhancers: Polysorbate 80 (T80), N-methyl pyrrolidone (NMP), laurocapram (Azone®) (Az), Transcutol P (Tc), Terpineol (Terp), and cineole (Cin) using vertical Franz diffusion cells and human cadaver skin. The results showed that all penetration enhancers improved the rate of permeation of DMF. The rank order for the highest concentration of each enhancer was as follows: Cin > Az>TC > Terp>T80≥NMP. The most effective penetration enhancer was shown to be 5% cineole with a 5.3-fold increase in the enhancement ratio (ER). The amounts of drug delivered suggest that DMF is a potential candidate for transdermal drug delivery.

Analytical Method for Transdermal Delivery of the Anti-angiogenic Compound TNP-470

Pathological angiogenesis is a critical component in cancer, in chronic systemic inflammatory diseases such as psoriasis and rheumatoid arthritis, and in ocular diseases. Anti-angiogenic drugs have the ability to prevent, inhibit, and regress newly formed blood vessels. The activity of TNP-470 (chloro acetylcarbamoylfumagillol), a potent anti-angiogenic drug, has been demonstrated in numerous preclinical studies and in eight clinical studies involving more than three hundred patients. Despite its encouraging efficacy, TNP-470 is unstable compound with short plasma half-life, and, as was found clinically it can cause neurotoxicity side-effects at high doses. In light of these limitations, developing a transdermal drug delivery for TNP-470, can offer a novel and promising clinical usage for this drug by improving its bioavailability, controlled dosage and safety profile. In this work, we developed a reliable method for skin permeation studies of TNP-470, using the pig skin in Franz diffusion cells and High-Performance Liquid Chromatography (HPLC) analysis. Additionally, we performed a broad stability and degradation studies of TNP-470 in different mediums and identify optimal stabilizing conditions in acetate buffer pH-4.5, which can be used for transdermal formulation. Our results demonstrated excellent permeability properties of TNP-470 through the pig skin, where 25% from the initial amount was crossed through the skin membrane after 72 hours. Our results suggesting that TNP-470 is a good candidate for transdermal drug delivery, whereas, an optimal dermal formulation would improve drug’s pharmacokinetic properties and toxicity profile by introducing it in a slow release system.

Physicochemical, in vitro and in vivo evaluation of flurbiprofen microemulsion.

Flurbiprofen, a potent nonsteroidal anti-inflammatory drug, is widely used for relief of pain in patients suffering from rheumatic diseases, migraine, sore throat and primary dysmenorrheal. However, this drug has many gastrointestinal side effects produced by its oral administration, such as gastric bleeding and peptic ulcer. These effects were responsible for non-compliance among patients, which ultimately results in treatment failure. The physicochemical properties of flurbiprofen, make it a suitable candidate for transdermal drug delivery, which can overcome the drawbacks of oral administration. In this sense, microemulsions have been proved to increase the cutaneous absorption of lipophilic drugs when compared to conventional drug delivery systems. The purpose of this study was to formulate and characterize gel based microemulsions, for topical delivery of flurbiprofen. Different gel bases, containing microemulsion and hydro-alcoholic solution of flurbiprofen, were developed and compared. In vitro study showed that gels containing microemulsion had a higher permeation rate than those containing hydro-alcoholic solutions. Additionally, formulation of Carbopol-I (microemulsion) showed higher percent of inhibition of inflammation than others bases. Further, skin irritation study demonstrated that Carbopol-I was none irritating. Flurbiprofen microemulsion incorporated on Carbopol-I showed physicochemical, in vitro and in vivo characteristics suitable for the development of alternative transdermal delivery formulation.

Transdermal Delivery of Verapamil HCl: Effect of Penetration Agent on In Vitro Penetration through Rat Skin

Verapamil Hydrochloride is a calcium channel blocking anti-anginal agent. Extensive first pass metabolism, low bioavailability (~20%) and short biological half life (4.8 hrs) altogether makes it an ideal candidate for transdermal drug delivery. The objectives of this study were to develop matrix-type transdermal patches of verapamil hydrochloride (VPL) with combinations of hydroxypropyl methyl cellulose (HPMC) and hydroxy propyl cellulose (HPC) as matrix polymers and to investigate the influence of oleic acid (OA) on in vitro permeation of VPL through rat skin. The permeation studies were performed using Franz-type diffusion cells and full-thickness excised abdominal rat skin. The effect of the polymers on the drug release, percentage moisture loss, percentage moisture absorption, folding endurance, and thickness, were investigated.. In vitro release studies showed zero-order release of the drug from all the patches, and the mechanism of release was diffusion mediated. Data was analysed using different release kinetic models. In vitro release profiles showed that from optimized combination the release of the drug was sustained and it extended over a period of 24 hr VPM 006 emerged as the most satisfactory formulation as far as its technological properties were concerned.

A high aspect ratio SU-8 fabrication technique for hollow microneedles for transdermal drug delivery and blood extraction

Protein drugs, e.g. hormonal drugs, cannot be delivered orally to a patient as they get digested in the gastro-intestinal (GI) tract. Thus, it is imperative that these kinds of drugs are delivered transdermally through the skin. To provide for real-time feedback as well as to test independently for various substances in the blood, we also need a blood sampling system. Microneedles can perform both these functions. Further, microneedles made of silicon or metal have the risk of breaking inside the skin thereby leading to complications. SU-8, being approved of as being biocompatible by the Food and Drug Agency (FDA) of the United States, is an attractive alternative because firstly it is a polymer material, thereby reducing the chances of breakages inside the skin, and secondly it is a negative photoresist, thereby leading to ease of fabrication. Thus, here we present very tall (around 1600 µm) SU-8 polymer-based hollow microneedles fabricated by a simple and repeatable process, which are a very good candidate for transdermal drug delivery as well as blood extraction. The paper elaborates on the details that allow the fabrication of such extreme aspect ratios (>100).

Effect of vehicles on the transdermal delivery of melatonin across porcine skin in vitro

Melatonin is a good candidate for transdermal drug delivery considering its variable oral absorption, a short biological half-life and extensive first pass metabolism. The purpose of this study was to investigate the effect of various vehicles on the in vitro permeation of melatonin across porcine skin. The skin permeation studies were carried out with vertical diffusion cells using dermatomed porcine skin. The flux of melatonin from isopropyl myristate, Lauroglycol FCC and ethanol were respectively 1.5, 1.4 and 1.3 times higher than that observed with water ( P<0.001). However, flux values of melatonin with Labrasol™, propylene glycol and mineral oil were significantly lower than that of water ( P<0.001). There was no significant difference between the flux of melatonin from the following vehicles: Transcutol™, Phosol 50 PG, ethyl oleate, PEG 400 and water ( F=0.2082, P>0.05). In general, vehicles with high melatonin solubility showed low permeability coefficient values. The flux had no correlation to the solubility data, suggesting that high solubility values do not translate to high drug permeation. The present study suggests that isopropyl myristate, Lauroglycol FCC and ethanol may be used as potential vehicles in the transdermal delivery of melatonin.

In Vitro Evaluation of the Release of Albuterol Sulfate from Polymer Gels: Effect of Fatty Acids on Drug Transport Across Biological Membranes

ABSTRACTIn this investigation, the diffusion of the beta2 agonist albuterol sulfate (ABS) across several membranes (cellulose, hairless mouse skin, human cadaver skin) from polymer gels was studied, and the effects of several fatty acids on drug permeation through skin were evaluated. The results were then used to predict whether transdermal delivery would be appropriate for ABS. All in vitro release studies were carried out at 37°C using modified Franz diffusion cells. In preliminary studies, ABS release through cellulose membranes was studied from two polymeric gels, Klucel® (hydroxypropylcellulose) and Methocel® (hydroxypropylmethylcellulose). Three polymer concentrations were used for each gel (0.5%, 1.0%, and 1.5%). From these experiments, Klucel 0.5% was selected as the optimal formulation to study ABS diffusion across hairless mouse skin. Experiments were conducted to evaluate the effects of capric acid, lauric acid, and myristic acid as penetration enhancers. The results suggested that lauric acid preferentially enhanced ABS diffusion compared to the other fatty acids studied, and follow-up studies were done to evaluate the release through human cadaver skin from a donor containing 2% ABS and lauric acid in 0.5% Klucel®. These experiments showed that a 2:1 (lauric acid:ABS) molar ratio gave the best ABS release rates. The release rate across human cadaver skin declined slowly over 24 hr, and an average flux over 24 hr of ˜0.09 mg/hr cm2 was measured. Using this value as a steady-state flux, extrapolations predicted that transdermal delivery can be used to maintain therapeutic ABS plasma levels (6–14 ng/mL) for extended periods. The results of this research suggest that ABS is a good candidate for transdermal drug delivery.

High Performance Liquid Chromatographic Assay of Terbutaline for Preformulation Studies

Abstract A reversed phase, stability indicating high performance liquid chromatographic (HPLC) assay was developed for the evaluation of terbutaline (TL) as a potential candidate for transdermal drug delivery. TL was quantitated in the permeation diffusate and human skin extract samples. The isocratic mobile phase was 30 % acetonitrile in pH 5.6 phosphate buffer. The effluent was monitored at 225 nm. Propranolol (PP, 2.5 μ/ml) was used as the internal standard. Baseline separation of TL and PP was attained with a cyano column. The linear range for the calibration curve was established at 5–15 μg/ml. The assay was reproducible with low inter-day and intra-day variation of the slopes of the calibration curves (3.5 and 4.2% for diffusate samples and 5 and 5.5% for the human skin extract samples respectively). The lowest detectable quantity was 0.1 μg/ml with a signal noise ratio of 4. The application of the assay in various preformulation studies was demonstrated.

Comparative in vitro diffusion studies for atenolol transdermal delivery system

The purpose of this study was to screen atenolol as a candidate for transdermal drug delivery, and to study the release of atenolol from various gels. The percent atenolol release over time profiles indicates that for all the gelling agents used the amount of atenolol released is decreased by increasing the polymer concentration in the gel. The amount of atenolol released was found to be higher from Klucel® gels, compared to Methocel® and Carbopol® gels, with Carbopol® gels giving the least release. In studying the effect of atenolol concentration in the gel, it was observed that the amount of atenolol released was increased by increasing the drug concentration in the donor up to a limit corresponding to an atenolol concentration of approximately 2%. This seems to resemble the saturation solubility of atenolol into the gels. Hairless mouse skin and TESTSKIN® LSE were used as in vitro skin models.

Clinical Efficacy of Current Transdermal Drug Delivery Systems: A Retrospective Evaluation: Basic and clinical research on this technology shows that the system development process needs serious review and revision

In spite of intensive research on transdermal drug delivery systems (TDDSs), only four--nitroglycerin, clonidine, estradiol, and scopolamine--have reached the market, and the clinical effectiveness of these systems has yet to be clearly demonstrated. Ideally, a candidate for transdermal drug delivery should demonstrate clinical significance within a wide therapeutic range for a well-documented indication for use. Continuous administration of a drug should result in better control of the disease with fewer side effects and a marked increase in patient compliance than when traditional dosage forms are used. It appears that nitroglycerin is a poor candidate for transdermal drug delivery by virtue of the ambiguity associated with its clinical pharmacology, substantial interpatient variation in dose-response relationship, and development of tolerance with potential toxicity risks in chronic administration. Clonidine's well-defined indication for use coupled with its high potency and low molecular weight with high lipid solubility is well suited to transdermal therapy. Because estradiol is unsuitable for use in people who smoke and has dermatotoxic potential, it is a marginal candidate for use in TDDSs. Transdermal scopolamine was not reviewed because it is a unique entity (no conventional dosage forms of this product are available) intended for short-term use. Its use is dictated more by the patient's unique circumstances, such as travel requirements, than by physiological condition. Although TDDSs provide a convenient and effective means of administering medications, the aforementioned clinical constraints need to be evaluated in depth before more widespread application of TDDSs can be recommended. In particular; conclusive demonstration of biocompatibility of a TDDS is warranted.