Chemical Penetration Enhancers Research Articles

Chemical Penetration Enhancers for Transdermal Drug Delivery - Success and Challenges.

Chemical penetration enhancers (CPEs), which are also referred to as sorption promoters or accelerants have several advantages in transdermal drug delivery. These are painlessness, noninvasiveness and the capacity to increase in transdermal flux in comparison with passive diffusion. Several investigators have used a number of chemical enhancers to demonstrate these important properties. Studies have also been carried out to have a better understanding of the mechanisms of penetration enhancement. It has been postulated that these compounds can enhance transdermal drug delivery by perturbing the stratum corneum, increasing partition coefficient or increasing solubility. In this paper, several compounds used in facilitating percutaneous penetration of drugs have been described and the potential of using them for transdermal drug delivery highlighted. Special attention has been paid to cell-penetrating proteins (protein transduction domains) as well as skin penetrating peptides. Ironically, these are substances that possess high molecular weight themselves but are capable of creating pores through which drugs can penetrate into and through the skin. Concerns relating to irritation and cytotoxicity and efforts to overcome them are discussed.

Effect of chemical penetration enhancer on transdermal iontophoretic delivery of diclofenac sodium under constant voltage

The study aimed to enhance the transdermal permeation of diclofenac sodium using combined strategy of constant voltage iontophoresis (CVI) and chemical penetration enhancers (CPE). Four hydrogels of diclofenac sodium were formulated with the key CPE and hydroxyethyl cellulose (HEC) as a viscosity imparting agent. In vitro permeation studies of the hydrogels indicated CVI significantly increased (ANOVA, P < 0.05) the steady state flux of diclofenac sodium through the porcine skin in the order geraniol (F1) > l-menthol (F2) > thymol (F3) > SLS-urea (F4) compared to the Fc (Passive control) under the applied voltage. F1 was identified as the lead formulation as an overall increase in steady state flux of 5.157 fold compared to Fc was observed at 1.5V. Pharmacokinetic studies in rats indicated that CVI at 1.5V following application of the lead formulation increased the Cmax and AUC0-8h by ∼3.5 folds compared to passive treatment. The higher systemic levels of diclofenac are likely to enhance the drug concentration in synovial fluid which is the site of action in most musculoskeletal disorders. The results of the study indicate that CVI can effectively deliver therapeutic amounts of diclofenac sodium transdermally to relieve chronic deep-seated muscular pain in several rheumatic disorders.

Aggravation of local immune responses caused by the chemical skin penetration enhancer oleic acid

Aggravation of local immune responses caused by the chemical skin penetration enhancer oleic acid

Influence of sonophoresis and chemical penetration enhancers on percutaneous transport of penbutolol sulfate

The effect of ultrasound and chemical penetration enhancers on transcutaneous flux of penbutolol sulfate across split-thickness porcine skin was investigated. Penbutolol sulfate is a potent, noncardioselective beta-blocker, which is used for the management of hypertension. The drug is one of the most lipid soluble of the β-adrenoceptor antagonists used clinically. It has an n-octanol/pH 7.4 buffer partition coefficient of 179 compared to a value of 22 for propranolol. The amount of penbutolol sulfate transported across the skin is low. In this project, we studied the effect of sonophoresis and chemical penetration enhancers on transdermal delivery of penbutolol sulfate. Low-frequency sonophoresis at a frequency of 20 kHz increased transcutaneous flux of penbutolol sulfate by 3.5-fold (27.37 ± μg cm−2 h−1) compared to passive delivery (7.82 ± 1.72 μg cm−2 h−1). We also investigated the effect of 50% ethanol, 1% limonene and 2% isopropyl myristate (IPM) on transcutaneous permeation of penbutolol sulfate. IPM, ethanol and limonene at the concentration of 1%, 50% and 2%, respectively, increased the steady-state flux values of penbutolol sulfate 2.2- (17.07 ± 3.24 μg cm−2 h−1), 2.6 - (19.40 ± 6.40 μg cm−2 h−1) and 3.4-times (26.38 ± 5.01 μg cm−2 h−1) compared to passive delivery (7.76 ± 2.9 μg cm−2 h−1). The results demonstrate that although there were slight increases in flux values, ultrasound, ethanol, limonene and IPM did not significantly enhance the transdermal delivery of penbutolol sulfate. Future studies will examine ways of optimizing sonophoretic and chemical enhancer parameters to achieve flux enhancement.

Chemical penetration enhancers.

To achieve an efficient skin penetration of most compounds it is necessary to overcome the barrier function of the skin, provided mainly (but not only) by the stratum corneum. Among various strategies used or studied to date, chemical penetration enhancers are the most frequently employed with one of the longest histories of use. There is a multitude of agents described as penetration enhancers, and they present varying properties and structures. In this manuscript, we aim to provide a brief overview of traditional enhancers and some of their properties, focusing on the benefits of combination of chemical enhancers and on selected novel compounds that have shown promise to increase drug delivery into/across the skin.

Synergistic iontophoretic drug delivery of risedronate sodium in combination with electroporation and chemical penetration enhancer: In‐vitro and in‐vivo evaluation

In the present investigation iontophoretic permeation of risedronate sodium (RS) through optimized gel based formulation was evaluated with respect to various electrical parameters like Current density and type of current. The study also involved enhancement the iontophoretic permeation of RS in combination with electroporation and chemical penetration enhancers with its in‐vivo Pharmacokinetic evaluation.The permeation studies were carried through the human cadaver skin by using modified Franz diffusion cell and microcontroller based devices for iontophoresis and electroporation developed in the laboratory. In‐vivo Pharmacokinetic studies were carried out in hairless rats. One way ANOVA followed by Tukey‐Kramer test for multiple comparisons. The permeation of RS was significantly increased with iontophoresis at 0.5 mA/Cm2 current density.The iontophoretic permeation was found depend on current density and ON:OFF ratio.The pulsatile current resulted in high permeation than continuous current. Maximum permeation was obtained at 0.5 mA/cm2 with 1:1 pulsed current. When iontophoresis was coupled with chemical penetration enhancers and electroporation for 100 ms at 220V, synergistic enhancement in permeation was observed with shortened lag time and high flux. The required flux was achieved with area of application 1.55 cm2. In‐vivo studies in hairless rats revealed high Cmax, low tmax and increased area under the curve with electroporation, followed by iontophoresis indicated increased bioavailability. Relative bio‐availability was 4.6 when calculated in comparison to passive studies. Key words: Electroporation, iontophoresis, penetration enhancers, risedronate sodium

Lopinavir metered-dose transdermal spray through microporated skin: Permeation enhancement to achieve therapeutic needs

A user friendly metered-dose transdermal spray (MDTS) of Lopinavir was developed and a combination of chemical and physical penetration enhancement techniques was utilized to enhance overall drug permeation across skin. Formulation was optimized varying Kollidon® VA 64 level while optimized batch was exhaustively characterized for in vitro drug release, ex vivo skin permeation and in vivo bioavailability. Safety and stability were also ascertained. Formulation containing 5 %w/v of Kollidon® had best sprayability and volatilization property. A significantly high permeation enhancement ratio (1.77) and steady state transdermal flux (52.5 μg/cm2/h) through microporated pig ear skin ex vivo indicated the permeation enhancement potential of the techniques applied. A remarkable 3-fold rise in relative bioavailability via transdermal route (FMDTS via microporated skin = 291.15%) as compared to oral suspension of marketed tablet (AUC0−∞ = 45.94 h*μg/ml) further confirmed the validity of our hypothesis. The outcomes of in vitro, ex vivo and in vivo characterization of Lopinavir MDTS represented the system as safe, effective and stable which seems promising for their extended clinical evaluation.

Formulation and evaluation of transdermal drug-delivery system of isosorbide dinitrate

&lt;p&gt;The purpose of this study was to develop a reservoir-type transdermal delivery system for isosorbide dinitrate (ISDN). The developed patch consisted of five layers from bottom to top, namely, a temporary liner, an adhesive layer, a rate-controlling membrane, a reservoir and a backing. The effects of chemical penetration enhancers, reservoir materials and rate-controlling membranes on the release behaviour of ISDN from the transdermal patch were studied, and the&lt;italic&gt; in vitro&lt;/italic&gt; release of ISDN from the developed patch was studied and compared with the commercially available ISDN patch. The results showed that there was no significant difference in permeation rates between the developed reservoir-type patch and the commercially available ISDN patch (&lt;italic&gt;p&lt;/italic&gt;&gt; 0.05). Moreover, the cumulative release ratio of the commercially available ISDN patch in 48 h was up to 89.8%, whereas the developed patch was only 34.9%, which meant the sustained release time of the developed patch was much longer than the commercially available ISDN patch, and would promote the satisfaction of the patient.&lt;/p&gt;

Breaking the skin barrier: achievements and future directions.

Skin delivery is more advantageous for drug administration than other routes since it is more compliant and can avoid the first-pass metabolic effect. More importantly, it can ensure stable blood level of transdermal drugs for a long period of time, avoiding fluctuation and reducing side effects. However, it is restricted by the barrier function of the stratum corneum. Therefore, significant attention has been paid to developing methods to modify the kinetics of skin drug delivery and expand the range of drugs that can be used for transdermal delivery. Novel mechanisms of increasing the intercellular and appendages penetration pathways have also been developed. This review focuses on chemical penetration enhancers, physical permeabilization (sonophoresis, iontophoresis and microneedles) and novel nanocarriers for skin delivery. Recent developments on skin delivery are also discussed.

Potential of Peptide-Based Enhancers for Transdermal Delivery

The skin presents several advantages as an administration route, including the possibility of localizing drugs in the tissue and overcoming the first-pass effect. However, its use is limited by the barrier function of the tissue, which is provided mainly (but not exclusively) by the stratum corneum. Various strategies to overcome this layer, have been considered over the years, ranging from the use of physical methods such as iontophoresis to wellknown conventional chemical penetration enhancers like oleic acid and DMSO. However, delivery of hydrophilic and large compounds remains a challenge. More recently, selected groups of peptides have attracted increasing attention due to their ability to penetrate into the skin promoting the transport of small and large molecules, including nanodispersed systems. Here, we will discuss the properties and application to cutaneous (into the skin) and transdermal (across the skin) delivery of three groups of peptides, namely protein-transduction domains, phage-displayed peptides and antimicrobial peptides.

Investigating transdermal delivery of vitamin D3.

Transdermal delivery of therapeutic amounts of vitamin D3 is proposed to overcome its variable oral bioavailability, especially for people who suffer from fat malabsorption. The main challenge for this delivery route is to overcome the barrier properties of skin, especially for very lipophilic compounds such as vitamin D3. In this study, the effect of different penetration enhancers, such as oleic acid, dodecylamine, ethanol, oleic acid in propylene glycol, isopropyl myristate, octyldodecanol, and oleyl alcohol in propylene glycol were evaluated in vitro for their effectiveness in delivering vitamin D3 through polyamide filter, polydimethylsiloxane membrane, and porcine skin. A diffusion cell was used to study the transdermal permeability of vitamin D3. Ointment formulations of vitamin D3 were prepared containing the most widely used penetration enhancers, oleic acid, and dodecylamine. The ointment containing oleic acid as chemical penetration enhancer did not improve delivery compared to control. On the other hand, the formulation containing dodecylamine as a penetration enhancer did improve the transdermal delivery of vitamin D3. However, statistical significance and an amount high enough for nutritional supplementation purposes were reached only when the skin was pretreated with 50% ethanol. In these conditions, the ointment delivered an amount of 760-ng vitamin D3 per cm(2) of skin. The research shows promise that transdermal delivery could be an effective administration route for vitamin D3 when ethanol and dodecylamine are used as penetration enhancers.

Synergistic iontophoretic drug delivery of risedronate sodium in combination with electroporation and chemical penetration enhancer: In-vitro and in-vivo evaluation

Synergistic iontophoretic drug delivery of risedronate sodium in combination with electroporation and chemical penetration enhancer: In-vitro and in-vivo evaluation

In Vitro and In Vivo Enhancement of Antitumoral Activity of Liposomal Antisense Oligonucleotides by Cineole as a Chemical Penetration Enhancer

Cellular uptake and cytoplasmic release of liposomal antisense oligonucleotides (AsODNs), which can act as rate‐limiting steps, are still remained to be completely optimized. Here, the possibility of enhancing such processes at cellular and animal levels by cineole, as a penetration enhancer, was investigated. A cationic nanoliposome containing an AsODN against PKC‐α and a cineole‐containing nanoliposome were prepared and characterized. The effect of nanoliposomal cineole on sequence‐specific cytotoxicity of nanoliposomal AsODN against A549, was studied in vitro (MTT, flow cytometry, fluorescence microscopy, and real time PCR) and in vivo (xenograft lung tumor in nude mice) using different concentrations and treatment times. Results showed specific cytotoxicity of nanoliposomal AsODN was increased significantly from 11% to 25% when A549 cells were exposed to 10 µg/mL cineole for 1 or 4 hours. This inhibitory effect was further increased to about 40% when the concentration was increased to 40 µg/mL for 1 hour. In animal studies, cineole significantly decreased the tumor volume (about 75%) and increased its doubling time from 13 days to 31 days. A linear relationship exists between cineole concentration and its enhancement effects. Finally it was concluded that cineole, and possibly other membrane fluidizers, can improve nanoliposomal gene therapy at cellular and animal levels.

Enhancement effect of essential oils from the fruits and leaves of Alpinia oxyphylla on skin permeation and deposition of indomethacin

Essential oils from plants are gaining increasing attention as potential chemical penetration enhancers.

The synergistic effect of ultrasound and chemical penetration enhancers on chorioamnion mass transport

In our previous study we proposed the use of chemical penetration enhancers for noninvasive detection of fetus abnormalities that can also be utilized for direct fetal drug delivery. In an attempt to further increase the mass transport rate across the amniotic membrane, thus shortening the procedure and improving the applicability of the proposed procedure, the effect and mechanism of combining ultrasound exposure with chemical penetration enhancers' application were assessed. The combined effect was evaluated in vitro on post-delivery human amniotic membrane and ex vivo on rat's whole amniotic sac. Ultrasound effect has been assessed by dye experiments using a customized image analysis program. Additional insights of ultrasound effect's mechanism on biological membranes are presented. Previously we have determined that chemical penetration enhancers affect the fetal membranes via two mechanisms termed as ‘extractors’ and ‘fluidizers’. In this study, we found that combining ultrasound with a ‘fluidizer’ CPE (e.g. bupivacaine) results in a synergistic enhancement (90-fold) of fetal membrane's mass transport, while combining ultrasound with ‘extractors’ (e.g. ethanol and NMP) results in an antagonistic effect. The combined procedure is faster and gain greater accuracy than the applications of sole chemical penetration enhancers.

Enhancing the buccal mucosal delivery of peptide and protein therapeutics.

With continuing advances in biotechnology and genetic engineering, there has been a dramatic increase in the availability of new biomacromolecules, such as peptides and proteins that have the potential to ameliorate the symptoms of many poorly-treated diseases. Although most of these macromolecular therapeutics exhibit high potency, their large molecular mass, susceptibility to enzymatic degradation, immunogenicity and tendency to undergo aggregation, adsorption, and denaturation have limited their ability to be administered via the traditional oral route. As a result, alternative noninvasive routes have been investigated for the systemic delivery of these macromolecules, one of which is the buccal mucosa. The buccal mucosa offers a number of advantages over the oral route, making it attractive for the delivery of peptides and proteins. However, the buccal mucosa still exhibits some permeability-limiting properties, and therefore various methods have been explored to enhance the delivery of macromoleculesvia this route, including the use of chemical penetration enhancers, physical methods, particulate systems and mucoadhesive formulations. The incorporation of anti-aggregating agents in buccal formulations also appears to show promise in other mucosal delivery systems, but has not yet been considered for buccal mucosal drug delivery. This review provides an update on recent approaches that have shown promise in enhancing the buccal mucosal transport of macromolecules, with a major focus on proteins and peptides.

Novel insights for permeant lead structures through in vitro skin diffusion assays of Prunus lusitanica L., the Portugal Laurel

As a contribution for the generation of libraries in which a natural product (NP) is used as the guiding structure, this work sought to investigate molecular features of triterpenes as deliver leads to cross the stratum corneum at a significant rate. Seeking a bioguided investigation of the dermocosmetic lead-like potential of triterpenes in Prunus lusitanica L., various extracts were obtained by two different methods (Soxhlet extractor and Accelerated Solvent Extraction-ASE) and analyzed by GC–MS and NMR. In vitro assays were conducted to quantify the friedelin 1 and crude plant extract permeation through a membrane of polydimethylsiloxane (PDMS), as well as their skin penetration enhancement capacity using two model molecules, caffeine 19 and ibuprofen 20. Friedelin 1 was identified as the major component (16–77%, GC) with isolated yield of 51% w/w (94%, GC) from Soxhlet residue (1.7% p/p) of the dried aerial parts of the plant harvested when in early flowering stage. Friedelin 1 promoted the penetration of the lipophilic molecule 20, however, it did not influence the permeation of the hydrophilic permeant 20. On the other hand, the crude extract acted as a retardant of the penetration of both substances. Molecular characteristics for the applicability of P. lusitanica L. in the development of dermocosmetics, as well as a new potential use for friedelin 1 in particular, are demonstrated. Probable mechanisms for chemical penetration enhancement using triterpenes as models for transdermal administration are herein discussed.

Pretreatment with Skin Permeability Enhancers: Importance of Duration and Composition on the Delivery of Diclofenac Sodium

The use of chemical penetration enhancers (CPEs) is one of the most common approaches to improve the dermal and transdermal delivery of drugs. However, often, incorporation of CPEs in the formulation poses compatibility and stability challenges. Moreover, incorporation of enhancers in the formulation leads to prolonged exposure to skin increasing the concern of causing skin reactions. This study was undertaken to assess whether pretreatment with CPEs is a rational approach to enhance the permeation of diclofenac sodium. In vitro experiments were performed across porcine epidermis pretreated with propylene glycol or oleic acid or their combinations for 0.5, 2, and 4 h, respectively. Pretreatment with combination of oleic acid in propylene glycol was found to enhance the permeation of diclofenac sodium significantly only at 10% and 20% (v/v) level, and only when the pretreatment duration was 0.5 h. Longer durations of pretreatment and higher concentration of oleic acid in propylene glycol did not enhance the permeation of diclofenac sodium. In vivo dermatokinetic studies were carried out on Sprague-Dawley rats. A twofold increase in AUC and Cmax was observed in case of rats pretreated with enhancers over the group that was pretreated with buffer. In conclusion, this study showed that composition of the enhancers and duration of pretreatment are crucial in determining the efficacy of CPEs.

RAPID INFORMATIVE SCREENING OF NANO-ALAPTIDE AS POTENTIAL TRANSDERMAL PERMEATION ENHANCER OF ACETYLSALICYLIC ACID AND PARACETAMOL

Summary This investigation deals with the affection of permeation of acetylsalicylic acid and paracetamol applied in the system propylene glycol-water 1:1 through full-thickness pig ear skin by alaptide that was applied in nanonized form as a potential chemical penetration enhancer. Alaptide, (S)-8-methyl-6,9diazaspiro[4.5]decan-7,10-dione, is the original Czech compound. The application of nanonized alaptide significantly enhanced the permeation of both drugs through the skin. Enhancement ratios in the studied time interval 0.5-2.0 h varied from 1.11 to 17.70 for acetylsalicylic acid and from 6.83 to 19.83 for paracetamol.

Strengthening the Skin with Topical Delivery of Keratinocyte Growth Factor-1 Using a Novel DNA Plasmid

Fragile skin, susceptible to decubitus ulcers and incidental trauma, is a problem particularly for the elderly and for those with spinal cord injury. Here, we present a simple approach to strengthen the skin by the topical delivery of keratinocyte growth factor-1 (KGF-1) DNA. In initial feasibility studies with the novel minimalized, antibiotic-free DNA expression vector, NTC8385-VA1, the reporter genes luciferase and enhanced green fluorescent protein were delivered. Transfection was documented when luciferase expression significantly increased after transfection. Microscopic imaging of enhanced green fluorescent protein–transfected skin showed green fluorescence in hair follicles, hair shafts, and dermal and superficial epithelial cells. With KGF-1 transfection, KGF-1 mRNA level and protein production were documented with quantitative reverse transcriptase–polymerase chain reaction and immunohistochemistry, respectively. Epithelial thickness of the transfected skin in the KGF group was significantly increased compared with the control vector group (26 ± 2 versus 16 ± 4 µm) at 48 hours (P = 0.045). Dermal thickness tended to be increased in the KGF group (255 ± 36 versus 162 ± 16 µm) at 120 hours (P = 0.057). Biomechanical assessment showed that the KGF-1–treated skin was significantly stronger than control vector–transfected skin. These findings indicate that topically delivered KGF-1 DNA plasmid can increase epithelial thickness and strength, demonstrating the potential of this approach to restore compromised skin.