madman
Super Moderator
Abstract: Sildenafil citrate is used to treat mild to moderate erectile dysfunction and premature ejaculation. However, it has low oral bioavailability, numerous adverse effects, and delayed onset of action. These problems may be resolved by transdermal delivery to the penis. Hence, sildenafil citrate was formulated as a microemulsion system using isopropyl myristate, Tween 80, PEG400, and water (30:20:40:10). The hydrogel used in the microemulsion was 2% w/w poloxamer 188. The sildenafil microemulsion-loaded hydrogels were characterized for their appearance, particle size, pH, spreadability, swelling index, viscosity, sildenafil drug content, membrane permeation, epithelial cell cytotoxicity, and in vitro drug metabolism. The optimized formulated microemulsion showed the lowest droplet size and highest solubility of sildenafil citrate. The in vitro skin permeation of the sildenafil citrate microemulsion-loaded hydrogel was significantly higher than that of the sildenafil suspension, with a 1.97-fold enhancement ratio. The formulated microemulsion exhibited 100% cell viability, indicating its safety for skin epithelial cells. The major metabolic pathway of sildenafil citrate loaded in the microemulsion formulation was hydroxylation. Furthermore, loading sildenafil in the microemulsion reduced the drug metabolite by approximately 50% compared to the sildenafil in aqueous suspension. The sildenafil citrate-loaded isopropyl myristate-based microemulsion hydrogels were physically and chemically stable over 6 months of storage. The sildenafil citrate microemulsion-loaded hydrogel showed in vitro results suitable for use as a transdermal drug delivery system.
1. Introduction
Sildenafil citrate is a selective phosphodiesterase type 5 (PDE5) inhibitor. The mechanism of action of sildenafil involves the specific degradation of cyclic guanosine monophosphate (cGMP), resulting in smooth muscle relaxation via the nitric oxide (NO) pathway [1]. Thus, sildenafil citrate is an effective oral treatment for erectile dysfunction and premature ejaculation [2,3]. It is available only in the form of tablets. Some studies have shown that sildenafil citrate or PDE inhibitor drugs can be administered topically [4–7]. The transdermal delivery of sildenafil citrate through a local tissue area could be considered as an alternative to the oral route, in order to avoid adverse effects, shorten the onset time, and sustain the therapeutic effects for longer periods [1]. The topical administration of sildenafil also has the advantage of the lack of significant systemic absorption, thus reducing systemic adverse effects. Therefore, delivery of the drug directly to the penis in a controlled manner would be preferable for men for whom oral medications are unsafe, or in whom this treatment could cause too many adverse effects. However, the lower efficacy of topical therapy compared to systemic therapy is a major limitation, especially in severe cases. Nonetheless, patients with mild and moderate erectile dysfunction and premature ejaculation may benefit from the accepted efficacy of topical therapy without systemic adverse effects. Results from randomized controlled trials on the efficacy of topical sildenafil in men with mild to moderate erectile dysfunction associated with premature ejaculation are limited and contradictory [2,6,8]. At present, two new treatment options, namely, topical anesthetic agents and oral sildenafil, are being considered for treating premature ejaculation. Topical anesthetic agents are applied to the glans penis before intercourse to delay ejaculation [2]; these agents do not show any dermal toxicity and wound healing properties were noted against traumatic wounds [5]. The absorption of topical sildenafil depended on the ability of the drug to penetrate through the skin to the target receptor to reach therapeutic levels. The stratum corneum is the outermost epidermal layer consisting of keratin-filled dead cells called corneocytes. These cells hinder the penetration of drugs. This skin barrier is overcome by using the most widely implemented approach involving chemical penetration enhancers that can, ideally, safely and reversibly alter the physicochemical nature of the stratum corneum to facilitate drug delivery through the skin [4].
Microemulsions are attractive drug-delivery systems because of the following advantages: ease of preparation owing to the spontaneous formation, thermodynamic stability, transparent and elegant appearance, increased drug loading, enhanced penetration through the biological membranes, increased bioavailability, and less inter- and intra-individual variability in drug pharmacokinetics [9]. In addition, hydrogels contain high water content and possess a degree of flexibility very similar to the natural tissue, are less greasy, and can be easily removed from the skin. Hydrogels have the ability to sense changes in pH, temperature, or metabolite concentration and release their load in response to such changes; they also possess good transport properties and can be modified easily [10].
In this study, sildenafil citrate transdermal delivery systems using microemulsion-loaded hydrogels were constructed and evaluated. The formulated microemulsion systems were characterized through visual inspection of their appearance, particle size, and pH and were analyzed for spreadability, swelling index, cell membrane permeability, sildenafil drug content, and viscosity. Moreover, in vitro epithelial cell cytotoxicity and drug metabolism from the formulated systems were determined. The knowledge of the mechanism of action of the novel sildenafil citrate formulation may help in evaluating drug efficacy or be used to develop formulation systems. Finally, long-term and accelerated stability studies were performed under high-stress conditions. A schematic diagram of the entire research is shown in Figure 1.
4. Conclusions
In this study, a novel formulation of sildenafil citrate microemulsion-loaded hydrogel was successfully developed for transdermal application and characterized in vitro. It was developed by checking the solubility of the drug in various oils, surfactants, and co-surfactants using pseudo-ternary phase diagrams, and was then optimized suitably for applying to the skin. The microemulsion composed of isopropyl myristate or oleic acid (oil) and a mixture of surfactant and co-surfactant (Tween 80/PEG400 or Tween 80/PG) was prepared, and poloxamer 188 was added to the microemulsion-loaded hydrogel. The membrane permeation rate of the microemulsion-loaded hydrogel was 1.97 times higher than that of the pure drug solution. According to the results of the characterization, stability, and in vitro permeation studies, the most desirable formulation for the topical delivery of sildenafil citrate was considered to be the isopropyl myristate-based microemulsion system. Moreover, it did not result in cytotoxicity in the cell line studied. The metabolism of the sildenafil citrate microemulsion-loaded hydrogel was concentration-dependent and decreased compared to the sildenafil citrate aqueous suspension. Moreover, the metabolic pathways were different and decreased sildenafil metabolism from the hydroxylation pathway compared to the sildenafil citrate aqueous suspension.
1. Introduction
Sildenafil citrate is a selective phosphodiesterase type 5 (PDE5) inhibitor. The mechanism of action of sildenafil involves the specific degradation of cyclic guanosine monophosphate (cGMP), resulting in smooth muscle relaxation via the nitric oxide (NO) pathway [1]. Thus, sildenafil citrate is an effective oral treatment for erectile dysfunction and premature ejaculation [2,3]. It is available only in the form of tablets. Some studies have shown that sildenafil citrate or PDE inhibitor drugs can be administered topically [4–7]. The transdermal delivery of sildenafil citrate through a local tissue area could be considered as an alternative to the oral route, in order to avoid adverse effects, shorten the onset time, and sustain the therapeutic effects for longer periods [1]. The topical administration of sildenafil also has the advantage of the lack of significant systemic absorption, thus reducing systemic adverse effects. Therefore, delivery of the drug directly to the penis in a controlled manner would be preferable for men for whom oral medications are unsafe, or in whom this treatment could cause too many adverse effects. However, the lower efficacy of topical therapy compared to systemic therapy is a major limitation, especially in severe cases. Nonetheless, patients with mild and moderate erectile dysfunction and premature ejaculation may benefit from the accepted efficacy of topical therapy without systemic adverse effects. Results from randomized controlled trials on the efficacy of topical sildenafil in men with mild to moderate erectile dysfunction associated with premature ejaculation are limited and contradictory [2,6,8]. At present, two new treatment options, namely, topical anesthetic agents and oral sildenafil, are being considered for treating premature ejaculation. Topical anesthetic agents are applied to the glans penis before intercourse to delay ejaculation [2]; these agents do not show any dermal toxicity and wound healing properties were noted against traumatic wounds [5]. The absorption of topical sildenafil depended on the ability of the drug to penetrate through the skin to the target receptor to reach therapeutic levels. The stratum corneum is the outermost epidermal layer consisting of keratin-filled dead cells called corneocytes. These cells hinder the penetration of drugs. This skin barrier is overcome by using the most widely implemented approach involving chemical penetration enhancers that can, ideally, safely and reversibly alter the physicochemical nature of the stratum corneum to facilitate drug delivery through the skin [4].
Microemulsions are attractive drug-delivery systems because of the following advantages: ease of preparation owing to the spontaneous formation, thermodynamic stability, transparent and elegant appearance, increased drug loading, enhanced penetration through the biological membranes, increased bioavailability, and less inter- and intra-individual variability in drug pharmacokinetics [9]. In addition, hydrogels contain high water content and possess a degree of flexibility very similar to the natural tissue, are less greasy, and can be easily removed from the skin. Hydrogels have the ability to sense changes in pH, temperature, or metabolite concentration and release their load in response to such changes; they also possess good transport properties and can be modified easily [10].
In this study, sildenafil citrate transdermal delivery systems using microemulsion-loaded hydrogels were constructed and evaluated. The formulated microemulsion systems were characterized through visual inspection of their appearance, particle size, and pH and were analyzed for spreadability, swelling index, cell membrane permeability, sildenafil drug content, and viscosity. Moreover, in vitro epithelial cell cytotoxicity and drug metabolism from the formulated systems were determined. The knowledge of the mechanism of action of the novel sildenafil citrate formulation may help in evaluating drug efficacy or be used to develop formulation systems. Finally, long-term and accelerated stability studies were performed under high-stress conditions. A schematic diagram of the entire research is shown in Figure 1.
4. Conclusions
In this study, a novel formulation of sildenafil citrate microemulsion-loaded hydrogel was successfully developed for transdermal application and characterized in vitro. It was developed by checking the solubility of the drug in various oils, surfactants, and co-surfactants using pseudo-ternary phase diagrams, and was then optimized suitably for applying to the skin. The microemulsion composed of isopropyl myristate or oleic acid (oil) and a mixture of surfactant and co-surfactant (Tween 80/PEG400 or Tween 80/PG) was prepared, and poloxamer 188 was added to the microemulsion-loaded hydrogel. The membrane permeation rate of the microemulsion-loaded hydrogel was 1.97 times higher than that of the pure drug solution. According to the results of the characterization, stability, and in vitro permeation studies, the most desirable formulation for the topical delivery of sildenafil citrate was considered to be the isopropyl myristate-based microemulsion system. Moreover, it did not result in cytotoxicity in the cell line studied. The metabolism of the sildenafil citrate microemulsion-loaded hydrogel was concentration-dependent and decreased compared to the sildenafil citrate aqueous suspension. Moreover, the metabolic pathways were different and decreased sildenafil metabolism from the hydroxylation pathway compared to the sildenafil citrate aqueous suspension.
