Papaverine Hydrochloride Containing Nanostructured Lyotropic Liquid Crystal Formulation As a Potential Drug Delivery System for the Treatment of Erectile Dysfunction

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Papaverine Hydrochloride Containing Nanostructured Lyotropic Liquid Crystal Formulation As a Potential Drug Delivery System for the Treatment of Erectile Dysfunction Journal name: Drug Design, Development and Therapy Article Designation: Original Research Year: 2018 Volume: 12 Drug Design, Development and Therapy Dovepress Running head verso: Berkó et al Running head recto: PaHCl–LLC erectile dysfunction open access to scientific and medical research DOI: 168218 Open Access Full Text Article ORIGINAL RESEARCH Papaverine hydrochloride containing nanostructured lyotropic liquid crystal formulation as a potential drug delivery system for the treatment of erectile dysfunction Szilvia Berkó1 Purpose: Papaverine hydrochloride (PaHCl) is an old, well-known drug with spasmolytic Stella Zsikó1 activity but it has therapeutic effect in erectile dysfunction, too. As an intracavernous injection, Gábor Deák2 it is not used in urologic clinics today because the side effects of the injection are pain, scar- Attila Gácsi1 ring or priapism. Our aim was to develop and test a topical semi-solid preparation containing Anita Kovács1 PaHCl that would provide an alternative administration option by eliminating the undesirable Mária Budai-Szűcs1 side effects of the injection. Lyotropic liquid crystal (LLC) systems were formulated as a László Pajor2 Materials and methods: semi-solid preparation with different concentrations of PaHCl. The characterization of the Zoltán Bajory2 LLC structure was performed by polarization microscopy using a Leica image analyzer and 1 Erzsébet Csányi rheological measurements. The drug diffusion and penetration tests were performed with in 1Institute of Pharmaceutical vitro synthetic membrane and an ex vivo human epidermis, using Franz diffusion cell to test Technology and Regulatory Affairs, the skin penetration of PaHCl. Human skin was investigated by Raman microscope to visualize University of Szeged, Szeged, Hungary; 2Department of Urology, University the Active Pharmaceutical Ingredient (API) in different skin layers. of Szeged, Szeged, Hungary Results: The results of diffusion and penetration showed reverse concentration dependency. The in vitro and ex vivo studies correlated with each other and the results of Raman microscopy. The LLC structure influenced the penetration results, the lower viscosity and lamellar structure increased penetration through the skin. Conclusion: Based on our results, a PaHCl containing topically used LLC formulation may be a suitable and effective alternative to the injectable formulation. Keywords: nanocarrier, dermal penetration, impotence, Raman microscopy Introduction Erectile dysfunction (ED) is described as the persistent disability to attain and sustain an erection sufficient to permit satisfactory sexual performance.1,2 ED is a common disease. There are about 100 million men having ED worldwide. According to surveys, 40% of men over the age of 40 have at least a slight degree of ED, which increases with 3 Correspondence: Erzsébet Csányi progressing age. Epidemiological data have proved a high prevalence and incidence of Institute of Pharmaceutical Technology ED in all countries. The real prevalence is hard to find out because a lot of people are and Regulatory Affairs, University ashamed of the problem. Because of this, up to 70% of men with ED are not treated. of Szeged, Eötvös u. 6, Szeged 6720, Hungary ED may change physical and psychosocial health, and may have an important influ- Tel +36 62 545 573 ence on the quality of life of patients and their partners, too.4 There is evidence that Fax +36 62 545 571 Email [email protected] ED can be an early sign of coronary artery and peripheral vascular disease.5 submit your manuscript | www.dovepress.com Drug Design, Development and Therapy 2018:12 2923–2931 2923 Dovepress © 2018 Berkó et al. This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License (http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you http://dx.doi.org/10.2147/DDDT.S168218 hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms (https://www.dovepress.com/terms.php). Berkó et al Dovepress The current therapeutic options for ED are the following.6 in Paris that PaHCl can be used as an intracavernosal In first-line treatment, oral phosphodiesterase-5 (PDE5) injection.23 The injection with PaHCl was used for a long time inhibitors are used. Classical drugs are sildenafil, vardenafil, as a second-line treatment but is not relevant today because and tadalafil, while the newest one is avanafil.7,8 These have of more discomfort or side effects for the patient. many unwanted side effects, such as headache, nausea, dizzi- A new drug delivery system with an old, well-known ness. In second-line treatment, intracavernosal or intraurethral drug can be a promising combination to achieve the expected alprostadil therapy is used in patients who do not respond or effect and improve the side effects profile. The aim of the are contraindicated for PDE5 inhibitors.9 Both methods are present study was to prepare PaHCl containing LLC formula- extremely uncomfortable for the patient; they are painful and tions (PaHCl–LLC) with improved drug release properties involve significant financial difficulties as well as undesirable (for the potential treatment of ED) and to characterize the side effects, such as penis pain, hemorrhages, and burning formulation by means of techniques such as polarization in the urethra. To increase the small number of therapeutic microscopy and rheology measurement, and to model the options and to avoid unpleasant side effects, more and more skin penetration by a vertical Franz diffusion cell system research is directed at the transdermal entry gate.10–12 and Raman microscopy.24,25 During topical treatment, if the active ingredient is delivered to the deeper layers of the skin, it is possible to Materials and methods penetrate into the corpus cavernosum by exerting the effect Materials through the underlying vessels. The topical administration The active ingredient, PaHCl was obtained from Hungaro- of drugs has many benefits compared to oral or injection pharma Ltd (Budapest, Hungary). The LLC was composed of applications. In the case of topical application, Active Phar- two nonionic surfactants: Kolliphor RH40 (polyoxyl 40 hydro- maceutical Ingredients (APIs) avoid the first pass effect and genated castor oil The United States Pharmacopeia- National better bioavailability becomes possible. There is no plasma Formulary [USP/NF]) was supplied by BASF SE Chemtrade peak concentration, so the incidence of side effects may be GmbH (Ludwigshafen, Germany), and Tween 80 (polyoxy- reduced. Moreover, topical use enables continuous drug ethylene [20] sorbitan oleate) and an oil component, isopropyl delivery and patient compliance can also be improved with myristate, were purchased from Merck (Budapest, Hungary). the Drug delivery systems of the preparation.13–19 In a 2015 survey, 153 ED patients were asked to rank the different Preparation of the samples therapies from most to least desirable. The survey shows PaHCl was used in three different concentrations, 2.5, 3 and that there is a need for topical therapy because 53% of the 4 w/w% in the LLC systems. Drug-loaded LLCs were pre- people chose this application method first.20 pared with the following procedure. PaHCl was dissolved in Lyotropic liquid crystals (LLCs) have a number of benefi- the hot water phase. Kolliphor RH 40 was melted, mixed with cial properties from the point of view of pharmaceutical tech- isopropyl myristate and Tween 80, and finally the aqueous nology. LLCs are usually formed of water, one or two tensides, phase was added in small portions to this mixture during gentle and oil in a specified concentration and temperature range. stirring to form the liquid crystals. A blank formulation were They are suitable carrier systems for hydrophilic, lipophilic also prepared without PaHCl with the same procedure. or amphiphilic drugs. They are extremely stable systems ther- modynamically and can be maintained for a long time without Polarization microscopy the separation of the phases, so their structure is retained for a To verify the special structure of the LLC composition, a long time without structural changes. They also promote the polarization microscope was used (Leica Q500MC image penetration of the active substances through the skin, due to processing and analyzing system, Leica Microsystems Cam- the low surface tension at the water–oil interface.21,22 Their bridge Ltd., Cambridge, United Kingdom) with crossed polar- use through the skin is especially advantageous, given the the izers at room temperature. The magnification was 200×. concentration ratio of the components of LLC; the structure of the double lipid layer of the stratum corneum presents a Rheological investigations similar lamellar structure and therefore their application can Frequency-dependent oscillatory rheological measurements improve the penetration of the active ingredients. were performed with a Physica MCR101 rheometer to verify Papaverine hydrochloride (PaHCl) is an old, well-known the structure of LLC systems and to differentiate the struc- opium alkaloid. It is primarily used with spasmolytic indications ture of compositions containing different concentrations of
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