Liposomal and Ethosomal Gels for the Topical Delivery of Anthralin: Preparation, Comparative Evaluation and Clinical Assessment in Psoriatic Patients

Dina Fathalla, Eman M K Youssef, Ghareb M Soliman, Dina Fathalla, Eman M K Youssef, Ghareb M Soliman

Abstract

To enhance anthralin efficacy against psoriasis and reduce its notorious side effects, it was loaded into various liposomal and ethosomal preparations. The nanocarriers were characterized for drug encapsulation efficiency, size, morphology and compatibility between various components. Optimum formulations were dispersed in various gel bases and drug release kinetics were studied. Clinical efficacy and safety of liposomal and ethosomal Pluronic®F-127 gels were evaluated in patients having psoriasis (clinicaltrials.gov identifier is NCT03348462). Safety was assessed by recording various adverse events. Drug encapsulation efficiency ≥97.2% and ≥77% were obtained for liposomes and ethosomes, respectively. Particle sizes of 116 to 199 nm and 146 to 381 nm were observed for liposomes and ethosomes, respectively. Fourier-Transform infrared (FT-IR) spectroscopy and differential scanning calorimetry (DSC) studies confirmed the absence of interaction between anthralin and various nanocarrier components. Tested gel bases showed excellent ability to sustain drug release. At baseline, the patients had a median Psoriasis Area and Severity Index (PASI) of 3.4 for liposomes and 3.6 for ethosomes without significant difference. After treatment, mean PASI change was -68.66% and -81.84% for liposomes and ethosomes, respectively with a significant difference in favor of ethosomes. No adverse effects were detected in both groups. Anthralin ethosomes could be considered as a potential treatment of psoriasis.

Keywords: anthralin; ethosomes; liposomes; psoriasis; topical drug delivery.

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
TEM photomicrographs of liposome formulation L5 (A) and ethosome formulation E4 (B).
Figure 2
Figure 2
(A): Differential scanning calorimetry (DSC) thermograms of anthralin, PL-90G, cholesterol, liposome physical mixture and anthralin liposomes (L5). (B): DSC thermograms of anthralin, PL-90G, ethosome physical mixture, and anthralin ethosomes (E4).
Figure 3
Figure 3
(A): Fourier-Transform infrared (FT-IR) spectra of anthralin, PL-90G, cholesterol, liposome physical mixture and anthralin liposomes (L5). (B): FT-IR spectra of anthralin, PL-90G, ethosome physical mixture, and anthralin ethosomes (E4).
Figure 4
Figure 4
In vitro cumulative percent anthralin released as a function of time from anthralin-loaded liposomes (L5) and anthralin-loaded liposomes suspended into various gel bases (A) and from anthralin-loaded ethosomes (E4) and anthralin-loaded ethosomes suspended into various gel bases (B).
Figure 5
Figure 5
Ex vivo permeation profiles of anthralin from different preparations through rat abdominal skin.
Figure 6
Figure 6
(A) A 44-year old male patient with a psoriasis vulgaris lesion on the dorsum of the right hand before treatment. (B) The same patient after 3 weeks of treatment with anthralin liposomal gel preparation showing marked improvement (Group I). (C) A 50-year old female patient with psoriasis vulgaris on the extensor surface of the right leg before treatment. (D) The same patient showing a marked improvement after 3 weeks of treatment with anthralin ethosomal gel preparation (Group II).
Figure 7
Figure 7
Histopathological manifestation of psoriasis vulgaris. (A) and (B) before and after treatment with anthralin liposomal gel preparation, respectively (Group I). (C) and (D) before and after treatment with anthralin ethosomal gel preparation, respectively (Group II). Magnification (10×, hematoxylin and eosin stain).

References

    1. Tsuruta D. NF-kappaB links keratinocytes and lymphocytes in the pathogenesis of psoriasis. Recent Pat. Inflamm. Allergy Drug Discov. 2009;3:40–48. doi: 10.2174/187221309787158399.
    1. Pradhan M., Singh D., Singh M.R. Novel colloidal carriers for psoriasis: Current issues, mechanistic insight and novel delivery approaches. J. Control. Release. 2013;170:380–395. doi: 10.1016/j.jconrel.2013.05.020.
    1. Boehncke W.H., Schon M.P. Psoriasis. Lancet. 2015 doi: 10.1016/S0140-6736(14)61909-7.
    1. Krueger J.G., Bowcock A. Psoriasis pathophysiology: Current concepts of pathogenesis. Ann. Rheum. Dis. 2005;64(Suppl. 2):ii30–ii36. doi: 10.1136/ard.2004.031120.
    1. Koo J. Population-based epidemiologic study of psoriasis with emphasis on quality of life assessment. Dermatol. Clin. 1996;14:485–496. doi: 10.1016/S0733-8635(05)70376-4.
    1. Peters B.P., Weissman F.G., Gill M.A. Pathophysiology and treatment of psoriasis. Am. J. Health Syst. Pharm. 2000;57:645–659. doi: 10.1093/ajhp/57.7.645.
    1. Ryan S. Psoriasis: Characteristics, psychosocial effects and treatment options. Br. J. Nurs. 2008;17:284–290. doi: 10.12968/bjon.2008.17.5.28823.
    1. Traub M., Marshall K. Psoriasis-pathophysiology, conventional, and alternative approaches to treatment. Altern. Med. Rev. 2007;12:319–330.
    1. Feely M.A., Smith B.L., Weinberg J.M. Novel psoriasis therapies and patient outcomes, part 1: Topical medications. Cutis. 2015;95:164–168, 170.
    1. Griffiths C.E., Taylor H., Collins S.I., Hobson J.E., Collier P.A., Chalmers R.J., Stewart E.J., Dey P. The impact of psoriasis guidelines on appropriateness of referral from primary to secondary care: A randomized controlled trial. Br. J. Dermatol. 2006;155:393–400. doi: 10.1111/j.1365-2133.2006.07354.x.
    1. Feely M.A., Smith B.L., Weinberg J.M. Novel psoriasis therapies and patient outcomes, part 2: Biologic treatments. Cutis. 2015;95:282–290.
    1. Parish L.C., Millikan L.E., Witkowski J.A. The modern story of anthralin. Int. J. Dermatol. 1989;28:373–374. doi: 10.1111/j.1365-4362.1989.tb02481.x.
    1. Saraswat A., Agarwal R., Katare O.P., Kaur I., Kumar B. A randomized, double-blind, vehicle-controlled study of a novel liposomal dithranol formulation in psoriasis. J. Dermatol. Treat. 2007;18:40–45. doi: 10.1080/09546630601028729.
    1. Agarwal R., Katare O.P., Vyas S.P. Preparation and in vitro evaluation of liposomal/niosomal delivery systems for antipsoriatic drug dithranol. Int. J. Pharm. 2001;228:43–52. doi: 10.1016/S0378-5173(01)00810-9.
    1. Shahwal V.K. Preformulation studies and preperation of dithranol loaded solid lipid nanoparticles. Int. J. Biomed. Res. 2012;3:343–350. doi: 10.7439/ijbr.v3i7.332.
    1. McGill A., Frank A., Emmett N., Turnbull D.M., Birch-Machin M.A., Reynolds N.J. The anti-psoriatic drug anthralin accumulates in keratinocyte mitochondria, dissipates mitochondrial membrane potential, and induces apoptosis through a pathway dependent on respiratory competent mitochondria. FASEB J. 2005;19:1012–1014. doi: 10.1096/fj.04-2664fje.
    1. Mendonca C.O., Burden A.D. Current concepts in psoriasis and its treatment. Pharmacol. Ther. 2003;99:133–147. doi: 10.1016/S0163-7258(03)00041-X.
    1. Sehgal V.N., Verma P., Khurana A. Anthralin/dithranol in dermatology. Int. J. Dermatol. 2014;53:e449–e460. doi: 10.1111/j.1365-4632.2012.05611.x.
    1. Gerritsen M.J., Boezeman J.B., Elbers M.E., van de Kerkhof P.C. Dithranol embedded in crystalline monoglycerides combined with phototherapy (UVB): A new approach in the treatment of psoriasis. Skin Pharmacol. Appl. Skin Physiol. 1998;11:133–139. doi: 10.1159/000029819.
    1. Raza K., Negi P., Takyar S., Shukla A., Amarji B., Katare O.P. Novel dithranol phospholipid microemulsion for topical application: Development, characterization and percutaneous absorption studies. J. Microencapsul. 2011;28:190–199. doi: 10.3109/02652048.2010.546435.
    1. Raza K., Katare O.P., Setia A., Bhatia A., Singh B. Improved therapeutic performance of dithranol against psoriasis employing systematically optimized nanoemulsomes. J. Microencapsul. 2013;30:225–236. doi: 10.3109/02652048.2012.717115.
    1. Savian A.L., Rodrigues D., Weber J., Ribeiro R.F., Motta M.H., Schaffazick S.R., Adams A.I., de Andrade D.F., Beck R.C., da Silva C.B. Dithranol-loaded lipid-core nanocapsules improve the photostability and reduce the in vitro irritation potential of this drug. Mater. Sci. Eng. C Mater. Biol. Appl. 2015;46:69–76. doi: 10.1016/j.msec.2014.10.011.
    1. Agrawal U., Mehra N.K., Gupta U., Jain N.K. Hyperbranched dendritic nano-carriers for topical delivery of dithranol. J. Drug Target. 2013;21:497–506. doi: 10.3109/1061186X.2013.771778.
    1. Dubey V., Mishra D., Dutta T., Nahar M., Saraf D.K., Jain N.K. Dermal and transdermal delivery of an anti-psoriatic agent via ethanolic liposomes. J. Control. Release. 2007;123:148–154. doi: 10.1016/j.jconrel.2007.08.005.
    1. Touitou E., Dayan N., Bergelson L., Godin B., Eliaz M. Ethosomes—Novel vesicular carriers for enhanced delivery: Characterization and skin penetration properties. J. Control. Release. 2000;65:403–418. doi: 10.1016/S0168-3659(99)00222-9.
    1. Dubey V., Mishra D., Jain M., Kumar N. Novel methothrexate-based topical therapies for effective treatment of psoriasis. Clin. Dermatol. 2008;24:124–130.
    1. Li G., Fan Y., Fan C., Li X., Wang X., Li M., Liu Y. Tacrolimus-loaded ethosomes: Physicochemical characterization and in vivo evaluation. Eur. J. Pharm. Biopharm. 2012;82:49–57. doi: 10.1016/j.ejpb.2012.05.011.
    1. Zhang Y.T., Shen L.N., Wu Z.H., Zhao J.H., Feng N.P. Comparison of ethosomes and liposomes for skin delivery of psoralen for psoriasis therapy. Int. J. Pharm. 2014;471:449–452. doi: 10.1016/j.ijpharm.2014.06.001.
    1. Faisal W., Soliman G.M., Hamdan A.M. Enhanced skin deposition and delivery of voriconazole using ethosomal preparations. J. Liposome Res. 2018;28:14–21. doi: 10.1080/08982104.2016.1239636.
    1. Bhatia A., Kumar R., Katare O.P. Tamoxifen in topical liposomes: Development, characterization and in-vitro evaluation. J. Pharm. Pharm. Sci. 2004;7:252–259.
    1. Fathalla D., Soliman G., Fouad E. Development and in vitro/in vivo evaluation of liposomal gels for the sustained ocular delivery of latanoprost. J. Clin. Exp. Ophthalmol. 2015;6:2.
    1. Dayan N., Touitou E. Carriers for skin delivery of trihexyphenidyl HCl: Ethosomes vs. liposomes. Biomaterials. 2000;21:1879–1885. doi: 10.1016/S0142-9612(00)00063-6.
    1. Schmolka I.R. Artificial skin. I. Preparation and properties of pluronic F-127 gels for treatment of burns. J. Biomed. Mater. Res. 1972;6:571–582. doi: 10.1002/jbm.820060609.
    1. Korsmeyer R.W., Gurny R., Doelker E., Buri P., Peppas N.A. Mechanisms of solute release from porous hydrophilic polymers. Int. J. Pharm. 1983;15:25–35. doi: 10.1016/0378-5173(83)90064-9.
    1. Hixson A.W., Crowell J.H. Dependence of reaction Vvelocity upon surface and agitation. Ind. Eng. Chem. 1931;23:923–931. doi: 10.1021/ie50260a018.
    1. Baker R.W., Lonsdale H. Controlled Release of Biologically Active Agents. Springer; Boston, MA, USA: 1974. Controlled release: Mechanisms and rates; pp. 15–71.
    1. Jain S., Tiwary A.K., Sapra B., Jain N.K. Formulation and evaluation of ethosomes for transdermal delivery of lamivudine. AAPS PharmSciTech. 2007;8:E111. doi: 10.1208/pt0804111.
    1. Sloan K.B., Beall H.D., Weimar W.R., Villanueva R. The effect of receptor phase composition on the permeability of hairless mouse skin in diffusion cell experiments. Int. J. Pharm. 1991;73:97–104. doi: 10.1016/0378-5173(91)90031-I.
    1. Zhang H. Thin-film hydration followed by extrusion method for liposome preparation. Methods Mol. Biol. 2017;1522:17–22. doi: 10.1007/978-1-4939-6591-5_2.
    1. van Hoogevest P. Review—An update on the use of oral phospholipid excipients. Eur. J. Pharm. Sci. 2017;108:1–12. doi: 10.1016/j.ejps.2017.07.008.
    1. Rojanapanthu P., Sarisuta N., Chaturon K., Kraisintu K. Physicochemical properties of amphotericin B liposomes prepared by reverse-phase evaporation method. Drug Dev. Ind. Pharm. 2003;29:31–37. doi: 10.1081/DDC-120016681.
    1. Kulkarni S.B., Betageri G.V., Singh M. Factors affecting microencapsulation of drugs in liposomes. J. Microencapsul. 1995;12:229–246. doi: 10.3109/02652049509010292.
    1. Bhosale S.S., Avachat A.M. Design and development of ethosomal transdermal drug delivery system of valsartan with preclinical assessment in Wistar albino rats. J. Liposome Res. 2013;23:119–125. doi: 10.3109/08982104.2012.753457.
    1. Maheshwari R.G., Tekade R.K., Sharma P.A., Darwhekar G., Tyagi A., Patel R.P., Jain D.K. Ethosomes and ultradeformable liposomes for transdermal delivery of clotrimazole: A comparative assessment. Saudi Pharm. J. 2012;20:161–170. doi: 10.1016/j.jsps.2011.10.001.
    1. Verma P., Pathak K. Nanosized ethanolic vesicles loaded with econazole nitrate for the treatment of deep fungal infections through topical gel formulation. Nanomedicine. 2012;8:489–496. doi: 10.1016/j.nano.2011.07.004.
    1. Paolino D., Lucania G., Mardente D., Alhaique F., Fresta M. Ethosomes for skin delivery of ammonium glycyrrhizinate: In vitro percutaneous permeation through human skin and in vivo anti-inflammatory activity on human volunteers. J. Control. Release. 2005;106:99–110. doi: 10.1016/j.jconrel.2005.04.007.
    1. Zhaowu Z., Xiaoli W., Yangde Z., Nianfeng L. Preparation of matrine ethosome, its percutaneous permeation in vitro and anti-inflammatory activity in vivo in rats. J. Liposome Res. 2009;19:155–162. doi: 10.1080/08982100902722381.
    1. Tosato M.G., Maya Girón J.V., Martin A.A., Krishna Tippavajhala V., Fernández Lorenzo de Mele M., Dicelio L. Comparative study of transdermal drug delivery systems of resveratrol: High efficiency of deformable liposomes. Mater. Sci. Eng. C. 2018;90:356–364. doi: 10.1016/j.msec.2018.04.073.
    1. Paliwal S., Tilak A., Sharma J., Dave V., Sharma S., Verma K., Tak K., Reddy K.R., Sadhu V. Flurbiprofen-loaded ethanolic liposome particles for biomedical applications. J. Microbiol. Methods. 2019;161:18–27. doi: 10.1016/j.mimet.2019.04.001.
    1. Danaei M., Dehghankhold M., Ataei S., Hasanzadeh Davarani F., Javanmard R., Dokhani A., Khorasani S., Mozafari M.R. Impact of particle size and polydispersity index on the clinical applications of lipidic nanocarrier systems. Pharmaceutics. 2018;10:57. doi: 10.3390/pharmaceutics10020057.
    1. Chen M., Liu X., Fahr A. Skin penetration and deposition of carboxyfluorescein and temoporfin from different lipid vesicular systems: In vitro study with finite and infinite dosage application. Int. J. Pharm. 2011;408:223–234. doi: 10.1016/j.ijpharm.2011.02.006.
    1. Abdulbaqi I.M., Darwis Y., Khan N.A., Assi R.A., Khan A.A. Ethosomal nanocarriers: The impact of constituents and formulation techniques on ethosomal properties, in vivo studies, and clinical trials. Int. J. Nanomed. 2016;11:2279–2304. doi: 10.2147/IJN.S105016.
    1. Hua S. Lipid-based nano-delivery systems for skin delivery of drugs and bioactives. Front. Pharmacol. 2015;6:219. doi: 10.3389/fphar.2015.00219.
    1. Verma D.D., Verma S., Blume G., Fahr A. Particle size of liposomes influences dermal delivery of substances into skin. Int. J. Pharm. 2003;258:141–151. doi: 10.1016/S0378-5173(03)00183-2.
    1. Gambhire M.S., Bhalekar M.R., Shrivastava B. Investigations in photostability of dithranol incorporated in solid lipid nanoparticles. Pharm. Chem. J. 2012;46:256–261. doi: 10.1007/s11094-012-0774-4.
    1. Almeida P.F., Carter F.E., Kilgour K.M., Raymonda M.H., Tejada E. Heat capacity of DPPC/cholesterol mixtures: Comparison of single bilayers with multibilayers and simulations. Langmuir. 2018;34:9798–9809. doi: 10.1021/acs.langmuir.8b01774.
    1. Salama A., Badran M., Elmowafy M., Soliman G.M. Spironolactone-loaded leciplexes as potential topical delivery systems for female acne: In vitro appraisal and ex vivo skin permeability studies. Pharmaceutics. 2019;12:25. doi: 10.3390/pharmaceutics12010025.
    1. Andersen K.B., Langgård M., Spanget-Larsen J. Molecular and vibrational structure of anthralin. Infrared linear dichroism spectroscopy and quantum chemical calculations. J. Mol. Struct. 1999;475:131–140. doi: 10.1016/S0022-2860(98)00499-2.
    1. Gupta U., Singh V.K., Kumar V., Khajuria Y. Spectroscopic studies of cholesterol: Fourier transform infra-red and vibrational frequency analysis. Mater. Focus. 2014;3:211–217. doi: 10.1166/mat.2014.1161.
    1. Bodratti A.M., Alexandridis P. Formulation of poloxamers for drug delivery. J. Funct. Biomater. 2018;9:11. doi: 10.3390/jfb9010011.
    1. Akash M.S., Rehman K. Recent progress in biomedical applications of Pluronic (PF127): Pharmaceutical perspectives. J. Control. Release. 2015;209:120–138. doi: 10.1016/j.jconrel.2015.04.032.
    1. El-Sayed M.M., Hussein A.K., Sarhan H.A., Mansour H.F. Flurbiprofen-loaded niosomes-in-gel system improves the ocular bioavailability of flurbiprofen in the aqueous humor. Drug Dev. Ind. Pharm. 2017;43:902–910. doi: 10.1080/03639045.2016.1272120.
    1. Mohanty D., Rani M.J., Haque M.A., Bakshi V., Jahangir M.A., Imam S.S., Gilani S.J. Preparation and evaluation of transdermal naproxen niosomes: Formulation optimization to preclinical anti-inflammatory assessment on murine model. J. Liposome Res. 2019;2019:1–11. doi: 10.1080/08982104.2019.1652646.
    1. Faria M.J., Machado R., Ribeiro A., Goncalves H., Real Oliveira M., Viseu T., das Neves J., Lucio M. Rational development of liposomal hydrogels: A strategy for topical vaginal antiretroviral drug delivery in the context of HIV prevention. Pharmaceutics. 2019;11:485. doi: 10.3390/pharmaceutics11090485.
    1. Ricci E.J., Lunardi L.O., Nanclares D.M., Marchetti J.M. Sustained release of lidocaine from Poloxamer 407 gels. Int. J. Pharm. 2005;288:235–244. doi: 10.1016/j.ijpharm.2004.09.028.
    1. Huang W., Tsui C.P., Tang C.Y., Gu L. Effects of compositional tailoring on drug delivery behaviours of silica xerogel/polymer core-shell composite nanoparticles. Sci. Rep. 2018;8:13002. doi: 10.1038/s41598-018-31070-9.
    1. El-Badry M., Fetih G., Shakeel F. Comparative topical delivery of antifungal drug croconazole using liposome and micro-emulsion-based gel formulations. Drug Deliv. 2014;21:34–43. doi: 10.3109/10717544.2013.843610.
    1. Glavas-Dodov M., Fredro-Kumbaradzi E., Goracinova K., Calis S., Simonoska M., Hincal A.A. 5-Fluorouracil in topical liposome gels for anticancer treatment-formulation and evaluation. Acta Pharm. 2003;53:241–250.
    1. Ritger P.L., Peppas N.A. A simple equation for description of solute release II. Fickian and anomalous release from swellable devices. J. Control. Release. 1987;5:37–42. doi: 10.1016/0168-3659(87)90035-6.
    1. Yucel C., Seker Karatoprak G., Degim I.T. Anti-aging formulation of rosmarinic acid-loaded ethosomes and liposomes. J. Microencapsul. 2019;36:180–191. doi: 10.1080/02652048.2019.1617363.
    1. Yang L., Wu L., Wu D., Shi D., Wang T., Zhu X. Mechanism of transdermal permeation promotion of lipophilic drugs by ethosomes. Int. J. Nanomed. 2017;12:3357–3364. doi: 10.2147/IJN.S134708.
    1. Kirjavainen M., Urtti A., Valjakka-Koskela R., Kiesvaara J., Monkkonen J. Liposome-skin interactions and their effects on the skin permeation of drugs. Eur. J. Pharm. Sci. 1999;7:279–286. doi: 10.1016/S0928-0987(98)00037-2.
    1. Van De Kerkhof P.C.M., Van Der Valk P.G.M., Swinkels O.Q.J., Kucharekova M., De Rie M.A., De Vries H.J.C., Damstra R., Oranje A.P., De Waard-van der Spek F.B., Van Neer P., et al. A comparison of twice-daily calcipotriol ointment with once-daily short-contact dithranol cream therapy: A randomized controlled trial of supervised treatment of psoriasis vulgaris in a day-care setting. Br. J. Dermatol. 2006;155:800–807. doi: 10.1111/j.1365-2133.2006.07393.x.
    1. Sminkels O.Q., Prins M., Veeniiuis R.T., De Boo T., Gerritsen M.J., Van Der Wilt G.J., Van De Kerkhof P.C., Van Der Valk P.G. Effectiveness and side effects of UVB-phototherapy, dithranol inpatient therapy and a care instruction programme of short contact dithranol in moderate to severe psoriasis. Eur. J. Dermatol. 2004;14:159–165.
    1. Ashton R.E., Andre P., Lowe N.J., Whitefield M. Anthralin: Historical and current perspectives. J. Am. Acad. Dermatol. 1983;9:173–192. doi: 10.1016/S0190-9622(83)70125-8.
    1. Mbah C.C., Builders P.F., Attama A.A. Nanovesicular carriers as alternative drug delivery systems: Ethosomes in focus. Expert Opin. Drug Deliv. 2014;11:45–59. doi: 10.1517/17425247.2013.860130.
    1. Fang Y.-P., Tsai Y.-H., Wu P.-C., Huang Y.-B. Comparison of 5-aminolevulinic acid-encapsulated liposome versus ethosome for skin delivery for photodynamic therapy. Int. J. Pharm. 2008;356:144–152. doi: 10.1016/j.ijpharm.2008.01.020.
    1. Bodade S.S., Shaikh K.S., Kamble M.S., Chaudhari P.D. A study on ethosomes as mode for transdermal delivery of an antidiabetic drug. Drug Deliv. 2013;20:40–46. doi: 10.3109/10717544.2012.752420.

Source: PubMed

スポンサーと協力者

医学的状態

薬物療法

3
購読する