Topical delivery of clobetasol propionate loaded microemulsion based gel for effective treatment of vitiligo – Part II: Rheological characterization and in vivo assessment through dermatopharmacokinetic and pilot clinical studies

doi:10.1016/j.colsurfb.2014.02.005

Colloids and Surfaces B: Biointerfaces

Volume 119, 1 July 2014, Pages 145-153

https://doi.org/10.1016/j.colsurfb.2014.02.005 Get rights and content

Highlights

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Microemulsion based gel (MBC) of clobetasol propionate (CP) was formualated.
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MBC was characterized by ex vivo permeation studies, rheological parameters and pilot clinical studies.
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MBC showed good retention in skin layers which was confirmed by CLSM studies and dermatopharmacokinetic studies.
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MBC was able to form repigmentation of patches in vitiligo patients.

Abstract

Vitiligo is a non contagious acquired pigmentation disorder with limited treatment possibilities. Clobetasol propionate (CP) is the drug-of-choice for vitiligo which suppresses the immune system by reducing immunoglobulin action and causes the restoration of melanocytes leading to repigmentation of skin. However, despite being effective, its low and variable bioavailability prompt for development of novel carrier that could effectively target CP to site of action without producing undesirable side-effects. Low solubility of CP in subsequent poor in vivo bioavailability was overcome by formulating microemulsion based gel of CP (MBC) which would enhance the percutaneous transport of CP into and across the skin barrier. Comprehensive characterization of MBC was carried out for viscosity, gel strength and rheological behavior. In vitro studies revealed much higher drug release, skin penetration and enhanced skin accumulation as compared to control (Cream of CP). In vitro and in vivo occlusion studies demonstrated similar occlusiveness for MBC and control. MBC exhibited 3.16 times higher stratum corneum CP levels compared to control. Visualization of cutaneous uptake in vivo using laser scanning microscopy confirmed targeting of CP to epidermis and dermis. Dermatopharmacokinetic studies of MBC showed enhanced drug deposition of CP in skin layers. MBC was assessed for in vivo efficacy by single blind randomized pilot clinical study. The efficacy was assessed by vitiligo area scoring index (VASI) method. After completion of trial, repigmentation of vitiligo patches in patients were evaluated and scored. MBC was superior in terms of faster repigmentation and efficacy when compared with control (p value < 0.5). Hence, it was concluded that CP loaded MBC possess enhanced skin localization as well as therapeutic activity in vitiligo patients.

Graphical abstract

Introduction

Vitiligo is a common skin disease which is reported to affect approximately 1% of the population worldwide, irrespective of skin color or ethnic origin [1]. The cause of this condition is uncertain but seems to be dependent on the interaction of genetic, immunologic, and neurogenic factors [2]. It is characterized by circumscribed depigmented macules or patches corresponding with a substantial loss of functioning epidermal and sometimes hair follicle melanocytes [1], [3]. Asymptomatic white patches induce psychological stress in many individuals leading to attempted suicide in few cases [4]. The conventional therapy of vitiligo comprises of medical, surgical and adjunctive treatment. Medical treatment resists the de-pigmentation of the skin by targeting the immune system. Dermatosurgical techniques along with cosmetics are sometimes used to achieve the re-pigmentation. Since dermatosurgical techniques are painful and traumatic, medical treatment remains as the most feasible option for the treatment of vitiligo. Drugs such as corticosteroids, calcineurin inhibitors, vitamin D derivatives, psoralens (phototherapy), etc. are most commonly used for the treatment of vitiligo. Moderate to high potent topical corticosteroids are considered to be the first-line therapy in the treatment of skin diseases [5], [6]. In the treatment of vitiligo drug retention in the stratum corneum is recommended, but such drugs may fail in efficacy due to their limited solubility and permeability [7].

Microemulsion is the viable approach for the transdermal and dermal delivery of drugs as several mechanisms have been proposed to explain its advantages [8], [9], [10], [11]. Due to microemulsion, the thermodynamics of drugs toward the skin is raised as large amount of a drug incorporated in carrier [12], [13], [14]. Subsequently the alleviated thermodynamic potential of the drug may favor its partitioning into the skin. Additionally the ingredients of microemulsion may hamper the diffusional barrier of the stratum corneum and hydration effect of microemulsion increase the permeation in skin [15], [16].

Clobetasol propionate (CP), a potent corticosteroid, is majorly used in the treatment of vitiligo [17], [18], [19]. It is currently available in different dosage forms such as cream, ointment, gel, solution and foam for topical use. The success of CP is restricted due to its poor solubility [20]. It is justifiable to load CP into carrier based drug delivery systems to maximize its biological efficacy [1]. Moreover, considering topical and transdermal application of drug, it is advisable to reside drug at the site of application for localized delivery. Many hydrophilic and swellable polymers are reported as vehicle for carrier based drug delivery. Singh et al. have incorporated tacrolimus-loaded modified nanolipid carrier based system into Carbopol 980 (0.5% w/w) to get adequate rheological characteristics and required consistency using glycerol (5% w/w) as hydrating agent [21], [22]. Han et al. have found comparative better retention and permeation of flurbiprofen in skin after application of nanostructured lipid carriers based Carbopol gel of flurbiprofen [23].

In our previous work, we have loaded microemulsion of CP into Carbopol 934P and developed microemulsion based gel of CP (MBC) which was partially characterized in regard of microemulsion based parameters only [24]. It is essential for pharmaceutical scientists to study the rheology and influencing factors, and its impact on pharmacological efficacy of thixotropic formulations. In addition for topical formulations, the targeting potential is an important parameter to be considered to cure the dermal diseases and the success of any formulation needs its proven clinical significance. So, in the present investigation major consideration is given in characterization of MBC regarding its rheological behavior, cutaneous deposition of drug, visualization of skin permeation, assessment of dermatopharmacokinetics parameters and in vivo efficacy by pilot scale clinical trials in vitiligo patients.

Section snippets

Materials

Clobetasol propionate was obtained as a gift sample from Sumit Laboratories (Vapi, India). Isopropyl myristate (IPM) was received as a gift sample from Bombay Tablets Pvt. Ltd. (Gandhinagar, India). Isopropyl alcohol (IPA) was purchased from National Chemicals (Vadodara, India). Cremophor EL and Fluoroscein isothiacyanate (FITC) were purchased from Sigma–Aldrich (Mumbai, India). Methanol was purchased from Baroda Chemicals Ltd. (Vadodara, India). Carbopol 934P was purchased from Corel Pharma

Viscosity and rheogram

Particle/globule size is considered to be a critical rheological variable of colloidal systems. The higher globule size and wider size distribution results into formulation with high viscosity as compared to formulations with lower globule size. Moreover, rheological behavior of gel formulation provides information about its thixotropic properties which is important for the application of the formulation to the target site. The rheograms of MBC, CPG and MFCP were almost identical with each

Conclusion

In a nutshell, ME of CP has improved the solubility of drug and incorporation of the same into Carbopol 934P has a prominent effect in the treatment of vitiligo. The rheogram of MBC was developed in order to optimize its viscosity so as to have suitable extrudability and spreadability for topical application. In vitro drug release and ex vivo cutaenous deposition studies concluded that MBC has better penetration as well as retention capacity in the dermal layers than MFCP and CPG. The dermal

Acknowledgements

The authors are thankful to Sumit Laboratories (Vapi, India) for providing CP. The authors are also grateful to Mr. Mehul Chorawala for providing assistance for animal study and Mrs. Mallika Babu for proof-reading the manuscript for grammatical and spelling errors. The authors are thankful to Dr. Nafisa Balasinor (National Institute of Research in Reproductive Health, Parel, Mumbai) for providing help for CLSM studies. This study is a part of research project carried out at Kadi Sarva

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Topical delivery of clobetasol propionate loaded microemulsion based gel for effective treatment of vitiligo – Part II: Rheological characterization and in vivo assessment through dermatopharmacokinetic and pilot clinical studies

Highlights

Abstract

Graphical abstract

Introduction

Section snippets

Materials

Viscosity and rheogram

Conclusion

Acknowledgements

J. Am. Acad. Dermatol.

Int. J. Pharm.

Int. J. Pharm.

Eur. J. Pharm. Sci.

Int. J. Pharm.

Int. J. Pharm.

Adv. Drug Deliv. Rev.

Clin. Ther.

Eur. J. Pharm. Biopharm.

Colloids Surf. B Biointerfaces

Int. J. Pharm.

Int. J. Pharm.

Colloids Surf. B Biointerfaces

Int. J. Pharm.

Int. J. Pharm.

Int. J. Pharm.

Int. J. Pharm.

J. Control. Release

Eur. J. Pharm. Biopharm.

Adv. Drug Deliv. Rev.

Int. J. Pharm.

Int. J. Pharm.

Eur. J. Pharm. Biopharm.