Pharmaceutics, Drug Delivery and Pharmaceutical Technology
In Vitro and In Vivo Scalp Retention and Penetration of 99mTc-Minoxidil Solution

https://doi.org/10.1016/j.xphs.2022.09.016Get rights and content

Abstract

The present study assessed the effect of retention on ex vivo skin and in vivo scalp penetration of radiolabeled minoxidil formulations (5% w/v). Minoxidil was radiolabeled with technetium (99mTc) with an efficiency of 99.1% using 0.2% stannous chloride as reducing agent at pH 6 and incubation temperature of 40 °C. Three different 99mTc-minoxidil formulations were prepared using aqueous ethanolic solution as vehicle. Formulation A contains 99mTc-minoxidil dissolved in vehicle, formulation B contains 10% propylene glycol (PG) and formulation C contains 10% hydroxypropyl cellulose (HPC), in addition. Results showed that addition of HPC resulted in enhanced viscosity (400 mPa.s) and significantly higher ex vivo retention (p < 0.05) and permeation (0.75±0.12%, 8 h). PG does not improve the permeation and the results (0.44±0.05%, 8 h) were not significantly different from vehicle alone (0.40±0.05%, 8 h). The results of the in vivo human scalp studies corroborated with the ex vivo results and addition of hydroxypropyl cellulose (HPH) showed significantly higher (p < 0.05) scalp retention. Post 8 h application, scalp penetration in group treated with formulation C was nearly 2.8-fold and 2.2-fold higher than those treated with formulation A and B, respectively. Further, absence of minoxidil in systemic circulation during study duration indicates safety. In conclusion, our results showed that increasing contact time of minoxidil with scalp by modifying viscosity results in reduced frequency of application and improved efficacy.

Introduction

Hair loss represents the most recurrent and stressful clinical complaint faced by dermatologists. Androgenetic alopecia (AGA), alopecia areata (AA) and telogen effluvium (TE) are the most common types of hair loss, with AGA being the most predominant affecting nearly 70% of men and 40% of women worldwide.1 The etiology and pathogenesis of AGA remains elusive; however, accumulating evidences have indicated that increased levels of dihydrotestosterone (DHT),2 overexpression of the androgen receptor gene,3 miniaturization of hair follicles in androgen-sensitive areas,4 genetic predisposition and emotional stress3 contributes to its development. Among the existing modalities, topical minoxidil is most widely accepted for the treatment of AGA.5 It has been also used off-label for the treatment of AA,6 scarring alopecia,6 hair shaft disorders7 and for promoting hair growth of beard and eyebrows.8 Numerous studies suggested that minoxidil is effective in AGA through its action mediated via multiple pathways including vasodilation, anti-inflammatory mechanism,9 antiandrogen activity10 and inducer of the Wnt/β-catenin signal,1112 From the recent studies it has been evident that minoxidil also affects the length of the anagen and telogen phases.12 Furthermore, enhanced microcirculation around the hair follicles and alteration of androgen effect on genetically programmed hair follicles are also contributed to its effect.13 An experimental study demonstrated that minoxidil extended the anagen phase in the dermal papilla by stimulating follicular proliferation and differentiation through β-catenin pathway.14 An increased percentage of anagen follicle and follicle size was also noted. Traditionally, minoxidil was available as 2% w/v and 5% w/v topical solution, meant for twice daily application. Both 2% w/v and 5% w/v minoxidil solution showed promising results compared to placebo.15 Mori and Uno demonstrated that minoxidil treatment reduced the telogen phase to 1 to 2 days compared to nearly 20 days in untreated rats.16 Comparative clinical studies in AGA patients demonstrated superior efficacy of 5% w/v minoxidil solution compared to 2% w/v solution. A significant increase in hair regrowth (45%) and higher hair density was evident with the 5% w/v formulation compared to 2% w/v minoxidil.17 Further, studies demonstrated comparatively higher side effects following treatment with 5% minoxidil solution.18 The topical solutions contain propylene glycol (PG) in hydro-alcoholic base as vehicles. Although PG enhances the solubility of minoxidil and facilitates its delivery into the scalp, its frequent administration results in dermatitis and scalp irritation including scaling, itching, dryness and redness.19 Further, higher PG content in 5% w/v solution was found to be responsible for its comparatively higher side effects,2021 With these concerns, the minoxidil (5% w/v) in PG-free topical foam was developed. Topical foams have less tendency to drip from the scalp surface and in comparison to solutions offered longer scalp retention, enhanced penetration and less irritation.22 Despite several advantages of foam, minoxidil topical solution remained the mainstay for AGA treatment.

Efficacy of minoxidil solution has been well established, however the frequency of application is still ambiguous and efficacy following once daily and twice daily application has been evident.7 No attempt has been made previously to determine scalp retention and penetration of minoxidil solution in vivo and only few ex vivo studies on rat23 or human cadaver skin24 exists. Thus, present study aimed to assess scalp retention and penetration of radiolabeled minoxidil solutions prepared analogous to existing marketed formulations. The effect of addition of hydroxypropyl cellulose (HPC) as viscosity modifier25 on scalp retention and penetration was also evaluated. The assessments were done by gamma imaging.

Section snippets

Materials

Minoxidil was received as a gift sample from Glenmark Pharmaceuticals (Mumbai, India). HPC (Klucel) was purchased from Ashland (Mumbai, India). Analytical grade ethanol was purchased from Merck Limited (Mumbai, India). Pig ear skin used for ex-vivo study was obtained from a local slaughter house. 99m- Technetium (99mTc) was obtained from Board of Radiation and Isotope Technology (BRIT, Mumbai, India) and all the radioactive experiments were performed at Must and More Diagnostic Center (New

Optimization of 99mTc-Minoxidil

Optimization results of radiolabeling of minoxidil with 99mTc are shown in Fig. 1. The results showed that 1000 µg of stannous chloride (0.2%) at pH 6 and at incubation temperature of 40 °C, effectively radiolabels 1 g of minoxidil (10 mCi) with radiolabeling efficiency of 99.1% (Fig. 1). Concentration of stannous chloride and pH affected the radiolabeling efficiency, however incubation temperature has limited effect (Fig. 1). 99mTc-minoxidil in aqueous ethanolic solution was found to be stable

Discussion

Till date, minoxidil topical solution (5%) is considered as the mainstay for the treatment of AGA and several formulations with varied composition and ingredients are available in the market.26 Most of the minoxidil topical formulation contains hydroalcoholic base, however few in addition uses PG as permeation enhancer. Recently, viscosity modifiers such as HPC has also been used in minoxidil topical solution. The application regimen of minoxidil topical solution is inconclusive due to lack of

Disclosures

There is no conflict of interest and disclosures associated with the manuscript.

Declaration of Competing Interest

The authors have no conflict of interest.

Acknowledgement

Authors are thankful to Glenmark Pharmaceuticals (Mumbai, India) for study design and technical support. The authors also acknowledge Dr. Anupam Gauba, MD (Nuclear Medicine), Must and More Diagnostic centre for his support in scintigraphy study.

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