Positioning of Low Alcohol or Alcohol-Free Minoxidil Formulation for the Management of Androgenetic Alopecia: Indian Perspective

ABSTRACT

Topical minoxidil is used for treating different hair disorders. Even though it is an effective therapy, many patients show poor compliance due to the cost, side effects, and duration of treatment. Topical minoxidil is the mainstay treatment for androgenetic alopecia (AGA). Recently, low alcohol or alcohol-free topical minoxidil formulation has proven to be an alternative for patients suffering from AGA, including those with poor compliance with other therapies. Thus, the current article provides the positioning of low alcohol or alcohol-free topical minoxidil to manage AGA in Indian clinical practice.

INTRODUCTION

Androgenetic alopecia (AGA) affects almost 80% of men and 50% of women. A progressive reduction in the diameter and length of the hair causes AGA. Hair thinning results from the testosterone metabolite dihydrotestosterone (DHT) effects on androgen-sensitive hair follicles. AGA manifests as diffuse thinning of the crown region while maintaining the front hairline. Premenopausal women with AGA suffer from hyperandrogenism, hirsutism, and acne, while men with AGA have a bitemporal recession of the frontal hairline followed by diffuse thinning at the vertex.[1]

White patients are commonly affected, followed by Asians and African Americans, then Native Americans and Eskimos. The Asian prevalence of AGA is lower than in Caucasians; AGA is also a common disorder in Asia. According to the epidemiologic data, about 58% of the male population in India develop AGA at some point in their lives, and this incidence increases with advancing age.[3]

The incidence approaches the age in Caucasian males, with 50% affected by 50 years and up to 80% affected by 70 years. In females, the disorder is relatively common, with an increase in incidence after menopause.[4] The psychological effect of hair loss is tremendous, potentially affecting a person's quality of life (QOL). There is a lack of awareness among people regarding the impact of hair loss on QOL. There is a moderate effect of visible hair loss on a person's emotions, social, symptomatic, and psychology. Medical practitioners can play a role in the improvement of patient's QOL by recognizing and addressing the psychological impact of alopecia.[5]

In the balding scalp, the concentration of 5α-reductase is increased, resulting in more DHT production. Due to increased androgen receptor concentration, more complexes are produced between androgen receptors and DHT, augmenting the regulation of androgen-dependent genes in the nucleus.[4]

Role of minoxidil in androgenetic alopecia

Topical minoxidil is a vasodilator, an anti-inflammatory agent, an inducer of the Went/b-catenin signaling pathway, and an antiandrogen. Minoxidil may also affect the length of the anagen and telogen phases. Thus, minoxidil may exert an effect through multiple pathways. Minoxidil stimulates the release of vascular endothelial growth factors (VEGF) in the dermal papilla cells and activates the VEGF-related b-catenin signaling pathway. β-catenin, accumulated in the cytoplasm by the Wingless–Int pathway, acts as a transcriptional factor and plays a role in hair follicle regeneration.[6] Its antiandrogenic property reduces the 5a-reductase type 2 gene expression. Minoxidil also increases DNA synthesis in the anagen bulb, which triggers secondary germ cells of telogen follicles, resulting in the earlier onset of the anagen phase. It extends the anagen phase, reduces the telogen phase's duration, or does both. Minoxidil has also been investigated for the autoimmune condition alopecia areata. It is hypothesized that topical minoxidil inhibits immunological events at the application site and helps hair growth in patients diagnosed with alopecia areata.[2] Topical Minoxidil is approved by Central Drugs Standard Control Organization (CDSCO) for the indication of Androgenetic alopecia and Female pattern hair loss [Table 1]. Guidelines recommendations and expert opinions for topical minoxidil are stated in Table 2.

Table 1.

Indications of topical minoxidil in hair disorders[2]

CDSCO approved indication	Year of approval
AGA	1988
FPHL	2021

AGA – Androgenetic alopecia; FPHL – Female pattern hair loss; CDSCO – Central Drugs Standard Control Organization

Table 2.

Recommendations for minoxidil based on International and National guidelines for managing androgenetic alopecia

Guideline/consensus	Recommendation
Expert consensus, India, 2019[9]	Minoxidil is the first-line therapy for AGA in men
Expert opinion, India, 2022[10]	Minoxidil is the mainstay treatment for AGA and FPHL
European Dermatology Forum, evidence-based guideline, 2017[11]	Topical minoxidil 2%–5% solution 1 mL or half a cap of 5% foam twice daily to improve or prevent AGA progression in male patients above 18 years with mild to moderate AGA
Asian Consensus Committee for AGA, guideline, 2012[12]	Mild-to-moderate AGA-monotherapy with 5% minoxidil in men and 2% or 3% minoxidil in women is recommended for 6–12 months
Japanese Dermatological Association’s guidelines for the management of AGA[13]	Topical 5% minoxidil twice daily for MPHL, and topical 1% minoxidil twice daily for FPHL, are recommended as the first-line treatments

AGA – Androgenetic alopecia; MPHL – Male pattern hair loss; FPHL – Female pattern hair loss

The serum concentration is usually below 5 ng/mL, sometimes even undetectable. Three percent minoxidil solution could detect the serum minoxidil level concentration between 0.4 and 7.5 ng/mL. Two-time applications of 5% topical minoxidil to the entire scalp could be equivalent to the oral dose of 5.4 mg. Approximately 1.4% of topical minoxidil is absorbed through the scalp, while increased absorption is associated with drug concentration and frequency of drug application. Absorption of topical minoxidil systematically is <99% when applied on the scalp. Minoxidil does not bind to plasma proteins or cross the blood–brain barrier. About 95% of the systemically absorbed drug and its metabolites are excreted through the kidney within 4 days.[7,8]

Place of topical minoxidil in guidelines

Limitations of alcohol-containing minoxidil formulations

Alcohol-based topical solutions, including minoxidil, commonly cause dryness of the skin/scalp. Dryness of the scalp occurs due to loss of moisture from the stratum corneum, leading to low skin hydration.[14] Propylene glycol-containing preparations are known to cause scalp sensitivity, itching, burning, and local irritation, and it has been evidenced in the literature that patients sensitive to propylene glycol are most likely susceptible to contact dermatitis.[8]

Evidence suggests that patients treated with alcohol-based minoxidil topical solutions often report local irritation of the scalp, pruritus, itching, burning, dryness, and redness. These adverse events are more familiar with 5% minoxidil formulations than 2% minoxidil formulations, as a higher percentage of propylene glycol is used in 5% than 2% formulation to solubilize minoxidil. The local irritation caused by the alcohol-based topical solutions affects patients’ self-tolerability and impacts patients’ compatibility and adherence to the treatment in the long term.[15] Evidence suggests that 11% of patients reported allergic contact dermatitis (11%) after using alcohol-based minoxidil solution. Patients suffering from allergic contact dermatitis may benefit from patch testing to prevent it.[8]

Limitation of various hair transplant therapy with alcohol-based minoxidil formulation

Although a combination therapy of hair transplant therapy such as microneedling, mesotherapy, light therapy, and topical minoxidil is beneficial for treating alopecia, these procedures induce adverse effects such as pinpoint bleeding, seborrheic dermatitis, irritation, and itching.[16,17] The application of alcohol-based minoxidil potentially may aggravate the procedure-related side effects. Thus, alcohol-free or low alcohol-based minoxidil formulations may be used in such cases.

Clinical benefits for less alcohol/alcohol-free minoxidil formulation

A double-blind, randomized controlled trial was conducted in androgenetic patients comparing 5% novel minoxidil topical solution and 5% minoxidil alcohol-based topical solutions for a month. After 30 days of therapy, the mean hydration significantly increased in patients treated with a 5% novel minoxidil formulation topical solution was 9.74 but was significantly reduced in patients treated with an alcohol-based solution (3.28) (P = 0.001). Novel minoxidil formulation was better tolerated compared with alcoholic formulations.[15] In another double-blind, randomized controlled study, AGA patients received 5% minoxidil topical propylene glycol-free foam for 52 weeks. Statistically significant increase in hair counts in the 5% MTF group versus placebo (P < 0.0001) and subjective assessment of improved hair loss condition (P < 0.0001) in the 5% MTF group versus placebo [Table 3].[18]

Table 3.

Clinical evidence of topical alcohol-free minoxidil in androgenetic alopecia

Study design	Intervention group, dose, and duration	Efficacy	Safety
DB RCT[15]	5% minoxidil alcohol-free topical solution or 5% minoxidil alcohol-based topical solutions for 30 days	The mean hydration increased in patients treated with 5% alcohol-free minoxidil (9.74) and reduced in patients treated with alcohol-based solution (3.28, P=0.001) after a month The mean score for redness was significantly decreased by 5% alcohol-free minoxidil (0.01, P=0.009)	Patients reported no burning or itching in the alcohol-free minoxidil group compared with alcohol-based minoxidil (96.7%, 80%)
DB RCT[18]	5% minoxidil topical PG-free foam or placebo for 52 weeks	Significant increase in hair counts in the 5% minoxidil group versus placebo (P<0.0001) and subjective assessment of improved hair loss condition (P<0.0001) in the 5% minoxidil group versus placebo	-
A pilot study[19]	PG-free 5% minoxidil lotion or 5% minoxidil lotion for 12 weeks	The global tolerability score mean value was 1.7 Clinical efficacy scores were 0.4, 0.6, and 1.2 at weeks 4, 8, and 12, respectively	-

DB – Double-blind; RCT – Randomized controlled trial; PG – Propylene glycol

The need of this position paper is to provide dermatologists consensus on the use of less alcohol or alcohol-free topical minoxidil formulation for patients with AGA.

METHODOLOGY

The primary target audience for this position paper is dermatologists. The recommendations are also to be used by policymakers to develop protocols and policies and support staff education. Twelve dermatologists practicing in India were chosen for the expert panel to represent a comprehensive and holistic view of alcohol-free minoxidil formulation for the treatment of AGA. The main aim is to give recommendations for better patient outcomes and services. Therefore, the experts were asked to deliberate on alcohol-free based minoxidil formulation to treat AGA from an Indian perspective.

Postdiscussion, a uniform consensus was said to have arrived if more than 75% of panel members agreed to the statement. The present paper is the outcome of aspects presented and discussed in the advisory board meetings.

RESULTS OF THE PANEL DISCUSSION

Dermatologists consult more than 60 patients a month with hair loss complaints depending on the location and practice. Patients visit the clinics within 2–4 months after noticing excessive hair fall. Most patients try home/Ayurvedic/homeopathic treatment before consulting dermatologists. According to the panel members, 5% topical minoxidil is the drug of choice for the management of AGA. They usually recommend liquid topical formulation with an average duration of treatment of more than a year. Most of the panel members do not prescribe hair serums along with topical treatment. The percentage of agreement given by the expert panel has been mentioned in Table 4.

Table 4.

Percentage of the agreement for each consensus statement

Statements	Percentage of agreement
Minoxidil topical foam formulation is a good choice for treating AGA, but it is poorly stable in India	75
Less than 20% of the patients are advised for hair procedures therapy in whom topical treatment is not showing any effect	83
About 5%–20% of patients complain of side effects with a conventional topical formulation	75
The severity of side effects with the conventional topical formulation is mild to moderate	92
Less alcohol/alcohol-free minoxidil topical formulation is preferred in the patients who were showing side effects with a conventional topical formulation	75
Patients show fewer side effects after applying less alcohol/alcohol-free minoxidil topical formulation than conventional topical minoxidil formulation	75
Dermatologists would prescribe less alcohol/alcohol-free minoxidil topical formulation for daily application in AGA patients	75
After platelet-rich plasma and microneedling hair procedure, less alcohol/alcohol-free minoxidil topical formulation should be recommended	75
The stability and efficacy of less alcohol/alcohol-free formulation are important parameters for adopting such formulation	83

AGA – Androgenetic alopecia

CONCLUSION

Alcohol-free topical minoxidil provides remarkable benefits to patients with alopecia. It is approved by the CDSCO for AGA. The position paper assessed that alcohol-free or less alcohol minoxidil formulation improves hydration and reduces the scalp's dryness, redness, and itching. In contrast, alcohol-based formulations increase the dryness and redness of the scalp after 15 and 30 days of treatment in men with AGA. The novel minoxidil formulation was better tolerated compared to the alcoholic formulations. Hence, the alcohol-free minoxidil formulation could be a safer and most satisfactory alternative to alcoholic formulations in treating AGA, especially after hair procedure treatments.

Financial support and sponsorship

The publication fee was paid by Dr. Reddy's Laboratories, India.

Conflicts of interest

Satish Udare, Anita Barua, Anurag Mathur, Dayanand TR, Kapil Jain, Manas Puhan, Pawan Bajaj, Richa Sharma, Sanjay Gamit, V Ramesh, V Venugopal and Vignesh Karthik are members of the advisory board of Dr. Reddy's Laboratories. Monil Yogesh Neena Gala, Snehal Muchhala and Amey Mane are employees of Dr. Reddy's Laboratories.