(W1230-03-17) Minoxidil Foaming Topical Formulation without Propellant and Inhibition of Crystalline Formation

Purpose: Minoxidil (3-hydroxy-2-imino-6-piperidin-1-ylpyrimidin-4-amine) is a potent vasodilator and the drug is indicated for the treatment of androgenetic alopecia. Minoxidil's action is restricted to the hair follicles and need to reach the hair bulb located in epidermis and dermis in effective concentrations. Minoxidil has low solubility in water (2.2 mg/mL), moderate solubility in ethanol (29 mg/mL), and higher solubility in propyleneglycol (75 mg/mL). In this way, the minoxidil solubility is the biggest challenge to be overcomed in terms of formulation and most commercial formulation are alcohol-based in solution form (usually in a concentration of 50 mg/mL). A drawback of this alcohol-based formulations is the solvent volatilization and minoxidil crystallization during product use and in the packaging components (e.g. application valve), which could impact in a not suitable bioavailability and sensory properties (e.g. irritation, itching, redness, dryness of the scalp and allergic contact dermatitis). Moreover, the low content of water, same with large amount of surfactants, hinders obtaining a foaming formulation. One of the best-selling commercial minoxidil topical product is applied in the foam form, but it is composed by a formulation based on alcohol and non-soluble surfactants, a viable formulation just with the use of propellant. In this work, we proposed a strategy to produce a minoxidil foaming solution that is water-based without propellant and with inhibition of crystalline formation, that presents a suitable bioavailability and sensory properties.

Methods: Different formulations of minoxidil 50 mg/mL containing always more than 50% m/v of water and a combination of excipients were produced. In all formulations were added at least one of the following kind of excipient: water-miscible organic solvent, co-solvent, amphoteric surfactant, non-ionic surfactant, and an antioxidant. The crystalline formation in the compositions and commercial products were analyzed using a microscope Olympus BX51 with 5x magnification and a Raman spectrometer Horiba LabRAM HR Evolution with a 633 nm laser excitation. After, formulations with less tendency to crystallization were tested for sensory properties and foaming quality. Finally, a permeation test using vertical diffusion cells (Franz cell) equipped with animal membrane were used to evaluate the minoxidil drug retention into the stratum corneum and epidermis/dermis.

Results: The results for the proposed formulation with the best performance compared with commercial products are presented below. Figure 1 shows the visual and microscopic foam aspect produced from this water-based solution that was obtained with a conventional commercial foaming pump. The Figure 2 illustrates the inhibition of crystalline formation of the foaming water-based formulation proposed in this work compared with commercial products. The solutions or emulsion (in the case of product with propellant) were exposed by 12 hours in room conditions (60% R.H. and 20°C) and analyzed after this period using optical microscopy and Raman spectroscopy. All commercial products present minoxidil crystals as confirmed by low frequency Raman spectra ( < 200 cm^-1). The formulation proposed in this work do not present crystals same after 12 hours and the Raman spectrum profile was characteristic of an amorphous material (as expected for a dried solution without crystals). It worth to mentioning that also the foaming generated with the water-based formulation proposed does not present minoxidil crystals. Finally, Figure 3 shows the results of permeation test using vertical diffusion cells equipped with animal membrane for the foaming water-based formulation proposed in this work compared with an alcohol-based commercial product. In the case of formulation proposed in work, the results indicate a greater availability after 24 hours of the minoxidil in the dermis layer, in which the hair bulb and the hair follicle are located, site of action of the drug. The permeation test also indicates a higher minoxidil release flow same in the first times (e.g. 0.03 µg/cm² for commercial product compared with 0.49 µg/cm² for formulation proposed in this work after 2 hours).

Conclusion: A pharmaceutical minoxidil foaming topical formulation for the treatment of alopecia composed by a water-based formulation with an organic solvent, co-solvent, amphoteric surfactant, non-ionic surfactant, and an antioxidant was developed in this work. The composition without propellant presents improved properties, as to prevent or attenuate the formation of crystals during storage and after application to the scalp, suitable sensory properties which might impact in the patient's adherence to the treatment, and a better drug delivery in the action site.

Figure 1. Foam formed by a minoxidil water-based solution proposed in this work obtained using a flask coupled with a conventional commercial foaming pump: Visual (A and B) and microscopic (C) aspect.

Figure 2. Visual aspect, microscopic view and low frequency Raman spectrum of water-based solution proposed and different commercial products exposed by 12 hours in room conditions (60% R.H. and 20°C): alcohol-based commercial product 1 (A), alcohol-based commercial product 2 (B), commercial product with propellant containing an alcohol-based foaming formulation (C), and water-based solution proposed in this work (D). It is also presented the Raman spectrum of minoxidil API crystal for comparison purposes.

Figure 3. The cutaneous retention of minoxidil after 24 h of study in the stratum corneum (A) and in the epidermis + dermis (B) of formulation proposed in this work and a commercial product.