WO2025167959A1 - Minoxidil-containing suspension, preparation method therefor, and use thereof - Google Patents

Abstract

Disclosed are a minoxidil-containing suspension, a preparation method therefor, and a use thereof. The suspension comprises, by total weight: about 2% to about 15% of minoxidil; about 0.05% to about 2% of an ionic stabilizer; about 0.1% to about 10% of a steric stabilizer; about 0% to about 80% of a solubilizer; and about 10% to about 97% of water.

Description

Suspension containing minoxidil and preparation method and use thereof

Citation of Related Applications

This disclosure claims all rights and interests in Chinese invention patent applications with application numbers 202410174780.5, entitled “A suspension containing minoxidil, its preparation method and use” and application number 202411599557.1, entitled “A suspension containing minoxidil, its preparation method and use”, filed with the State Intellectual Property Office of the People’s Republic of China on February 7, 2024 and November 11, 2024, respectively, and incorporates the entire contents thereof into this disclosure by reference.

field

The present disclosure relates generally to the field of pharmaceutical preparations, and more particularly to suspensions containing minoxidil, methods for their preparation, and uses.

background

Hair loss generally includes androgenetic alopecia (AGA), alopecia areata (AA) and chemotherapy-induced hair loss, among which AGA is the most common.

Minoxidil or finasteride are commonly used clinically to treat AGA. Finasteride is an oral preparation and can cause decreased libido in the early stages of use. Minoxidil can be taken orally or applied topically. Oral minoxidil can irritate the cardiovascular system, making topical minoxidil the current best option for patients with hair loss.

Currently, the main topical minoxidil product on the market is a solution. Minoxidil solutions contain high levels of propylene glycol (20% to 50%) and ethanol (30% to 50%) to increase the solubility of minoxidil and achieve an effective drug concentration. This high concentration of organic solvents can easily cause local skin allergies and irritation in patients and also has an unpleasant odor. Skin smear tests have revealed that, after the ethanol evaporates from existing minoxidil solution products, large drug crystals precipitate, preventing the drug from being absorbed by the skin and hair follicles.

Furthermore, according to literature reports, minoxidil requires sulfotransferase catalysis to convert it into minoxidil sulfate in order to exert its effects on lowering blood pressure and stimulating hair growth. The conversion of minoxidil in the scalp primarily occurs in the hair follicles. The applicant's research has found that current minoxidil solutions are primarily absorbed by the stratum corneum in the skin, but are less absorbed by the hair follicles, the site of hair loss. Therefore, the solution has difficulty delivering the drug to the hair follicles, making it difficult to efficiently convert minoxidil into active minoxidil sulfate. This may be a key reason for the slow onset and low efficacy of existing minoxidil solutions. Furthermore, the solution needs to be applied twice daily, which is inconvenient for patients.

Overview

In one aspect, the present disclosure relates to a suspension comprising minoxidil, comprising, by total weight, from about 2% to about 15% minoxidil, from about 0.05% to about 2% ionic stabilizer, from about 0.1% to about 10% steric stabilizer, from about 0% to about 80% solubilizer, and from about 10% to about 97% water.

In another aspect, the present disclosure relates to a method for preparing a suspension comprising minoxidil, comprising:

Mix the prescribed amount of minoxidil, steric stabilizer, ionic stabilizer and water, and

After the particles are micronized, a suspension containing minoxidil is obtained;

The suspension comprises, by total weight, about 2% to about 15% of minoxidil, about 0.05% to about 2% of an ionic stabilizer, about 0.1% to about 10% of a steric stabilizer, about 0% to about 80% of a solubilizer, and about 10% to about 97% of water.

In yet another aspect, the present disclosure relates to use of a suspension comprising minoxidil for the preparation of a medicament for treating hair loss, wherein the suspension comprises, by total weight, from about 2% to about 15% minoxidil, from about 0.05% to about 2% ionic stabilizer, from about 0.1% to about 10% steric stabilizer, from about 0% to about 80% solubilizer, and from about 10% to about 97% water.

In yet another aspect, the present disclosure relates to a method for treating hair loss comprising administering to an individual in need thereof a therapeutically effective amount of a suspension comprising minoxidil, wherein the suspension comprises, by total weight, from about 2% to about 15% minoxidil, from about 0.05% to about 2% ionic stabilizer, from about 0.1% to about 10% steric stabilizer, from about 0% to about 80% solubilizer, and from about 10% to about 97% water.

Details

In the following description, certain specific details are included to provide a thorough understanding of each disclosed embodiment. However, one skilled in the relevant art will recognize that the embodiments can be implemented without one or more of these specific details and with other methods, components, materials, etc.

Unless otherwise required by this disclosure, throughout this specification and the claims that follow, the words "include" and "comprising" should be construed in an open, inclusive sense, ie, "including, but not limited to."

Reference throughout this specification to "one embodiment" or "another embodiment" or "an embodiment" or "certain embodiments" means that the particular referenced elements, structures, or features described in connection with that embodiment are included in at least one embodiment. Thus, appearances of the phrases "one embodiment" or "an embodiment" or "another embodiment" in various places throughout this specification are not necessarily all referring to the same embodiment. Furthermore, the particular elements, structures, or features may be combined in any suitable manner in one or more embodiments.

It will be understood that the singular articles “a,” “an,” and “the,” as used in the specification of this disclosure and the appended claims, include plural referents unless the context clearly dictates otherwise.

definition

In the present disclosure, the term "suspension" refers to a liquid drug preparation in which the drug is dispersed in a dispersion medium in the form of solid particles, with an interface between the particles and the dispersion medium.

In the present disclosure, the term "minoxidil" refers to a drug molecule with a chemical formula of C ₉ H ₁₅ N ₅ O, which is a white crystalline powder and is clinically used as a first-line drug for the treatment of hair loss diseases.

In the present disclosure, the term "ionic stabilizer" refers to an ionic surfactant that is adsorbed on the surface of solid drug molecule particles and generates electrostatic repulsion between drug particles to increase the stability of the nanosuspension.

In the present disclosure, the term "steric stabilizer" refers to non-ionic surfactants and polymers that are adsorbed or wrapped on the surface of particles and form a steric barrier around the particles, hindering aggregation between particles and maintaining the stability of the suspension.

In the present disclosure, the term "solubilizer" refers to an organic solvent that increases the solubility of drug molecules in a suspension.

In this disclosure, the term "hydroxypropyl methylcellulose (HPMC)" refers to a nonionic cellulose mixed ether, which is a semi-synthetic, inert, viscoelastic polymer commonly used as a steric stabilizer for suspensions.

In the present disclosure, the term "hydroxypropyl cellulose (HPC)" refers to a nonionic cellulose ether obtained by reacting alkaline cellulose with propylene oxide under high temperature and high pressure. It is a semi-synthetic organic compound and is often used as a steric stabilizer for suspensions.

In the present disclosure, the term "polyethylene caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (Soluplus)" refers to a graft copolymer formed by the polymerization of 13% polyethylene glycol (PEG) 6000, 57% vinyl caprolactam and 30% vinyl acetate, which is a new type of amphiphilic non-ionic pharmaceutical polymer material that can be used as a steric stabilizer for suspensions.

In this disclosure, the term "PDI" refers to the polydispersity index (PDI or PI). PDI is a dimensionless value that reflects the width of the particle size distribution, usually ranging from 0 to 1. The smaller the value, the more uniform the particle size and the more concentrated the particle size distribution.

In the present disclosure, the term "D ₉₀ particle size" refers to the 90th percentile particle size, which means that in the cumulative distribution of particle sizes, particles smaller than this particle size account for 90% of the total volume.

In the present disclosure, the term " _D50 particle size" refers to the 50th percentile particle size, which means that in the cumulative distribution of particle sizes, particles smaller than this particle size account for 50% of the total volume.

In this disclosure, the term "about" means a variation of ±10% of the stated value.

DETAILED DESCRIPTION

In one aspect, the present disclosure relates to a suspension comprising minoxidil, comprising, by total weight, from about 2% to about 15% minoxidil, from about 0.05% to about 2% ionic stabilizer, from about 0.1% to about 10% steric stabilizer, from about 0% to about 80% solubilizer, and from about 10% to about 97% water.

In certain embodiments, the suspension comprises, by total weight, 2% to 15% minoxidil, 0.05% to 2% ionic stabilizer, 0.1% to 10% steric stabilizer, 0% to 80% solubilizer, and 10% to 97% water.

In certain embodiments, the suspension comprises from about 0.01% to about 1% of an ionic stabilizer.

In certain embodiments, the suspension comprises 0.01% to 1% of an ionic stabilizer.

In certain embodiments, the suspension comprises about 0.01% to about 0.9%, about 0.01% to about 0.8%, about 0.01% to about 0.7%, about 0.01% to about 0.6%, about 0.01% to about 0.5%, about 0.01% to about 0.4%, about 0.01% to about 0.3%, about 0.01% to about 0.2%, about 0.0% to about 0.15%, or about 0.01% to about 0.1% of an ionic stabilizer by total weight.

In certain embodiments, the suspension comprises 0.01% to 0.9%, 0.01% to 0.8%, 0.01% to 0.7%, 0.01% to 0.6%, 0.01% to 0.5%, 0.01% to 0.4%, 0.01% to 0.3%, 0.01% to 0.2%, 0.0% to 0.15%, or 0.01% to 0.1% of an ionic stabilizer by total weight.

In certain embodiments, the suspension comprises from about 0.05% to about 1% of an ionic stabilizer by total weight.

In certain embodiments, the suspension comprises 0.05% to 1% of an ionic stabilizer by total weight.

In certain embodiments, the suspension comprises about 0.05% to about 0.9%, about 0.05% to about 0.8%, about 0.05% to about 0.7%, about 0.05% to about 0.6%, about 0.05% to about 0.5%, about 0.05% to about 0.4%, about 0.05% to about 0.3%, about 0.05% to about 0.2%, about 0.05% to about 0.15%, or about 0.05% to about 0.1% of an ionic stabilizer by total weight.

In certain embodiments, the suspension comprises 0.05% to 0.9%, 0.05% to 0.8%, 0.05% to 0.7%, 0.05% to 0.6%, 0.05% to 0.5%, 0.05% to 0.4%, 0.05% to 0.3%, 0.05% to 0.2%, 0.05% to 0.15%, or 0.05% to 0.1% of an ionic stabilizer by total weight.

In certain embodiments, the suspension comprises about 0.01%, about 0.02%, about 0.03%, about 0.04%, about 0.05%, about 0.1%, about 0.15%, about 0.2%, about 0.25%, about 0.3%, about 0.35%, about 0.4%, about 0.45%, about 0.5%, about 0.55%, about 0.6%, about 0.65%, about 0.7%, about 0.75%, about 0.8%, about 0.85%, about 0.9%, about 0.95%, or about 1% of an ionic stabilizer by total weight.

In certain embodiments, the suspension comprises 0.01%, 0.02%, 0.03%, 0.04%, 0.05%, 0.1%, 0.15%, 0.2%, 0.25%, 0.3%, 0.35%, 0.4%, 0.45%, 0.5%, 0.55%, 0.6%, 0.65%, 0.7%, 0.75%, 0.8%, 0.85%, 0.9%, 0.95%, or 1% of an ionic stabilizer by total weight.

In certain embodiments, examples of exemplary ionic stabilizers that can be used in the present disclosure include, but are not limited to, docusate sodium, sodium dodecyl sulfate (SDS), and sodium deoxycholate.

In certain embodiments, the ionic stabilizer is docusate sodium.

In certain embodiments, the suspension comprises from about 0.01% to about 5% of the steric stabilizer by total weight.

In certain embodiments, the suspension comprises from 0.01% to 5% by weight of the total suspension.

In certain embodiments, the suspension comprises from about 0.1% to about 5% of the steric stabilizer by total weight.

In certain embodiments, the suspension comprises 0.1% to 5% of the steric stabilizer by total weight.

In certain embodiments, the suspension comprises about 0.1% to about 4%, about 0.1% to about 3%, about 0.1% to about 2%, about 0.1% to about 1.5%, or about 0.1% to about 1% of the steric stabilizer by total weight.

In certain embodiments, the suspension comprises 0.1% to 4%, 0.1% to 3%, 0.1% to 2%, 0.1% to 1.5%, or 0.1% to 1% of the total weight of the steric stabilizer.

In certain embodiments, the suspension comprises about 0.1%, about 0.15%, about 0.2%, about 0.25%, about 0.3%, about 0.35%, about 0.4%, about 0.45%, about 0.5%, about 0.55%, about 0.6%, about 0.65%, about 0.7%, about 0.75%, about 0.8%, about 0.85%, about 0.9%, about 0.95%, about 1%, about 1.5%, about 2%, about 2.5%, about 3%, about 3.5%, about 4%, about 4.5%, or about 5% of the steric stabilizer by total weight.

In certain embodiments, the suspension comprises 0.1%, 0.15%, 0.2%, 0.25%, 0.3%, 0.35%, 0.4%, 0.45%, 0.5%, 0.55%, 0.6%, 0.65%, 0.7%, 0.75%, 0.8%, 0.85%, 0.9%, 0.95%, 1%, 1.5%, 2%, 2.5%, 3%, 3.5%, 4%, 4.5%, or 5% of the total weight of the steric stabilizer.

In certain embodiments, examples of exemplary steric stabilizers that can be used in the present disclosure include, but are not limited to, hydroxypropyl methylcellulose (HPMC), hydroxypropyl cellulose (HPC), and polyethylene caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (Soluplus).

In certain embodiments, the steric stabilizer is polyethylene caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (Soluplus).

In certain embodiments, examples of exemplary steric stabilizers and ionic stabilizers that can be used in the present disclosure include, but are not limited to, docusate sodium/HPMC, docusate sodium/HPC, docusate sodium/Soluplus, SDS/HPMC, SDS/HPC, SDS/Soluplus, sodium deoxycholate/HPMC, sodium deoxycholate/HPC, and sodium deoxycholate/Soluplus.

In certain embodiments, the ionic stabilizer and steric stabilizer are SDS/Soluplus.

In certain embodiments, the ionic stabilizer and steric stabilizer is sodium deoxycholate/Soluplus.

In certain embodiments, the ionic stabilizer and steric stabilizer is docusate sodium/Soluplus.

In certain embodiments, the suspension comprises from about 20% to about 80% of the solubilizer, based on total weight.

In certain embodiments, the suspension comprises 20% to 80% of a solubilizer by total weight.

In certain embodiments, the suspension comprises from about 30% to about 70% of the solubilizer, based on total weight.

In certain embodiments, the suspension comprises 30% to 70% of a solubilizer by total weight.

In certain embodiments, the suspension comprises from about 35% to about 65% of the solubilizer, based on total weight.

In certain embodiments, the suspension comprises 35% to 65% of a solubilizer by total weight.

In certain embodiments, the suspension comprises from about 40% to about 60% of the solubilizer, based on total weight.

In certain embodiments, the suspension comprises 40% to 60% of a solubilizer by total weight.

In certain embodiments, the suspension comprises from about 45% to about 60% of the solubilizer, based on total weight.

In certain embodiments, the suspension comprises 45% to 60% of a solubilizer by total weight.

In certain embodiments, the suspension comprises from about 45% to about 55% of the solubilizer, based on total weight.

In certain embodiments, the suspension comprises 45% to 55% of a solubilizer by total weight.

In certain embodiments, the suspension comprises about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, or about 70% solubilizer by total weight.

In certain embodiments, the suspension comprises 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, or 70% solubilizer by total weight.

In certain embodiments, examples of exemplary solubilizing agents that can be used in the present disclosure include, but are not limited to, glycerol, ethanol, propylene glycol, ethylene glycol, diethylene glycol monoethyl ether, propylene carbonate, PEG-200, PEG-400, and PEG-600.

In certain embodiments, the solubilizing agent is glycerol.

In certain embodiments, the solubilizer is a combination of any one selected from ethanol, propylene glycol, ethylene glycol, diethylene glycol monoethyl ether, propylene carbonate, PEG-200, PEG-400 and PEG-600 and glycerol.

In certain embodiments, the suspension comprises from about 2% to about 10% minoxidil by total weight.

In certain embodiments, the suspension comprises 2% to 10% minoxidil by total weight.

In certain embodiments, the suspension comprises about 2% to about 9%, about 2% to about 8%, about 2% to about 7%, about 2% to about 6%, or about 2% to about 5% minoxidil by total weight.

In certain embodiments, the suspension comprises 2% to 9%, 2% to 8%, 2% to 7%, 2% to 6%, or 2% to 5% minoxidil by total weight.

In certain embodiments, the suspension comprises from about 3% to about 9%, from about 3% to about 8%, from about 3% to about 7%, or from about 3% to about 6% minoxidil by total weight.

In certain embodiments, the suspension comprises 3% to 9%, 3% to 8%, 3% to 7%, or 3% to 6% minoxidil by total weight.

In certain embodiments, the suspension comprises about 4% to about 9%, about 4% to about 8%, about 4% to about 7%, or about 4% to about 6% minoxidil by total weight.

In certain embodiments, the suspension comprises 4% to 9%, 4% to 8%, 4% to 7%, or 4% to 6% minoxidil by total weight.

In certain embodiments, the suspension comprises about 2%, about 2.5%, about 3%, about 3.5%, about 4%, about 4.5%, about 5%, about 5.5%, about 6%, about 6.5%, about 7%, about 7.5%, about 8%, about 8.5%, about 9%, about 9.5%, or about 10% minoxidil.

In certain embodiments, the suspension comprises 2%, 2.5%, 3%, 3.5%, 4%, 4.5%, 5%, 5.5%, 6%, 6.5%, 7%, 7.5%, 8%, 8.5%, 9%, 9.5%, or 10% minoxidil.

In certain embodiments, the suspension comprises about 5% minoxidil.

In certain embodiments, the suspension comprises 5% minoxidil.

In certain embodiments, the suspension further comprises one or more other pharmaceutically active ingredients.

In certain embodiments, examples of exemplary other pharmaceutically active ingredients that can be used in the present disclosure include, but are not limited to, finasteride and dutasteride.

In certain embodiments, the suspension is a combined suspension of minoxidil and finasteride.

In certain embodiments, the suspension is a combination suspension of minoxidil and dutasteride.

In certain embodiments, the compounded suspension comprises from about 0.01% to about 0.5% finasteride by total weight.

In certain embodiments, the compound suspension comprises 0.01% to 0.5% finasteride by total weight.

In certain embodiments, the composite suspension comprises about 0.01%, about 0.015%, about 0.02%, about 0.025%, about 0.03%, about 0.035%, about 0.04%, about 0.045%, about 0.05%, about 0.06%, about 0.07%, about 0.08%, about 0.09%, about 0.1%, about 0.15%, about 0.2%, about 0.25%, about 0.3%, about 0.35%, about 0.4%, about 0.45%, or about 0.5% finasteride by total weight.

In certain embodiments, the composite suspension comprises 0.01%, 0.015%, 0.02%, 0.025%, 0.03%, 0.035%, 0.04%, 0.045%, 0.05%, 0.06%, 0.07%, 0.08%, 0.09%, 0.1%, 0.15%, 0.2%, 0.25%, 0.3%, 0.35%, 0.4%, 0.45%, or 0.5% finasteride by total weight.

In certain embodiments, the compound suspension comprises about 0.025% finasteride by total weight.

In certain embodiments, the compound suspension comprises 0.025% finasteride by total weight.

In certain embodiments, the compound suspension comprises about 0.1% finasteride by total weight.

In certain embodiments, the compound suspension comprises 0.1% finasteride by total weight.

In certain embodiments, the compound suspension comprises about 0.25% finasteride by total weight.

In certain embodiments, the compound suspension comprises 0.25% finasteride by total weight.

In certain embodiments, the compounded suspension comprises from about 0.01% to about 0.5% dutasteride by total weight.

In certain embodiments, the compound suspension comprises 0.01% to 0.5% dutasteride by total weight.

In certain embodiments, the compound suspension comprises about 0.01%, about 0.015%, about 0.02%, about 0.025%, about 0.03%, about 0.035%, about 0.04%, about 0.045%, about 0.05%, about 0.06%, about 0.07%, about 0.08%, about 0.09%, about 0.1%, about 0.15%, about 0.2%, about 0.25%, about 0.3%, about 0.35%, about 0.4%, about 0.45%, or about 0.5% dutasteride by total weight.

In certain embodiments, the compound suspension comprises 0.01%, 0.015%, 0.02%, 0.025%, 0.03%, 0.035%, 0.04%, 0.045%, 0.05%, 0.06%, 0.07%, 0.08%, 0.09%, 0.1%, 0.15%, 0.2%, 0.25%, 0.3%, 0.35%, 0.4%, 0.45% or 0.5% dutasteride by total weight.

In certain embodiments, the suspension comprises from about 10% to about 95% water by total weight.

In certain embodiments, the suspension comprises 10% to 95% water by total weight.

In certain embodiments, the suspension comprises from about 10% to about 90% water by total weight.

In certain embodiments, the suspension comprises 10% to 90% water by total weight.

In certain embodiments, the suspension comprises from about 10% to about 80% water by total weight.

In certain embodiments, the suspension comprises 10% to 80% water by total weight.

In certain embodiments, the suspension comprises from about 10% to about 75%, from about 15% to about 70%, from about 25% to about 50%, from about 30% to about 50%, from about 25% to about 45%, from about 30% to about 45%, from about 35% to about 45%, or from about 40% to about 55% water by total weight.

In certain embodiments, the suspension comprises 10% to 75%, 15% to 70%, 25% to 50%, 30% to 50%, 25% to 45%, 30% to 45%, 35% to 45%, or 40% to 55% water by total weight.

In certain embodiments, the suspension comprises about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, or about 80% water by total weight.

In certain embodiments, the suspension comprises 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, or 80% water by total weight.

In certain embodiments, the suspension further comprises one or more of an antioxidant and a preservative.

In certain embodiments, the antioxidants and preservatives can improve the stability of the suspension.

In certain embodiments, the antioxidants and preservatives are added in amounts according to the concentration ranges commonly used as excipients.

In certain embodiments, the suspension comprises an antioxidant.

In certain embodiments, the suspension comprises a preservative.

In certain embodiments, examples of exemplary antioxidants that can be used in the present disclosure include, but are not limited to, sodium sulfite, sodium thiosulfate, propyl gallate, disodium edetate, calcium sodium edetate, butylated hydroxytoluene, butylated hydroxyanisole, alpha-tocopherol, ascorbyl palmitate, and ascorbic acid.

In certain embodiments, the antioxidant is selected from one or more of sodium sulfite and disodium edetate.

In certain embodiments, examples of exemplary preservatives that can be used in the present disclosure include, but are not limited to, benzyl alcohol, methylparaben, ethylparaben, and propylparaben.

In certain embodiments, the preservative is methylparaben.

In certain embodiments, the average particle size of the drug particles in the suspension is about ≤1 μm and the PDI is about <0.3.

In certain embodiments, the average particle size of the drug particles in the suspension is ≤1 μm and the PDI is <0.3.

In certain embodiments, the average particle size of the drug particles in the suspension is about ≤ 0.9 μm, about ≤ 0.8 μm, about ≤ 0.7 μm, about ≤ 0.6 μm, about ≤ 0.5 μm, about ≤ 0.4 μm, or about ≤ 0.3 μm.

In certain embodiments, the average particle size of the drug particles in the suspension is ≤0.9 μm, ≤0.8 μm, ≤0.7 μm, ≤0.6 μm, ≤0.5 μm, ≤0.4 μm, or ≤0.3 μm.

In certain embodiments, the PDI of the drug particles in the suspension is about <0.2.

In certain embodiments, the PDI of the drug particles in the suspension is <0.2.

In certain embodiments, the suspension drug particles have a D ₉₀ particle size of about ≤1 μm and a PDI of about <0.3.

In certain embodiments, the suspension drug particles have a D ₉₀ particle size of ≤1 μm and a PDI of <0.3.

In certain embodiments, the _D90 particle size of the drug particles in the suspension is about ≤ 0.9 μm, about ≤ 0.8 μm, about ≤ 0.7 μm, about ≤ 0.6 μm, about ≤ 0.5 μm, about ≤ 0.4 μm, or about ≤ 0.3 μm.

In certain embodiments, the D ₉₀ particle size of the drug particles in the suspension is ≤ 0.9 μm, ≤ 0.8 μm, ≤ 0.7 μm, ≤ 0.6 μm, ≤ 0.5 μm, ≤ 0.4 μm, or ≤ 0.3 μm.

In certain embodiments, the PDI of the drug particles in the suspension is about <0.2.

In certain embodiments, the PDI of the drug particles in the suspension is <0.2.

In certain embodiments, the drug particles in the suspension have a _D50 particle size of about ≤1 μm and a PDI of about <0.3.

In certain embodiments, the drug particles in the suspension have a D ₅₀ particle size of ≤1 μm and a PDI of <0.3.

In certain embodiments, the _D50 particle size of the drug particles in the suspension is about ≤ 0.7 μm, about ≤ 0.6 μm, about ≤ 0.5 μm, about ≤ 0.4 μm, or about ≤ 0.3 μm.

In certain embodiments, the _D50 particle size of the drug particles in the suspension is ≤0.7 μm, ≤0.6 μm, ≤0.5 μm, ≤0.4 μm, or ≤0.3 μm.

In certain embodiments, the PDI of the drug particles in the suspension is about <0.2.

In certain embodiments, the PDI of the drug particles in the suspension is <0.2.

In certain embodiments, the suspension containing minoxidil of the present disclosure has at least one of the following excellent properties: small particle size of the active pharmaceutical ingredient particles, relatively concentrated size distribution, good stability, high drug loading, little or no precipitation of the active pharmaceutical ingredient on the skin, good efficacy, high patient efficacy, rapid onset of action, few adverse reactions, low scalp irritation, easy to use, non-greasy after use, good transdermal absorption of the drug, high absorption at the hair follicle site, good patient compliance, etc.

In another aspect, the present disclosure relates to a method for preparing a suspension comprising minoxidil, comprising:

Mix the prescribed amount of minoxidil, steric stabilizer, ionic stabilizer and water, and

After the particles are micronized, a suspension containing minoxidil is obtained;

The suspension comprises, by total weight, about 2% to about 15% of minoxidil, about 0.05% to about 2% of an ionic stabilizer, about 0.1% to about 10% of a steric stabilizer, about 0% to about 80% of a solubilizer, and about 10% to about 97% of water.

In certain embodiments, after the particles are miniaturized, a suspension containing minoxidil is obtained with water as the dispersion medium.

In certain embodiments, the method further comprises mixing a prescribed amount of a solubilizer with the suspension to obtain a suspension containing minoxidil with water and the solubilizer as a dispersion medium.

In certain embodiments, the method comprises: mixing a prescribed amount of minoxidil, finasteride or dutasteride, a steric stabilizer, an ionic stabilizer, and water, and subjecting the particles to micronization to obtain a compound suspension comprising minoxidil and finasteride or a compound suspension of minoxidil and dutasteride.

In certain embodiments, examples of exemplary particle miniaturization processes that can be used in the present disclosure include, but are not limited to, grinding, high-pressure homogenization, impact milling, and airflow milling.

In certain embodiments, the particle miniaturization process is ball milling (abbreviated as ball milling).

In certain embodiments, the ball milling process comprises milling at a temperature of about 0 to about 20°C.

In certain embodiments, the ball milling method comprises grinding at a temperature of 0 to 20°C.

In certain embodiments, the ball milling method comprises milling at a temperature of about 0 to about 10°C.

In certain embodiments, the ball milling method comprises grinding at a temperature of 0 to 10°C.

In certain embodiments, the ball milling method comprises milling at a temperature of about 2 to about 8°C, about 2 to about 6°C, or about 2 to about 4°C.

In certain embodiments, the ball milling method comprises grinding at a temperature of 2 to 8°C, 2 to 6°C, or 2 to 4°C.

In certain embodiments, a prescribed amount of solubilizer may be added after the particle miniaturization process.

In certain embodiments, the suspension or compound suspension may further contain a prescribed amount of antioxidants and preservatives.

In yet another aspect, the present disclosure relates to use of a suspension comprising minoxidil for the preparation of a medicament for treating hair loss, wherein the suspension comprises, by total weight, from about 2% to about 15% minoxidil, from about 0.05% to about 2% ionic stabilizer, from about 0.1% to about 10% steric stabilizer, from about 0% to about 80% solubilizer, and from about 10% to about 97% water.

In certain embodiments, the hair loss is pathological hair loss.

In certain embodiments, exemplary hair loss that can be used in the present disclosure include, but are not limited to, androgenic alopecia, alopecia areata, anagen effluvium, self-induced alopecia, telogen effluvium and scarring alopecia, psychogenic alopecia, endocrine alopecia, nutritional alopecia, and chemical alopecia.

In certain embodiments, the hair loss is androgenetic alopecia (AGA).

In certain embodiments, the hair loss is androgenetic alopecia in young and middle-aged men.

In yet another aspect, the present disclosure relates to a method for treating hair loss comprising administering to an individual in need thereof a therapeutically effective amount of a suspension comprising minoxidil, wherein the suspension comprises, by total weight, from about 2% to about 15% minoxidil, from about 0.05% to about 2% ionic stabilizer, from about 0.1% to about 10% steric stabilizer, from about 0% to about 80% solubilizer, and from about 10% to about 97% water.

In certain embodiments, the individual is administered about 40 mg to about 100 mg of minoxidil per day.

In certain embodiments, the individual is administered 40 mg to 100 mg of minoxidil per day.

In certain embodiments, the suspension comprising minoxidil is topically applied to the subject once or twice daily.

In certain embodiments, the individual is applied 1 ml at a time to the affected area of the head, starting from the center of the affected area and massaging with the hands for 3 to 5 minutes. The total amount per day should not exceed 2 ml.

In certain embodiments, the suspension should be used when the hair and scalp are completely dry, and after use, hands should be washed.

In certain embodiments, the method further comprises administering to the individual an additional pharmaceutical agent.

In certain embodiments, examples of exemplary other drugs that can be used in the present disclosure include, but are not limited to, finasteride, dutasteride, spironolactone, ketoconazole, furitan, clacodone, bicalutamide, botulinum toxin type A, and autologous platelet-rich plasma.

In certain embodiments, the additional drug is selected from finasteride or dutasteride.

In certain embodiments, the hair loss is pathological hair loss.

In certain embodiments, exemplary hair loss that can be used in the present disclosure include, but are not limited to, androgenic alopecia, alopecia areata, anagen effluvium, self-induced alopecia, telogen effluvium and scarring alopecia, psychogenic alopecia, endocrine alopecia, nutritional alopecia, and chemical alopecia.

In certain embodiments, the hair loss is androgenetic alopecia (AGA).

In certain embodiments, the hair loss is androgenetic alopecia in young and middle-aged men.

In certain embodiments, the suspension containing minoxidil disclosed herein exhibits excellent physical stability. The stabilizer used in the suspension disclosed herein is a combination of a specific ionic stabilizer and a non-ionic stabilizer, resulting in the suspension having small particle size, narrow size distribution, dimensional stability, and good redispersibility of the active pharmaceutical ingredient particles. Furthermore, the suspension maintains a stable appearance, particle size, and distribution without significant aggregation or sedimentation even after storage under accelerated conditions (40°C/75% RH) for more than three months.

In certain embodiments, the suspension containing minoxidil disclosed herein has good chemical stability. The active pharmaceutical ingredient and excipients in the suspension formulation disclosed herein are well compatible, and the active pharmaceutical ingredient content does not change significantly, nor does the impurities increase significantly, after storage under accelerated conditions (40°C/75% RH) for more than six months.

In certain embodiments, the suspension containing minoxidil disclosed herein has good absorption by the skin and hair follicles. The suspension disclosed herein contains both dissolved and undissolved minoxidil. The dissolved minoxidil can be rapidly absorbed through the stratum corneum of the skin, achieving a rapid onset of action. The undissolved minoxidil can accumulate on the skin surface and in tissues (including hair follicles), forming a drug reservoir, achieving follicle-targeted delivery and sustained release of minoxidil, and enhancing the therapeutic efficacy of minoxidil.

In certain embodiments, the suspension containing minoxidil disclosed herein has good drug solubility. The addition of non-volatile glycerin as a solubilizing agent further increases the solubility of minoxidil, avoids the problem of drug precipitation and growth due to solvent volatilization, and thus hinders skin absorption, thereby improving the bioavailability of the drug.

In certain embodiments, the suspension containing minoxidil disclosed herein has low scalp irritation and few adverse reactions. The suspension disclosed herein does not use irritating propylene glycol and ethanol, thereby reducing scalp irritation and reducing discomfort symptoms such as itching, dandruff, and redness.

Hereinafter, the present disclosure will be explained in detail through the following examples in order to better understand the various aspects and advantages of the present disclosure. However, it should be understood that the following examples are non-limiting and are only used to illustrate certain embodiments of the present disclosure.

Example

In the present disclosure, unless otherwise specified, various raw materials, reagents, instruments and equipment used in the present disclosure can be purchased from the market or can be prepared by existing methods.

Experimental Example 1 Prescription Screening

1.1 Screening of stabilizers

1.1.1 According to Table 1, mix the prescribed amounts of minoxidil, stabilizer, and water, and prepare suspension samples by ball milling to investigate the use of different stabilizers.

Table 1

The results showed that when SDS+PVP K30, SDS+Tween 80, SDS+HPMC E5, SDS+HPC and SDS+Soluplus were used as stabilizers, the samples obtained had good properties, were not stratified, and were evenly distributed 2% minoxidil suspensions; when SDS alone was used as a stabilizer, or when SDS+caprylic/capric macrogol glycerides, SDS+polyoxyethylene castor oil EL and SDS+polyoxyethylene hydrogenated castor oil RH 40 were used as stabilizers, no evenly suspended samples could be obtained; in addition, when SDS+Eudragit L100 was used as a stabilizer, the obtained sample looked even, but in fact Eudragit L100 was not dissolved.

1.1.2 According to Table 2, mix the prescribed amounts of minoxidil, stabilizer, and water, and prepare suspension samples by ball milling to investigate the use of different stabilizers.

Table 2

The results showed that when SDS+PVP K30, SDS+HPMC E5, SDS+HPC or SDS+Soluplus were used as stabilizers, the prepared suspension samples had good properties, no stratification, and were evenly distributed 10% minoxidil suspensions; when SDS+Tween 80 was used as a stabilizer, a small amount of minoxidil precipitated at the bottom of the suspension sample, which could be dispersed after shaking; when sodium docusate was used instead of SDS and combined with PVP K30, HPMC E5, HPC or Soluplus as a stabilizer, a uniformly suspended minoxidil suspension could also be obtained; when sodium deoxycholate and PVP K30 were used in combination as stabilizers, a uniformly suspended minoxidil suspension could also be obtained; when chitosan and Soluplus were used in combination as stabilizers, no suspension sample with good properties could be obtained.

1.1.3 According to Table 3, mix the prescribed amounts of minoxidil, stabilizer, and water, and prepare suspension samples by ball milling to investigate the use of different stabilizers.

Table 3

The results showed that it was impossible to prepare a uniformly distributed suspension sample using any one of SDS, docusate sodium, sodium deoxycholate, PVP K30, Tween 80, HPMC E5, HPC or Soluplus as a stabilizer.

1.1.4 The inventors of the present disclosure also used Tween 20 + PEG 4000, Tween 20 + Span 20, Span 80, Poloxamer 407, sodium carboxymethylcellulose + carbomer 980, PVP K12 + Tween 80, carbomer 981, TPGS, Poloxamer 188 + Tween 80, PVP K17 + HPβCD, carbomer 980, and HPβCD as stabilizers, and then added minoxidil and water to prepare suspension samples. The results showed that no uniformly mixed suspension samples were obtained.

SDS, docusate sodium or sodium deoxycholate are ionic stabilizers, and PVP K30, HPMC E5, HPC-L and Soluplus are steric stabilizers. By observing the physical state of the suspension samples, it can be seen that when any of the above ionic stabilizers or steric stabilizers are used alone, a uniformly suspended minoxidil suspension cannot be prepared; while SDS or docusate sodium combined with PVP K30, HPMC E5, HPC-L and Soluplus as stabilizers, or sodium deoxycholate combined with PVP K30 or as stabilizers, can prepare a uniformly suspended minoxidil suspension; in addition, the use of other stabilizers alone or in combination, such as the stabilizers mentioned in 1.1.4, also cannot prepare a uniformly distributed minoxidil suspension.

1.1.5 Furthermore, in order to control the particle size range and particle polydispersity index (PDI) of the suspension, the inventors of the present disclosure found through screening that after preparing a minoxidil suspension using 10% minoxidil, 0.1% SDS, 1% PVP K30 and 88.9% water, its average particle size on day 0 was 412.3 nm, and its PDI was 0.128. The average particle size on day 37 reached 642.3 nm, and the PDI reached 0.371. After replacing 1% PVP K30 with 1% HPMC E5, 1% HPC or 1% Soluplus, the average particle size of the minoxidil suspension prepared was below 600 nm on day 0 and on day 37, and the PDI was below 0.3.

In summary, the stabilizer screened in the present disclosure is a specific combination of ionic stabilizers and steric stabilizers, wherein the ionic stabilizer is selected from SDS, docusate sodium and sodium deoxycholate, and the steric stabilizer is selected from HPMC E5, HPC-L and Soluplus.

1.2 Screening of solubilizers

1.2.1 To further increase the solubility of minoxidil in the system, the inventors of the present disclosure screened solubilizers. According to Table 4, the prescribed amounts of minoxidil, SDS, Soluplus, and water were mixed with isopropyl alcohol, diethylene glycol monoethyl ether, propylene glycol, ethanol, glycerol, 1-3 butylene glycol, 1-2 hexanediol, PEG-200, and PEG-400, respectively. Suspension samples were prepared using the ball milling method, and the performance of different solubilizers was evaluated.

Table 4

The results showed that the suspension samples using glycerol as a solubilizer exhibited good dispersion effects within a week; the suspension samples using PEG-200 or PEG-400 as solubilizers showed mild stratification after long-term storage; and the suspension samples using other solubilizers immediately stratified after one to two days, with particle clusters settling or growing rapidly.

1.2.2 Table 5 compares the solubility of minoxidil in formulations with different amounts of glycerol added as a solubilizer and in formulations without glycerol. The results are shown in Table 5.

Table 5

The results showed that when glycerol was added to the formulation, the solubility of minoxidil was significantly improved. For example, when 49% glycerol was added to the formulation, the solubility of minoxidil increased by about 3.5 times compared to the formulation without glycerol.

Example 1

2% minoxidil, 0.1% SDS, 1% Soluplus, and 96.9% water were weighed and mixed, and then ball-milled using a Netzsch Minicer mill at a temperature of 2 to 4° C. and a rotation speed of 3600 rpm for 1 h to obtain a minoxidil suspension.

The average particle size was determined to be 238 nm and the PDI was 0.121.

Example 2

2% minoxidil, 0.1% SDS, 1% Soluplus, and 96.9% water were weighed and mixed, and then ball-milled using a Netzsch Minicer mill at a temperature of 2 to 4° C. and a rotation speed of 3600 rpm for 2 h to obtain a minoxidil suspension.

The average particle size was determined to be 164 nm and the PDI was 0.105. After being placed at room temperature for 50 days, the average particle size was determined to be 200 nm and the PDI was 0.096.

Example 3

10% minoxidil, 0.1% SDS, 1% Soluplus, and 88.9% water were weighed and mixed, and then ball-milled using Jingxin JXFSTPRP-CLN at a temperature of 2 to 4° C. and a frequency of 60 Hz for 8 h to obtain a minoxidil suspension.

The average particle size was determined to be 240 nm and the PDI was 0.117.

Example 4

10% minoxidil, 0.2% SDS, 2% Soluplus, and 87.8% water were weighed and mixed, and then ball-milled using Jingxin JXFSTPRP-CLN at a temperature of 2 to 4° C. and a frequency of 60 Hz for 8 h to obtain a minoxidil suspension.

Example 5

10% minoxidil, 0.1% SDS, 1% HPMC E5, and 88.9% water were weighed and mixed, and then ball-milled using a Jingxin JXFSTPRP-CLN at a temperature of 2 to 4°C and a frequency of 60 Hz for 8 h to obtain a minoxidil suspension.

The average particle size was measured to be 552 nm and the PDI was 0.239. After 37 days of storage at room temperature, the average particle size was measured to be 504 nm and the PDI was 0.228.

Example 6

10% minoxidil, 0.1% SDS, 1% HPC and 88.9% water were weighed and mixed, and then ball-milled using Jingxin JXFSTPRP-CLN at a temperature of 2 to 4° C. and a frequency of 60 Hz for 8 h to obtain a minoxidil suspension.

The average particle size was measured to be 508 nm and the PDI was 0.218. After 37 days of storage at room temperature, the average particle size was measured to be 597 nm and the PDI was 0.236.

Example 7

12.86% minoxidil, 0.26% SDS, 2.57% Soluplus, and 84.31% water were weighed and mixed, and then ball-milled using Jingxin JXFSTPRP-CLN at a temperature of 2 to 4° C. and a frequency of 60 Hz for 8 h to obtain a minoxidil suspension.

After being allowed to stand at room temperature for 41 days, the average particle size was measured to be 483 nm and the PDI was 0.256.

Example 8

10% minoxidil, 0.1% docusate sodium, 1% Soluplus, and 88.9% water were weighed and mixed, and then ball-milled using Jingxin JXFSTPRP-CLN at a temperature of 2 to 4°C and a frequency of 60 Hz for 8 h to obtain a minoxidil suspension.

After being placed at room temperature for 37 days, the average particle size was measured to be 274 nm and the PDI was 0.159.

Example 9

5% minoxidil, 0.1% docusate sodium, 1% Soluplus, and 93.9% water were weighed and mixed, and then ball-milled using Jingxin JXFSTPRP-CLN at a temperature of 2 to 4° C. and a frequency of 60 Hz for 8 h to obtain a minoxidil suspension.

Example 10

5% minoxidil, 0.1% docusate sodium, 0.5% Soluplus, and 94.4% water were weighed and mixed, and then ball-milled using Jingxin JXFSTPRP-CLN at a temperature of 2 to 4° C. and a frequency of 60 Hz for 8 h to obtain a minoxidil suspension.

Example 11

5% minoxidil, 0.1% docusate sodium, 0.25% Soluplus, and 94.65% water were weighed and mixed, and then ball-milled using Jingxin JXFSTPRP-CLN at a temperature of 2 to 4° C. and a frequency of 60 Hz for 8 h to obtain a minoxidil suspension.

Example 12

5% minoxidil, 0.1% docusate sodium, 0.1% Soluplus, and 94.8% water were weighed and mixed, and then ball-milled using Jingxin JXFSTPRP-CLN at a temperature of 2 to 4° C. and a frequency of 60 Hz for 8 h to obtain a minoxidil suspension.

Example 13

A mixture of 5% minoxidil, 0.25% finasteride, 0.1% docusate sodium, 1% Soluplus, and 93.65% water was weighed and mixed. The mixture was then ball-milled using a Jingxin JXFSTPRP-CLN mill at 2 to 4°C and 60 Hz for 8 hours to obtain a minoxidil and finasteride compound suspension. The average particle size of the drug particles was 223 nm, and the PDI was 0.148.

Example 14

5% minoxidil, 0.25% finasteride, 0.1% docusate sodium, 1% Soluplus, and 63.65% water were weighed and mixed. The mixture was then ball-milled using a Jingxin JXFSTPRP-CLN mill at 2 to 4°C and 60 Hz for 8 hours. 30% glycerol was then added and mixed to obtain a minoxidil and finasteride compound suspension. The average particle size of the drug particles was 222 nm, and the PDI was 0.117.

Example 15

5% minoxidil, 0.25% finasteride, 0.1% docusate sodium, 1% Soluplus, and 43.65% water were weighed and mixed. The mixture was then ball-milled using a Jingxin JXFSTPRP-CLN mill at 2 to 4°C and 60 Hz for 8 hours. 50% glycerol was then added and mixed to obtain a minoxidil and finasteride compound suspension. The average particle size of the drug particles was 227 nm, and the PDI was 0.122.

Example 16

5% minoxidil, 0.25% finasteride, 0.1% docusate sodium, 1% Soluplus, and 23.65% water were weighed and mixed. The mixture was then ball-milled using a Jingxin JXFSTPRP-CLN mill at 2 to 4°C and 60 Hz for 8 hours. 70% glycerol was then added and mixed to obtain a minoxidil and finasteride compound suspension. The average particle size of the drug particles was 247 nm, and the PDI was 0.137.

Example 17

5% minoxidil, 0.25% finasteride, 0.1% docusate sodium, 1% Soluplus, and 43.65% water were weighed and mixed, then ball-milled using a Netzsch Minicer at 20°C and 3200 rpm for 30 minutes. 50% glycerol was then added and mixed to obtain a minoxidil and finasteride compound suspension. The average particle size of the drug particles was 220 nm, and the PDI was 0.144.

Example 18

5% minoxidil, 0.25% finasteride, 0.1% docusate sodium, 0.5% Soluplus, and 44.15% water were weighed and mixed. The mixture was then ball-milled using a Jingxin JXFSTPRP-CLN at 2 to 4°C and 60 Hz for 8 hours. 50% glycerol was then added, the mixture was diluted to volume with water, and the mixture was mixed to obtain a minoxidil and finasteride compound suspension. The average particle size of the drug particles was 245 nm, and the PDI was 0.161.

Example 19

5% minoxidil, 0.25% finasteride, 0.1% docusate sodium, 0.25% Soluplus, and 44.40% water were weighed and mixed. The mixture was then ball-milled using a Jingxin JXFSTPRP-CLN at 2 to 4°C and 60 Hz for 8 hours. 50% glycerol was then added, the mixture was diluted to volume with water, and the mixture was mixed to obtain a minoxidil and finasteride compound suspension. The average particle size of the drug particles was 258 nm, and the PDI was 0.176.

Example 20

5% minoxidil, 0.25% finasteride, 0.1% docusate sodium, 0.1% Soluplus, and 44.55% water were weighed and mixed. The mixture was then ball-milled using a Jingxin JXFSTPRP-CLN at 2 to 4°C and 60 Hz for 8 hours. 50% glycerol was then added, the mixture was diluted to volume with water, and the mixture was mixed to obtain a minoxidil and finasteride compound suspension. The average particle size of the drug particles was 310 nm, and the PDI was 0.212.

Example 21

5% minoxidil, 0.1% dutasteride, 0.1% docusate sodium, 1% Soluplus, and 93.8% water were weighed and mixed by weight, and then ball-milled using a Jingxin JXFSTPRP-CLN at a temperature of 2 to 4° C. and a frequency of 60 Hz for 8 h to obtain a minoxidil and dutasteride compound suspension.

Example 22

5% minoxidil, 0.25% finasteride, 0.1% docusate sodium, 0.1% Soluplus and 44.45% water were weighed and mixed by weight, and then ball-milled using a Netzsch Minicer at a temperature of 20°C and a speed of 3200 rpm for 30 min. 50% glycerol was then added, the mixture was diluted to volume with water, and the mixture was mixed. 0.05% methyl parahydroxybenzoate was added and stirred until dissolved to obtain a minoxidil and finasteride compound suspension.

Example 23

5% minoxidil, 0.25% finasteride, 0.1% docusate sodium, 0.1% Soluplus and 44.45% water were weighed and mixed by weight, and then ball-milled using a Netsch Minicer at a temperature of 20°C and a speed of 3200 rpm for 30 min. 50% glycerol was then added, and the mixture was diluted to volume with water. The mixture was mixed, and 0.05% methyl parahydroxybenzoate and 0.05% disodium edetate were added and stirred until dissolved to obtain a minoxidil and finasteride compound suspension.

Example 24

5% minoxidil, 0.25% finasteride, 0.1% docusate sodium, 0.1% Soluplus and 44.45% water were weighed and mixed by weight, and then ball-milled using a Netsch Minicer at a temperature of 20°C and a speed of 3200 rpm for 30 min. 50% glycerol was then added, and the mixture was diluted to volume with water. The mixture was mixed, and 0.05% sodium sulfite and 0.05% disodium edetate were added and stirred until dissolved to obtain a minoxidil and finasteride compound suspension.

Test Example 1

The suspension containing minoxidil prepared in the present invention and the marketed 5% minoxidil solution were tested for in vitro crystallization during topical use.

The treated pigskin was placed on a glass slide, and the 10% suspension prepared in Example 4 and a marketed minoxidil solution were added dropwise to the outer layer of the pigskin, respectively. Then, the crystallization of the drug on the pigskin surface was observed after 2 hours and 24 hours, and the morphology and size of the drug crystals were observed using an optical microscope.

The results showed that, as can be observed from the appearance, after the addition of the commercially available 5% minoxidil solution, due to the evaporation of ethanol, clear drug crystals were observed on the pigskin surface 2 hours later. After 24 hours, a large number of crystals were precipitated and the particles grew significantly. However, after the addition of the suspension of Example 4 of the present disclosure, no drug particle crystals were precipitated, and no crystal aggregation or growth was observed after 2 or 24 hours.

Test Example 2

The stability of the minoxidil-containing suspensions of the present disclosure was studied.

The suspensions prepared in the examples of the present disclosure were placed under accelerated conditions (40°C/75% RH) and the physicochemical stability was investigated using the average particle size of the drug particles and impurities as indicators. The test results are shown in Tables 6 and 7.

Table 6

Table 7

The results show that the drug particles in the suspension of the embodiment of the present disclosure remain stable during the placement under accelerated conditions, without obvious growth, and the maximum single impurities and total impurities are at a low level before and after placement, without obvious changes, indicating that the active ingredient of the drug has no obvious degradation and has good stability.

Test Example 3

The drug absorption of the minoxidil suspension (Example 17) and the commercial minoxidil tincture (5%) in the skin and hair follicles was compared.

Test method:

1-month-old Bama miniature pig skin was pipetted with 30 μL of the test sample. Using a thin loop (1 mm thick), the sample was dripped onto the center of the skin and massaged for 3 minutes to promote sample absorption. The cell was then placed on a diffusion cell, and a 5 mm thick gasket was placed on the skin surface. The assembled pig skin and loop were then placed on top of a glass receiving cell (with a stirring bar pre-placed at the bottom). The lid was then secured with a stainless steel horseshoe clamp and the knob was tightened to its full position, pressing the lid against the gasket. A syringe was used to fill the sampling tube with normal saline to the mark, and the tube was sealed with parafilm. The Franz diffusion cell was placed in a transdermal diffusion tester water bath (bath temperature 32°C, stirring speed 600 rpm). After 17 hours, the sample was removed from the diffusion cell and analyzed for drug content in different skin tissues.

(1) Stratum corneum: Wipe the surface of the pigskin (with sample) with a dry cotton swab, then wipe it with a cotton swab soaked in extractant (80% methanol in water), and then wipe the pigskin again with a dry cotton swab. After the cotton swab treatment, peel the pigskin 15 times with tape. Place the peeled tape in a 20ml sample vial. Add 10ml of extractant to each vial, sonicate for 30 minutes, and filter through a nylon filter into a sample vial. Analyze the API content by HPLC.

(2) Follicles: Place the tape-treated pigskin on a glass slide with glue, flatten and adhere tightly. After the glue polymerizes for 5 minutes, remove the pigskin. Hairs may stick to the glass slide. Use a spatula to scrape off the glue and hairs. Place the sample in a 20 ml sample bottle. Repeat the above steps twice. Add 5 ml of extractant to each sample, sonicate for 30 minutes, filter through a nylon filter into a sample vial, and determine the API content by HPLC.

(3) The remaining pigskin (epithelial and dermal layers) was minced with scissors and placed in 20 ml sample bottles. 5 ml of extractant was added to each sample, and the mixture was ultrasonicated for 30 min. The sample was filtered through a nylon filter into a sample vial and the API content was determined by HPLC.

The results are shown in Table 8:

Table 8

The results show:

The drug absorption ratio of the minoxidil suspension group in the hair follicles and epithelial dermis was better than that of the minoxidil tincture group, indicating that the minoxidil suspension can more effectively deliver the drug to the diseased site of the hair follicles.

Test Example 4

The therapeutic effects of minoxidil suspension (Example 17) and commercially available minoxidil tincture (5%) on androgenic alopecia (AGA) in C57 mice were compared.

Test method:

Grouping, modeling and treatment:

The animals were randomly divided into blank group, model group, minoxidil tincture group and minoxidil suspension group.

5-6 week old mice were selected and anesthetized. The hair on the back of the mice was shaved short in an area of approximately 2 cm × 3 cm using a hair shaver. Depilatory cream was then applied according to the instructions to remove residual hair. Mice whose skin color turned pink and entered the resting phase were selected for enrollment. Testosterone propionate ethanol solution (6 mg/mL) was applied to the back of the mice. The modeling drug was applied once a day, with a dose of 3 mg/mouse/day, and the testosterone propionate was evenly applied to the depilated area. The drug was administered once a day, with an interval of more than 4 hours between the daily modeling. 60 μL/mouse of purified water, positive drug, or test drug was applied to the depilated area on the back of the mouse. After administration, the mouse was gently applied and massaged for 3 minutes to promote absorption. After application, the mouse was placed in an anesthesia induction chamber for continued anesthesia to allow the drug to continue to be absorbed for 10 minutes. Purified water was used to remove residual drug on the skin surface before applying the modeling drug and treatment drug. Modeling and drug administration continued for 28 consecutive days.

Evaluation of therapeutic effect: After 28 days of administration, the changes in hair scores of each group were evaluated as shown in Table 9.

Table 9

The results are shown in Table 10.

Table 10

The results show:

After 28 days of treatment, it was observed that the hair growth in the minoxidil suspension group was significantly better than that in the minoxidil tincture group, indicating that minoxidil suspension showed a better therapeutic effect.

It will be appreciated from the foregoing that, although specific embodiments of the present disclosure have been described for illustrative purposes, various modifications or variations may be made by those skilled in the art without departing from the spirit and scope of the present disclosure. Such modifications or variations are intended to fall within the scope of the appended claims of the present disclosure.

Claims (33)

A suspension comprising minoxidil, the suspension comprising, by total weight, about 2% to about 15% minoxidil, about 0.05% to about 2% ionic stabilizer, about 0.1% to about 10% steric stabilizer, about 0% to about 80% solubilizer, and about 10% to about 97% water. The suspension of claim 1, wherein the suspension comprises about 0.01% to about 1% of an ionic stabilizer, preferably, the suspension comprises about 0.05% to about 1% of an ionic stabilizer, based on the total weight. The suspension according to claim 1 or 2, wherein the ionic stabilizer is selected from one or more of docusate sodium, SDS and sodium deoxycholate, preferably, the ionic stabilizer is docusate sodium. The suspension according to any one of claims 1 to 3, wherein the suspension comprises from about 0.01% to about 5% of a steric stabilizer, preferably from about 0.1% to about 5% of a steric stabilizer, based on the total weight of the suspension. The suspension according to any one of claims 1 to 4, wherein the steric stabilizer is selected from one or more of hydroxypropyl methylcellulose (HPMC), hydroxypropyl cellulose (HPC) and polyethylene caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (Soluplus), preferably, the steric stabilizer is polyethylene caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (Soluplus). The suspension according to any one of claims 1 to 5, wherein the steric stabilizer and the ionic stabilizer in the suspension are any one of docusate sodium/HPMC, docusate sodium/HPC, docusate sodium/Soluplus, SDS/HPMC, SDS/HPC, SDS/Soluplus, sodium deoxycholate/HPMC, sodium deoxycholate/HPC, and sodium deoxycholate/Soluplus. Preferably, the ionic stabilizer and the steric stabilizer are docusate sodium/Soluplus. The suspension according to any one of claims 1 to 6, wherein the suspension comprises from about 20% to about 80% of a solubilizer, preferably from about 30% to 70% of a solubilizer, more preferably from 40% to 60% of a solubilizer, based on the total weight. The suspension according to any one of claims 1 to 7, wherein the solubilizer is selected from one or more of glycerol, ethanol, propylene glycol, ethylene glycol, diethylene glycol monoethyl ether, propylene carbonate, PEG-200, PEG-400, and PEG-600, preferably, the solubilizer is glycerol. The suspension according to any one of claims 1 to 8, wherein the suspension comprises from about 2 to about 10% minoxidil, preferably from about 2% to 5% minoxidil, based on the total weight. The suspension according to any one of claims 1 to 9, wherein the suspension further comprises one or more other pharmaceutically active ingredients. The suspension of claim 10, wherein the other active pharmaceutical ingredients are selected from one or more of finasteride and dutasteride. The suspension according to claim 10 or 11, characterized in that the suspension is a compound suspension of minoxidil and finasteride. The suspension of claim 12, wherein the compound suspension comprises about 0.01% to about 0.5% finasteride by total weight. The suspension according to any one of claims 1 to 13, comprising from about 10% to about 95% water, preferably from about 10% to about 90% water, more preferably from about 10% to 80% water, based on the total weight of the suspension. The suspension according to any one of claims 1 to 14, further comprising one or more of an antioxidant and a preservative. The suspension of claim 15, wherein the antioxidant is selected from one or more of sodium sulfite and disodium edetate, and the preservative is selected from methyl parahydroxybenzoate. The suspension according to any one of claims 1 to 16, wherein the average particle size of the minoxidil particles in the suspension is about ≤1 μm, and the PDI is about <0.3. Preferably, the average particle size of the minoxidil particles in the suspension is about ≤0.5 μm, and the PDI is about <0.2. The suspension according to any one of claims 1 to 17, wherein the _D90 particle size of the minoxidil particles in the suspension is about ≤1 μm and the PDI is about <0.3, preferably, the _D90 particle size of the minoxidil particles in the suspension is about ≤0.5 μm and the PDI is about <0.2. The suspension according to any one of claims 1 to 18, wherein the _D50 particle size of the minoxidil particles in the suspension is about ≤1 μm and the PDI is about <0.3, preferably, the _D50 particle size of the minoxidil particles in the suspension is about ≤0.5 μm and the PDI is about <0.2. A method for preparing a suspension containing minoxidil according to any one of claims 1 to 19, comprising: Mix the prescribed amount of minoxidil, steric stabilizer, ionic stabilizer and water, and After the particles are micronized, a suspension containing minoxidil is obtained; Preferably, the particle miniaturization process is selected from any one of grinding, high-pressure homogenization, impact pulverization and airflow pulverization. More preferably, the particle miniaturization process is a ball milling method. The method of claim 20, wherein the grinding temperature in the ball milling method is about 0 to about 20°C, preferably about 0 to about 10°C, for example about 2 to about 8°C, about 2 to about 6°C or about 2 to about 4°C. The method according to claim 20 or 21, wherein the particles are miniaturized to obtain a suspension containing minoxidil with water as the dispersion medium. The method according to any one of claims 20 to 22, further comprising mixing a prescribed amount of a solubilizer with the suspension to obtain a suspension containing minoxidil with water and the solubilizer as a dispersion medium. Use of a suspension comprising minoxidil according to any one of claims 1 to 19 in the preparation of a medicament for treating hair loss. The use according to claim 24, wherein the hair loss is pathological hair loss, preferably, at least one selected from androgenic alopecia, alopecia areata, anagen effluvium, self-induced alopecia, telogen effluvium and scarring alopecia, psychogenic alopecia, endocrine disorder alopecia, nutritional alopecia, and chemical alopecia. The use according to claim 24 or 25, wherein the hair loss is androgenic alopecia; preferably androgenic alopecia in young and middle-aged men. A method for treating hair loss, comprising administering to an individual in need thereof a therapeutically effective amount of a suspension comprising minoxidil according to any one of claims 1 to 19. The method of claim 27, wherein the hair loss is pathological hair loss, preferably, at least one selected from androgenic alopecia, alopecia areata, anagen effluvium, autoinduced alopecia, telogen effluvium and scarring alopecia, psychogenic alopecia, endocrine disorder alopecia, nutritional alopecia, and chemical alopecia. The method of claim 27 or 28, wherein the hair loss is androgenic alopecia; preferably androgenic alopecia in young and middle-aged men. The method of any one of claims 27 to 29, wherein the method comprises administering to the subject from about 40 mg to about 100 mg of minoxidil per day. The method of any one of claims 27 to 30, wherein the method comprises topically applying the suspension comprising minoxidil to the subject once or twice daily. The method of any one of claims 27 to 31, further comprising administering an additional drug to the individual. The method of claim 32, wherein the other drug is selected from one or more of finasteride, dutasteride, spironolactone, ketoconazole, furitan, clacodone, bicalutamide, botulinum toxin type A and autologous platelet-rich plasma, preferably, the other drug is selected from finasteride or dutasteride.