Minoxidil adjuvant therapy

Abstract

This application discloses compositions and methods for inducing (upregulating) the expression and / or activity of sulfotransferase in hair follicles, such as in the scalp. An increase in sulfotransferase is beneficial for metabolizing prodrugs that require sulfonation for activation, for example, minoxidil sulfate is the active metabolite of minoxidil. Methods of combining the compositions described herein with topical minoxidil to improve minoxidil treatment of male pattern baldness are described. Further methods and compositions include the use of retinoid X receptor agonists, retinoic acid receptor agonists, and nuclear receptor agonists in RXR-NR heterodimers. Further methods and compositions include the use of topical solutions containing an alkalizing agent or an alkalizing agent and a penetration enhancer to upregulate the sulfonation ability of hairy skin, hair follicles, and / or keratinocyte cells. Also described are compositions and methods for increasing or decreasing the growth rate of hair follicles by changing the intracellular pH. Further described is a method for producing a stable liposome-containing solution.

Description

Technical Field

[0001] (Cross - Reference to Related Applications) This application claims the benefit of priority based on U.S. Patent Application No. 17 / 806,363, filed on June 10, 2022, the content of which is hereby incorporated by reference in its entirety as part of this specification.

[0002] (Field of the Invention) The present invention relates to methods and compositions for inducing the expression of sulfotransferase in hair follicles. Topical compositions are described that contain agents that bind to transcription factors (e.g., PDX and CAR) that mediate the foreign body response in cells. Upregulation of sulfotransferase is beneficial for activating certain prodrugs that require sulfonation for activation. One such drug is minoxidil, which is used in the treatment of male pattern hair loss. The present invention relates to a method for treating, alleviating, or preventing alopecia and other hair loss disorders by applying a sulfotransferase - inducing composition to the scalp prior to treatment with minoxidil. Further embodiments relate to compositions and kits for diagnosing and controlling hair follicle stem cell differentiation. Methods and compositions are described for changing the intracellular pH of hair follicle stem cells and thereby controlling hair follicle stem cell differentiation. In some examples, an increase in the intracellular pH of hair follicle stem cells induces and / or increases the enzyme activity of sulfotransferase in hair follicle cells. Induction of sulfotransferase in hair follicles increases the sulfonation ability of minoxidil, and thus increases the response levels to oral and topical minoxidil in the treatment of alopecia.

Background Art

[0003] In 1988, the US FDA approved 2% topical minoxidil solution as an OTC drug for the treatment of androgenetic alopecia (AGA). Since the FDA approval, minoxidil has become the mainstream treatment for AGA. However, the effectiveness of minoxidil in the general population is low, with only 39% of patients responding to the drug (see Olsen EA, Whiting D, Bergfeld W, Miller J, Hordinsky M, Wanser R, et al. A multicenter, randomized, placebo-controlled, double-blind clinical trial of a novel formulation of 5% minoxidil topical foam versus placebo in the treatment of androgenetic alopecia in men. J Am Acad Dermatol. 2007 57(5):767-74). In the pivotal trial submitted to the US FDA to support the effectiveness of 5% topical minoxidil foam, no subjects showed a large improvement, but moderate improvement was seen in 8% of the subjects and slight improvement was seen in 31% of the subjects (see US FDA Application 21-812 Medical Review).

[0004] Minoxidil is a prodrug that is converted to its active form, minoxidil sulfate, by sulfotransferase present in the outer root sheath (ORS) of hair follicles (see Buhl AE, Waldon DJ, Baker CA, Johnson GA Minoxidil sulfate is the active metabolite that stimulates hair follicles. J Invest Dermatol. 1990 Nov; 95(5):553-7). The activity of sulfotransferase in the ORS has been shown to determine the clinical response to minoxidil (see Goren A, Castano JA, McCoy J, Bermudez F, Lotti T. Novel enzymatic assay predicts minoxidil response in the treatment of androgenetic alopecia. Dermatol Ther. 2014;27(3): 171-3). Sulfotransferase is abundantly expressed in the human liver. In the human liver, sulfotransferase is part of the phase II enzyme system that reduces xenobiotic toxicity (see Jancova P, Anzenbacher P, Anzenbacherova E. Phase II drug metabolizing enzymes. Biomed Pap Med Fae Univ Palacky Olomouc Czech Repub. 2010; 154(2):103-16).

[0005] Xenobiotics are foreign chemicals (e.g., drugs) that can be present in the human body (see Croom E. Metabolism of xenobiotics of human environments. Prog Mol Biol Transl Sci 2012; 112:31-88). They are included in specific metabolic pathways that have evolved to reduce toxicity to organisms. Xenobiotic metabolism includes several pathways designed to modify chemical structures and reduce the toxicity of compounds. However, in some cases, the intermediates of xenobiotic metabolism themselves can cause toxic effects (see Bunchomtavakul C, Reddy KR Acetaminophen (APAP or N-Acetyl-p-Aminophenol) and Acute Liver Failure. Clinics in Liver Disease 2018; 22(2):325-346). Xenobiotic metabolism is divided into three stages and is organized to convert lipophilic compounds into hydrophilic conjugates that can be more easily excreted. In Phase I, lipophilic xenobiotic molecules are metabolized by enzymes such as cytochrome P450 oxidases, which introduce polar groups and provide sites for downstream conjugation reactions. Phase I reactions are mainly localized in the liver. In Phase II, conjugating enzymes interact with the metabolites produced by Phase I enzymes and are removed by both passive and active transport. Conjugating enzymes include a large group of transferases with broad specificities, with glutathione S-transferase as the most important representative (see Jakoby WB, Ziegler DM. The enzymes of detoxication. J Biol Chem 1990; 265(34):20715-20718). After conjugation, any xenobiotic conjugates or their metabolites that are not removed in Phase II are further processed and removed in Phase III by transporter proteins.

[0006] Some phase I and phase II metabolic enzymes are known to be inducible by both endogenous and xenobiotic molecules. The most widely studied drug-metabolizing enzymes have been, to date, the cytochrome P450 family. Many members of the cytochrome P450 family are inducible by nuclear receptor-mediated induction. For example, cytochrome family 1 genes are upregulated by the aryl hydrocarbon receptor (AhR) after binding to an aromatic hydrocarbon ligand (see Gonzalez FJ, Liu SY, Yano M. Regulation of cytochrome P450 genes: molecular mechanisms. Pharmacogenetics 1993; 3(1): 51-57). Similarly, sulfotransferases have been shown to be regulated by endogenous hormones (see Runge-Morris M, Kocarek TA, Falany CN. Regulation of the cytosolic sulfotransferases by nuclear receptors. Drug metabolism reviews 2013; 45(1): 15-33) and xenobiotics (see Runge-Morris M, Kocarek TA Regulation of sulfotransferases by xenobiotic receptors. Curr Drug Metab 2005; 6(4): 299-307).

[0007] Minoxidil sulfate is required for both the hair growth-promoting and vasodilatory effects of minoxidil. Sulfotransferases are localized in both the skin and the liver and are important phase II xenobiotic-metabolizing enzymes for many phenolic molecules, including minoxidil (see Nimmagadda D, Cherala G, Ghatta S. Cytosolic sulfotransferases. Indian J Exp Biol 2006; 44(3):171-182).

[0008] Xenobiotic-metabolizing enzymes are important for the metabolism, elimination, or detoxification of xenobiotics. Various nuclear receptors, including the aryl hydrocarbon receptor (AhR) and the constitutive androstane receptor (CAR), regulate the gene expression of xenobiotic-metabolizing enzymes (see Xu, C., Li, C.Y., Kong, AN., 2005. Induction of phase I, II and III drug metabolism / transport by xenobiotics. Arch. Pharm. Res. 28, 249-268). Upon ligand binding, AhR forms a heterodimer with the AhR nuclear translocator (Arnt), and the AhR-Arnt complex binds to specific xenobiotic response elements and activates a series of genes, including members of the cytochrome P450 family 1 (CYP1), such as CYP1A1, CYP1A2, CYP1B1, and UDP-glucuronosyltransferases (UGT) 1A1, 1A6, 1A7, and 1A9, which are involved in the detoxification and elimination of xenobiotics, as well as certain endogenous steroids. CAR and the pregnane X receptor (PXR) are nuclear receptors that form functional heterodimers with the retinoid X receptor (RXR) (see Honkakoski, P., Sueyoshi, T., Negishi, M., 2003. Drug-activated nuclear receptors CAR and PXR. Ann. Med. 35, 172-182).CAR and PXR are involved in the xenobiotic-mediated induction of many genes, including the CYP1A, 2B, 2C, and 3A families, UGT1A1 and 1A3, and sulfotransferases (SULT) 1A1 and 2A1 (see Handschin, C., Meyer, U.A., 2003. Induction of drug metabolism: the role of nuclear receptors. Pharmacol. Rev. 55, 649-673 and Maglich, J.M., Stoltz, C.M., Goodwin, B., Hawkins-Brown, D., Moore, J.T., Kliewer, S.A., 2002. Nuclear pregnane x receptor and constitutive androstane receptor regulate overlapping but distinct sets of genes involved in xenobiotic detoxification. Mol. Pharmacol. 62, 638-646).In addition, 3'-phosphoadenosine-5'-phosphosulfate (PAPS) synthase (PAPSS), which catalyzes the biosynthesis of PAPS and functions as a universal sulfonate donor compound for all sulfotransferase reactions, is regulated by PXR and CAR (see Owen BM, Milona A, van Mil S, Clements P, Holder J, Boudjelal M, Cairns W, Parker M, White R, Williamson C. Intestinal detoxification limits the activation of hepatic pregnane X receptor by lithocholic acid. Drug Metab Dispos. 2010 Jan; 38(1):143-9. and Alnouti Y, Klaassen CD. Regulation of sulfotransferase enzymes by prototypical microsomal enzyme inducers in mice. J Pharmacol Exp Ther. 2008 Feb; 324(2):612-21).

[0009] Many compounds have been reported to bind to nuclear factors and induce or suppress the expression of xenobiotic-metabolizing enzymes. For a comprehensive list, see A. Parkinson, B.W. Ogilvie, D.B. Buckley, F. Kazmi, M. Czerwinski, 0. Parkinson, Biotransformation of xenobiotics, in: C. Klaassen (Ed.), Casarett & Doull's Toxicology, The Basic Science of Poisons, McGraw-Hill Education, New York, NY, USA, 2013, pp. 185-366.

[0010] Furthermore, changes in intracellular or extracellular pH are important regulatory mechanisms that can affect cell function in various stem cells and cause cell differentiation (see Charruyer A, Ghadially R. Influence of pH on Skin Stem Cell and Their Differentiation. Curr Probl Dermatol. 2018; 54:71-78). Cell differentiation is associated with changes in the expression of many proteins, including xenobiotic-metabolizing enzymes. In particular, an increase in sulfotransferase is a marker of keratinocyte differentiation (see Johnson GA, Baker CA, Knight KA Minoxidil sulfotransferase, a marker of human keratinocyte differentiation. J Invest Dermatol. 1992 May; 98(5):730-3).

[0011] All previous studies exploring the ability of nuclear factors to induce or suppress the expression of xenobiotic-metabolizing enzymes have been conducted in cultured hepatocytes, cultured colon cells, or mice. To determine the induction of xenobiotic-metabolizing enzymes in scalp tissue, new methods need to be adopted. One such technique is the colorimetric assay for detecting sulfotransferase in depilated hair samples, as described in U.S. Patent No. 8,691,518 (incorporated herein by reference in its entirety).

[0012] There are many methods for increasing the skin penetration of active ingredients through the stratum corneum (SC). For example, the use of chemical agents to improve penetration has been described (see Trammer H, Neubert RH. Overcoming the stratum corneum: the modulation of skin penetration. A review. Skin Pharmacol Physiol. 2006; 19(2):106-21). However, many of these agents can actively change the structure of the SC and cause irreversible damage to the SC. Another approach to the use of agents that modify the SC is the use of encapsulation technology (see Tiwari N, Osorio-Blanco ER, Sonzogni A, Esporrin-Ubieto D, Wang H, Calderon M. Nanocarriers for Skin Applications: Where Do We Stand? Angew Chem Int Ed Engl. 2022 Jan 17; 61(3):e202107960). Such technology involves surrounding the active ingredient with carrier molecules that share a similar morphology to cell membranes, interact more gently with the SC, and can be used to deliver large payloads. Such systems are highly biocompatible and offer advantages such as biodegradability and low toxicity. Many examples of such encapsulation technology have been described, for example, liposomes, micelles, nanogels, lipid nanoparticles, selenium nanoparticles, virosomes, dendrimers, and carbon nanotubes. Unfortunately, the use of encapsulation technology poses further challenges in the manufacture of stable topical formulations. Many of the encapsulation systems used are susceptible to the effects of hydrolysis, oxidation, and aggregation or disruption of the macroencapsulation structure. Therefore, there is a need for a new formulation technology that can achieve stable and practical topical formulations containing encapsulated active ingredients. Summary of the Invention

[0013] Compositions and methods for inducing (upregulating) the expression of sulfotransferase in hairy skin, hair follicles and / or keratinocyte cells, such as on the scalp, are disclosed herein. Also disclosed herein are compositions, methods and kits for controlling hair follicle stem cell differentiation. In some examples, the compositions and methods induce (upregulate) the expression and / or activity of sulfotransferase in hairy skin, hair follicles and / or keratinocyte cells. Combining the compositions described herein with topical minoxidil is a more effective treatment for male pattern baldness. For example, embodiments of the methods and compositions disclosed herein can be used to increase the metabolism of minoxidil in the hair follicles of patients suffering from a form of alopecia (which can result in an increase in bioavailable minoxidil sulfate). Also described are examples of topical compositions, shampoos used to increase sulfotransferase in the scalp. Further described is a method of making a stable topical formulation containing an encapsulated active ingredient. In other examples, the compositions and methods change the hair follicle stem cell pH, thereby delaying hair growth. This is beneficial for delaying normal hair growth and can reduce the frequency of shaving.

Brief Description of the Drawings

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Mode for Carrying Out the Invention

[0021] Androgenetic alopecia (AGA) is a common skin disease that affects approximately 50% of the population by the age of 50. Currently, the only drug approved by the US Food and Drug Administration (FDA) for the treatment of AGA in both men and women is topical minoxidil. Clinical trials have demonstrated that approximately 30 - 40% of patients experience hair regrowth after 16 weeks of treatment with 5% minoxidil.

[0022] The exact mechanism of action of minoxidil in AGA treatment is not fully understood, but studies have demonstrated that minoxidil sulfate is the active compound that stimulates hair follicles. Minoxidil is converted to active minoxidil sulfate by endogenous sulfotransferase enzymes that utilize 3'-phosphoadenosine-5'-phosphosulfate (PAPS) within the outer root sheath of hair follicles. PAPS is generated intracellularly using 3'-phosphoadenosine-5'-phosphosulfate synthase (PAPSS). Some studies have reported a correlation between sulfotransferase activity in plucked hair follicles and minoxidil response in AGA patients. Theoretically, an increase in scalp sulfotransferase or PAPS may enhance the likelihood that a subject will respond to topical minoxidil (thereby increasing the effectiveness of topical minoxidil); however, this has not been demonstrated in clinical trials. Also, in the medical field, induction of a deficient enzyme often does not result in a clinical benefit. For example, the prodrug acyclovir, used in the treatment of HSV, is activated by the human thymidine kinase enzyme; however, induction of the thymidine kinase enzyme in vitro activates acyclovir, but in human trials, induction of the thymidine kinase enzyme does not convert non-responders to responders to acyclovir. As described herein, minoxidil compositions can be used to treat multiple forms of alopecia. Thus, by enhancing the effectiveness of minoxidil (which may include converting male pattern baldness patients who are non-responders to minoxidil to responders), hair growth (including hair diameter) of a subject can be improved using topical minoxidil. Also, the methods and compositions disclosed herein for enhancing the effectiveness of minoxidil for the treatment of multiple forms of alopecia can promote hair growth of a subject using topical minoxidil.

[0023] Biological sulfation is the conversion of highly stable oxyanion sulfate esters to 3'-phosphoadenosine-5'-phosphosulfate (PAPS), a high-energy sulfate donor. The sulfation of various biomolecules depends on the availability of the precursor PAPS, which is rate-limiting. In mammals, PAPS is synthesized in two steps by a bifunctional enzyme called PAPS synthetase (PAPSS). The synthesis of PAPS from inorganic sulfate and ATP is catalyzed by PAPSS. Natural inorganic sulfur sources are extensive and include cysteine, 1-cysteine, hydrogen sulfide, elemental sulfur, sulfite, thiosulfate, and various polythionates (e.g., tetrathionate).

[0024] In one embodiment, the present invention relates to upregulating the sulfonation ability of hairy skin by applying a topical solution containing an inorganic sulfur source to increase the concentration of PAPS. Examples of inorganic sulfur sources include, but are not limited to, cysteine, 1-cysteine, hydrogen sulfide, elemental sulfur, sulfite, thiosulfate, and various polythionates (e.g., tetrathionate). Also, sulfates such as magnesium sulfate or sodium sulfate can be used.

[0025] As used herein, the term "prevent" or "prevention" and other derivatives of such terms, when used with respect to alopecia, such as male pattern baldness, refer to reducing the likelihood of alopecia in an individual undergoing a given treatment as compared to that of a similar individual at risk for alopecia but not undergoing such treatment. Thus, the terms "prevent" and "prevention" encompass treatments that result in a less severe form of alopecia, such as male pattern baldness, than would be expected for a given individual. The effectiveness of preventing alopecia, such as male pattern baldness, can be established, for example, by a controlled trial in which a treatment (e.g., a topical treatment) is administered to a subject and a placebo is administered to another subject. Under these circumstances, if a subject treated with the topical treatment has less hair loss over time, e.g., at least less than 5%, at least less than 10%, at least less than 15%, at least less than 20%, at least less than 25%, at least less than 30%, at least less than 35%, at least less than 40%, at least less than 45%, at least less than 50% or more than that, compared to a subject receiving the placebo, the treatment is effective in preventing alopecia, such as male pattern baldness.

[0026] As used herein, the terms "treating," "treatment," or "treat" refer to a therapeutic treatment, the purpose of which is to reverse, alleviate, ameliorate, inhibit, slow down, or stop the progression or severity of a disease or condition, such as androgenetic alopecia or other forms of hair loss. The term "treat" includes reducing or alleviating at least one adverse effect or symptom of a disease or condition, such as androgenetic alopecia or other forms of hair loss. Generally, a treatment is "effective" if one or more symptoms are reduced. Alternatively, a treatment is "effective" if the progression of the disease is reduced or stopped. That is, "treatment" includes not only improvement of symptoms, but also halting or at least slowing the progression or worsening of symptoms as compared to what would be expected in the absence of treatment. Beneficial or desired clinical outcomes include, but are not limited to, alleviation of one or more symptoms, reduction of the extent of the disease, stabilization of the disease state (i.e., does not worsen), delay or slowing of the progression of the disease, improvement or alleviation of the disease situation, remission (partial or complete), and / or reduction of the mortality rate. For example, a treatment is considered effective if the degree or amount of hair loss is reduced, or if the progression of hair shedding is slowed or stopped. The term "treatment" of a disease also includes reducing (including palliative treatment) the symptoms or side effects of the disease.

[0027] As used herein, the term "comprising" or "comprises" is used with respect to compositions, methods, etc., and refers to a component or method step that is present in the method or composition, but that allows the composition, method, etc. to also include unspecified elements.

[0028] The term "consisting of" refers to the compositions, methods, and their respective components described herein, and does not include elements not described in the description of the embodiments.

[0029] As used herein, the term "consisting essentially of" refers to the elements required for a given embodiment. The term allows for the presence of elements that do not substantially affect the basic and novel or functional characteristics of that embodiment.

[0030] As used herein, the term "alopecia" refers to all forms of alopecia in men and women, including but not limited to traction alopecia, androgenetic alopecia, male pattern baldness (MPB), female pattern hair loss (FPHL), alopecia areata, alopecia totalis, telogen effluvium, chemotherapy-induced alopecia, hair loss, eyebrow loss, beard loss, and thinning hair. The term allows for the presence of elements that do not substantially affect the basic and novel or functional characteristics of the embodiments thereof.

[0031] As used herein, the term "alkalinizing agent" refers to any agent that (i) directly raises intracellular pH; (ii) indirectly raises intracellular pH by activating or inhibiting various ion carriers that control cellular pH; (iii) upregulates or downregulates various ion carriers; or (iv) raises intracellular pH by changing extracellular pH. The term allows for the presence of elements that do not substantially affect the basic and novel or functional characteristics of the embodiments thereof.

[0032] As used herein, the term "acidifying agent" refers to any agent that (i) directly lowers intracellular pH; (ii) directly lowers intracellular pH by activating or inhibiting various ion carriers that control cellular pH; (iii) upregulates or downregulates various ion carriers; or (iv) lowers intracellular pH by changing extracellular pH. The term allows for the presence of elements that do not substantially affect the basic and novel or functional characteristics of the embodiments thereof.

[0033] As used herein, the term "ion carrier" refers to all cellular ion carriers that raise or lower intracellular pH. In the context of the present application, an ion carrier may be referred to as a proton pump. The term allows for the presence of elements that do not substantially affect the basic and novel or functional characteristics of the embodiments thereof.

[0034] The singular terms "a," "an," and "the" include plural referents unless the context clearly indicates otherwise. Similarly, unless the context clearly indicates otherwise, the term "or" is intended to include "and." Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present disclosure, suitable methods and materials are described below. The abbreviation "e.g." is derived from the Latin "exempli gratia" and is used herein to indicate non-limiting examples. Thus, the abbreviation "e.g." is synonymous with the term "for example."

[0035] Various aspects of the technology are described as measuring the sulfonation ability of hairy skin, hair follicles, and / or keratinocyte cells. An increase in the sulfonation ability of hairy skin, hair follicles, and / or keratinocyte cells can be interpreted as an increase in the concentration of an enzyme or substrate required for this reaction, i.e., an increase in the substrate leads to an increase in the reaction product (Le Chatelier's principle). For example, an increase in available sulfotransferase increases the sulfonation ability of hairy skin, hair follicles, and / or keratinocyte cells. Similarly, an increase in available PAPS or PAPSS (which generates PAPS) increases the sulfonation ability of hairy skin, hair follicles, and / or keratinocyte cells.

[0036] The measurement of the sulfonation ability of the hairy skin, hair follicles and / or keratinocyte cells or hair follicles can be carried out, if necessary, by a colorimetric assay adapted to that purpose. Examples are described, for example, in Goren A, Shapiro J, Roberts J, McCoy J, Desai N, Zarrab Z, Pietrzak A, Lotti T. Clinical utility and validity of minoxidil response testing in androgenetic alopecia. Dermatol Ther 2015: 28(1): 13-16, ("the Minoxidil Response Test") (incorporated herein by reference in its entirety). Briefly, anagen hairs that have been plucked are collected from the scalp and the intact hair bulbs are visually inspected. Suitable hairs are trimmed to a length of about 1 cm and first immersed from the hair bulbs into 100 μL of an assay solution containing 50 mM phosphate buffer (pH 8), 5 mM 4-nitrophenyl potassium sulfate, 20 μM adenosine 3',5'-diphosphate, 100 μM minoxidil and 5 mM MgCl2. The hairs are reacted with the solution at room temperature for 24 hours. After incubation, the hairs are removed and the optical absorbance of the solution at 405 nm is determined using a spectrophotometer (e.g., Shimadzu UV-1700, Kyoto, Japan) with a single scan and a 1 cm optical path length.

[0037] An increase in intracellular pH is required for the differentiation of adult epithelial cells and embryonic stem cells. Various aspects of the present invention describe an increase or decrease in the rate, differentiation rate and / or proliferation of hair follicle stem cells (HFSCs). An increase in intracellular pH (pHi) can be used to increase the rate of differentiation and / or proliferation of hair follicle stem cells (HFSCs). Similarly, a decrease in intracellular pH (pHi) can be used to decrease the rate of differentiation and / or proliferation of hair follicle stem cells (HFSCs). In one aspect of the present invention, pHi can be changed by changing extracellular pH (pHe).

[0038] Applicants disclose herein methods for treating or preventing various forms of alopecia, such as female pattern alopecia or male pattern alopecia. The methods include the use of a topical composition applied to the scalp that upregulates the sulfonation ability of hair follicles. The methods further include the use of topical minoxidil applied after applying a topical composition that upregulates the sulfonation ability of hair follicles to the scalp.

[0039] Also, applicants disclose herein a method for delaying hair growth. The method includes applying an acidifying agent to the HFSC niche, followed by reducing the pHi of HFSCs.

[0040] In one embodiment, the present invention relates to upregulating the sulfonation ability of hairy skin, hair follicles, and / or keratinocyte cells by applying a topical solution containing an alkalizing agent that raises the intracellular pH of cells in the outer root sheath of hair follicles. Examples of alkalizing agents include, but are not limited to, sodium bicarbonate, sodium citrate, potassium citrate, calcium carbonate, sodium lactate, and calcium acetate, carmabarb, sodium citrate / citric acid.

[0041] In one embodiment, the present invention relates to upregulating the sulfonation ability of hairy skin, hair follicles, and / or keratinocyte cells by applying a topical solution containing an alkalizing agent that raises the extracellular pH of cells in the outer root sheath of hair follicles.

[0042] In one embodiment, the present invention relates to upregulating the sulfonation ability of hairy skin, hair follicles and / or keratinocyte cells by applying a topical solution containing one or more penetration enhancers and an alkalizing agent. Examples of penetration enhancers include, but are not limited to, alcohols, glycols (e.g., diethylene glycol and tetraethylene glycol; diethylene glycol monoethyl ether; PEG-6 caprylic / capric triglyceride, such as Accanon-CC6), fatty acids (e.g., lauric acid, myristic acid and capric acid), fatty acid esters, fatty acid ethers, cyclodextrins, occlusive agents, surfactants, dimethylaminopropionic acid derivatives, terpenes, sulfoxides, cyclic ethers, amides, and amines. Other examples of penetration enhancers include sulfoxides (e.g., dimethyl sulfoxide, DMSO, decyl methyl sulfoxide), azones (e.g., 1-dodecylazacycloheptan-2-one, laurocapram, or laurocaprum), pyrrolidones (e.g., 2-pyrrolidone, 2P, N-methylpyrrolidone, N-methyl-2-pyrrolidone, NMP, 1-propyl-3-dodecyl-2-pyrrolidone, 1-butyl-3-dodecyl-2-pyrrolidone), alcohols and alkanols (ethanol, or decanol), glycols (e.g., propylene glycol), surfactants (e.g., polyoxyethylene-2-oleyl ether, polyoxyethylene-2-stearyl ether, sodium dodecyl sulfate, SDS, sodium lauryl sulfate, SLS), oxazolidinones (e.g., 4-decyloxazolidin-2-one), urea, 2-(1-nonyl)-1,3-dioxolane, and terpenes. Further examples of penetration enhancers include polyester nanosponges, liposomes, phospholipids, cyclopentadecalactone, pentadecalactone, SNAC, sodium N-[8-(2-hydroxybenzoyl)amino]caprylate, CNAC, 5-CNAC, 8-(N-2-hydroxy-5-chloro-benzyl)-amino-caprylic acid, sodium caprate, glyceryltriglyceride, and peptides.In some embodiments, the penetration enhancer is present in the composition in an amount of 0.10% to 3.00% by weight; for example, 0.50% to 2.00% by weight; for example, 0.75% to 1.25% by weight; for example, 1.00% by weight; or 0.10% to 7.00% by weight; for example, 0.50% to 5.00% by weight; for example, 0.75% to 4.0% by weight; for example, 2.6% by weight.

[0043] In one embodiment, the present invention relates to upregulating the sulfonation ability of hairy skin, hair follicles and / or keratinocyte cells by applying a topical solution containing an alkalizing agent with a device designed to increase transdermal penetration. Examples of devices designed to increase transdermal penetration include microneedle arrays and iontophoresis patches.

[0044] In one embodiment, the present invention relates to upregulating the sulfonation ability of hairy skin, hair follicles and / or keratinocyte cells by increasing the intracellular pH of stem cells in the outer root sheath of the hair follicle. In one embodiment, the intracellular pH of the stem cells can be alkalized by the application of a topical proton pump agonist. In another embodiment, the intracellular pH of the stem cells can be alkalized by the application of a topical proton pump agonist.

[0045] In one embodiment, the present invention relates to the treatment of alopecia by inducing HFSC differentiation and prolonging the hair growth cycle by applying a topical solution containing an alkalizing agent that increases the extracellular pH of cells in the outer root sheath of the hair follicle.

[0046] In one embodiment, the present invention relates to the treatment of alopecia by inducing HFSC differentiation and prolonging the hair growth cycle by applying a topical solution containing an alkalizing agent together with a penetration enhancer. Examples of penetration enhancers include, but are not limited to, alcohols, glycols (e.g., diethylene glycol and tetraethylene glycol), fatty acids (e.g., lauric acid, myristic acid, and capric acid), fatty acid esters, fatty acid ethers, cyclodextrins, occlusive agents, surfactants, dimethylaminopropionic acid derivatives, terpenes, sulfoxides, cyclic ethers, amides, and amines. Other examples of penetration enhancers include sulfoxides (e.g., dimethyl sulfoxide, DMSO, decyl methyl sulfoxide), azones (e.g., 1-dodecylazacycloheptan-2-one, laurocapram, or laurocaprum), pyrrolidones (e.g., 2-pyrrolidone, 2P, N-methylpyrrolidone, N-methyl-2-pyrrolidone, NMP, 1-propyl-3-dodecyl-2-pyrrolidone, 1-butyl-3-dodecyl-2-pyrrolidone), alcohols and alkanols (ethanol, or decanol), glycols (e.g., propylene glycol), surfactants (e.g., polyoxyethylene-2-oleyl ether, polyoxyethylene-2-stearyl ether, sodium dodecyl sulfate, SDS, sodium lauryl sulfate, SLS), oxazolidinones (e.g., 4-decyloxazolidin-2-one), urea, 2-(1-nonyl)-1,3-dioxolane, and terpenes. Further examples of penetration enhancers include polyester nanosponges, liposomes, phospholipids, cyclopentadecalactone, pentadecalactone, SNAC, sodium N-[8-(2-hydroxybenzoyl)amino]caprylate, CNAC, 5-CNAC, 8-(N-2-hydroxy-5-chloro-benzyl)-amino-caprylic acid, sodium caprate, glyceryl triglycéride, and peptides.One preferred penetration enhancer is a polyethylene glycol derivative of a mixture of mono-, di- and tri-glycerides of caprylic acid and capric acid containing an average of 6 molecules of ethylene oxide, sold under the trade name Acconon® CC-6. Another preferred penetration enhancer comprises or consists of carbitol, diethylene glycol monoethyl ether, ethyl carbitol, ethyl carbitol, transcutol, transcutol HP, transcutol P.

[0047] In one embodiment, the present invention relates to the treatment of alopecia by inducing HFSC differentiation and prolonging the anagen phase of the hair cycle by applying a topical solution containing an alkalizing agent with a device designed to increase transdermal penetration. Examples of devices designed to increase transdermal penetration include microneedle arrays and iontophoresis patches.

[0048] In one embodiment, the present invention relates to increasing hair graft engraftment and reducing shock loss after hair surgery by applying a topical solution containing an alkalizing agent that raises the extracellular pH of cells in the outer root sheath of the hair follicle. Application of the topical solution can be performed by a nebulizer or a mist.

[0049] In one embodiment, the present invention relates to increasing hair graft engraftment and reducing shock loss after hair transplantation surgery by applying a topical solution containing an alkalizing agent together with a penetration enhancer. Examples of penetration enhancers include, but are not limited to, alcohols, glycols (e.g., diethylene glycol and tetraethylene glycol), fatty acids (e.g., lauric acid, myristic acid, and capric acid), fatty acid esters, fatty acid ethers, cyclodextrins, occlusive agents, surfactants, dimethylaminopropionic acid derivatives, terpenes, sulfoxides, cyclic ethers, amides, and amines. Other examples of penetration enhancers include sulfoxides (e.g., dimethyl sulfoxide, DMSO, decyl methyl sulfoxide), azones (e.g., 1-dodecylazacycloheptan-2-one, laurocapram, or laurocaprum), pyrrolidones (e.g., 2-pyrrolidone, 2P, N-methylpyrrolidone, N-methyl-2-pyrrolidone, NMP, 1-propyl-3-dodecyl-2-pyrrolidone, 1-butyl-3-dodecyl-2-pyrrolidone), alcohols and alkanols (ethanol, or decanol), glycols (e.g., propylene glycol), surfactants (e.g., polyoxyethylene-2-oleyl ether, polyoxyethylene-2-stearyl ether, sodium dodecyl sulfate, SDS, sodium lauryl sulfate, SLS), oxazolidinones (e.g., 4-decyloxazolidin-2-one), urea, 2-(1-nonyl)-1,3-dioxolane, and terpenes. Further examples of penetration enhancers include polyester nanosponges, liposomes, phospholipids, cyclopentadecalactone, pentadecalactone, SNAC, sodium sarcaprostate N-[8-(2-hydroxybenzoyl)amino]caprylate, CNAC, 5-CNAC, 8-(N-2-hydroxy-5-chloro-benzyl)-amino-caprylic acid, sodium caprate, glyceryltriglyceride, and peptides.

[0050] In one embodiment, the present invention relates to increasing hair graft engraftment and reducing shock loss after hair transplantation surgery by applying a topical solution containing an alkalizing agent with a device designed to increase transdermal penetration. Examples of devices designed to increase transdermal penetration include microneedle arrays and iontophoresis patches.

[0051] In one embodiment, the present invention relates to reducing hair or decreasing the hair growth rate in the hairy skin, hair follicles, and / or keratinocyte cells by applying a topical solution containing an acidifying agent that reduces the intracellular pH of cells in the outer root sheath of the hair follicle. Examples of acidifying agents include, but are not limited to, citric acid, ascorbic acid, vitamin C, lactic acid, acetic acid, and the like.

[0052] In one embodiment, the present invention relates to reducing hair or decreasing the hair growth rate in the hairy skin, hair follicles, and / or keratinocyte cells by applying a topical solution containing an acidifying agent and a penetration enhancer.

[0053] In one embodiment, the present invention relates to upregulating the sulfonation ability of the hairy skin, hair follicles, and / or keratinocyte cells by applying a topical solution containing an agonist of the AhR nuclear receptor. Examples of AhR agonists include, but are not limited to, PAH, TCDD (other PHAHs), -naphthoflavone, indigoids, tryptophan metabolites, omeprazole, and lansoprazole.

[0054] In one embodiment, the present invention relates to upregulating the sulfonation ability of hairy skin, hair follicles, and / or keratinocyte cells by applying a topical solution containing an agonist of the CAR nuclear receptor. Examples of CAR agonists include, but are not limited to, phenobarbital, phenytoin, carbamazepine, CITCO (human), TCPOBOP (mouse), clotrimazole, Yin Zhi Wuang (many PXR agonists are also CAR agonists and vice versa), and meclizine.

[0055] In one embodiment, the present invention relates to upregulating the sulfonation ability of hairy skin, hair follicles, and / or keratinocyte cells by applying a topical solution containing an agonist of the PXR nuclear receptor. Examples of PXR agonists include, but are not limited to, amprenavir, abacimib, bosentan, bile acids, carbamazepine, clindamycin, clotrimazole, cortisol, cyproterone acetate, dicloxacillin, efavirenz, etoposide, dexamethasone, genistein, griseofulvin, guggulsterone, guggiferone G, galcinoal, isogalcinoal, hyperforin (St. John's wort), indinavir, lovastatin, mifepristone, nafcillin, nelfinavir, nifedipine, omeprazole, paclitaxel, PCB, phenobarbital, phthalic acid monoester, 5-pregnan-3,20-dione, rifabutin, rifampin, ritonavir, saquinavir (saqumav1r), simvastatin, spironolactone, sulfinpyrazone, TAO, tetracycline, topotecan, transnanoclor, troglitazone, verapamil, vitamin E, vitamin K2, artemisinin, PCN, LCA, caffeic acid phenethyl ester, SR-12813, rifaximin, mevastatin, TO901317, solomonsterol A, and meclizine.

[0056] In one embodiment, the present invention relates to upregulating the sulfonation ability of hairy skin, hair follicles and / or keratinocyte cells by applying a topical solution containing an agonist of the PPARa nuclear receptor. In one embodiment, the present invention relates to upregulating the sulfonation ability of hairy skin, hair follicles and / or keratinocyte cells by applying a topical solution containing an agonist of the PPARa nuclear receptor together with an alkalizing agent or an alkalizing agent and a penetration enhancer. Examples of PPARa agonists include, but are not limited to, fibrates, WY-14,643, and perfluorodecanoic acid.

[0057] In one embodiment, the present invention relates to upregulating the sulfonation ability of hairy skin, hair follicles and / or keratinocyte cells by applying a topical solution containing an agonist of the Nrf2 nuclear receptor. In one embodiment, the present invention relates to upregulating the sulfonation ability of hairy skin, hair follicles and / or keratinocyte cells by applying a topical solution containing an agonist of the Nrf2 nuclear receptor together with an alkalizing agent or an alkalizing agent and a penetration enhancer. Examples of Nrf2 agonists include, but are not limited to, -naphthoflavone, oltipraz, phenolic antioxidants (e.g., BHA and BHT), and various glutathione depleting agents.

[0058] In one embodiment, the present invention relates to upregulating the sulfonation ability of hairy skin, hair follicles, and / or keratinocyte cells by applying a composition containing an activator of the Nrf2 (Nuclear factor erythroid 2-related factor 2) nuclear factor to hair follicle cells and / or keratinocyte cells. Examples of Nrf2 activators include sulforaphane, resveratrol, curcumin, quercetin, epigallocatechin-3-gallate, diallyl sulfide, naringenin, pterostilbene, phenethyl caffeate, phycetin, lithospermate B, ferulic acid, zerumbone, carnosol, caffeic acid phenethyl ester, ellagic acid, eugenol, kempferol, β-naphthoflavone, orciprenaline, bardoxolone methyl, RTA 408, CDDO-Im, bardoxolone, danshensu, CDDO-EA, mangiferin, acetylcysteine (also known as N-acetylcysteine (NAC)), butylated hydroxytoluene, BHA (butylated hydroxyanisole), BHT (butylated hydroxytoluene), phenolic antioxidants (e.g., BHA and BHT), and various glutathione depleting agents, but are not limited thereto.

[0059] In one embodiment, the present invention relates to upregulating the sulfonation ability of hairy skin, hair follicles, and / or keratinocyte cells by applying a composition containing an inducer of the Nrf2 nuclear factor (encoding the NFE2L2 gene), i.e., an agent that increases the transcription of NFE2L2, to hair follicle cells and / or keratinocyte cells. Examples of the inducer are 4-hydroxyphenylacetic acid and acetylation by p300 / CBP.

[0060] In one embodiment, the present invention relates to upregulating the sulfonation ability of hairy skin, hair follicles, and / or keratinocyte cells by applying a composition comprising an agent that dissociates Nrf2 from Keap1 (Kelch-like ECH-associated protein 1) in hair follicle cells and / or keratinocyte cells. The agent can be selected to dissociate Nrf2 from Keap1 by alkylation of Keap1 or other processes. The repressor protein Keap1 binds to Nrf2 and promotes its degradation via the ubiquitin proteasome pathway. The binding of Keap1 and the subsequent promotion of ubiquitination are the main regulatory mechanisms of Nrf2-regulated genes. An example of such an agent is 4-octyl itaconate.

[0061] In one embodiment, the present invention relates to upregulating the sulfonation ability of hairy skin, hair follicles, and / or keratinocyte cells by applying a composition comprising a direct or indirect inhibitor of Keap1 (either a protein inhibitor (e.g., a competitive / non-competitive inhibitor of Nrf2 binding) or an agent that reduces the transcriptional expression of Keap1 mRNA) in hair follicle cells and / or keratinocyte cells. Examples of direct inhibitors are mir-200a, RTA 408, and LH601A.

[0062] In one embodiment, the present invention relates to upregulating the sulfonation ability of hairy skin, hair follicles, and / or keratinocyte cells by applying a composition comprising an agent that downregulates the expression of Keap1 (Keap1 gene) in hair follicle cells and / or keratinocyte cells.

[0063] In one embodiment, the present invention relates to upregulating the sulfonation ability of hairy skin, hair follicles and / or keratinocyte cells by applying a composition comprising an inducer of p300 / CBP activity or an agent that increases the activity of p300 / CBP to hair follicle cells and / or keratinocyte cells. Examples of such agents are agents that raise intracellular pH. This can include raising the intracellular pH to an alkaline pH range of 7.4 to 11.0.

[0064] In one embodiment, the present invention relates to upregulating the sulfonation ability of hairy skin, hair follicles and / or keratinocyte cells by applying a composition comprising an agent that increases the state of oxidative stress of cells, wherein the composition is applied to hair follicle cells and / or keratinocyte cells. Examples of oxidative stress-inducing substances are agents that raise intracellular pH (alkaline pH range 7.4 to 11.0), such as alkaline solutions containing buffers, such as bicarbonates (e.g., sodium bicarbonate).

[0065] In one embodiment, the present invention relates to a kit having any of the compositions and / or therapeutic agents disclosed herein configured to upregulate the sulfonation ability of hairy skin, hair follicles and / or keratinocyte cells. The kit includes a dispenser, an implant or a pill. The composition and / or therapeutic agent is mixed with minoxidil or packaged with minoxidil in a dispenser, an implant or a pill.

[0066] In one embodiment, the present invention relates to a kit having any of the compositions and / or therapeutic agents disclosed herein configured to upregulate the sulfonation ability of hairy skin, hair follicles and / or keratinocyte cells. The kit includes a first dispenser, a first implant or a first pill. The kit includes a second dispenser, a second implant or a second pill. The composition and / or therapeutic agent is packaged in the first dispenser, the first implant or the first pill. Minoxidil is packaged in the second dispenser, the second implant or the second pill.

[0067] In one embodiment, the present invention relates to upregulating the sulfonation ability of hairy skin, hair follicles and / or keratinocyte cells by applying a topical solution containing an agonist of the GR nuclear receptor. In one embodiment, the present invention relates to upregulating the sulfonation ability of hairy skin, hair follicles and / or keratinocyte cells by applying a topical solution containing an alkalizing agent or an alkalizing agent and a penetration enhancer together with an agonist of the GR nuclear receptor. Examples of GR agonists include, but are not limited to, glucocorticoids.

[0068] In one embodiment, the present invention relates to upregulating the sulfonation ability of hairy skin, hair follicles and / or keratinocyte cells by applying a topical solution containing an agonist of the FXR nuclear receptor. In one embodiment, the present invention relates to upregulating the sulfonation ability of hairy skin, hair follicles and / or keratinocyte cells by applying a topical solution containing an alkalizing agent or an alkalizing agent and a penetration enhancer together with an agonist of the FXR nuclear receptor. Examples of FXR agonists include, but are not limited to, bile acids, GW4064, AGN29, AGN31, cafestol, fexaramine, XL335, WAY-362450, FXR-450, obeticholic acid (OCA), PX 20350, and DY 268.

[0069] In one embodiment, the present invention relates to upregulating the sulfonation ability of hairy skin, hair follicles and / or keratinocyte cells by applying a topical solution containing an agonist of the LXRa nuclear receptor. In one embodiment, the present invention relates to upregulating the sulfonation ability of hairy skin, hair follicles and / or keratinocyte cells by applying a topical solution containing an alkalizing agent or an alkalizing agent and a penetration enhancer together with an agonist of the LXRa nuclear receptor. Examples of LXRa agonists include, but are not limited to, GW3965, T0901317, paclitaxel, F3 methyl AA, and acetylpodocarpic dimer (APD).

[0070] In one embodiment, the present invention relates to upregulating the sulfonation ability of hairy skin, hair follicles, and / or keratinocyte cells by applying a topical solution containing an agonist of the VDR nuclear receptor. In one embodiment, the present invention relates to upregulating the sulfonation ability of hairy skin, hair follicles, and / or keratinocyte cells by applying a topical solution containing an agonist of the VDR nuclear receptor together with an alkalizing agent or an alkalizing agent and a penetration enhancer. Examples of VDR agonists include, but are not limited to, la,25-dihydroxyvitamin D3 and lithocholate.

[0071] In one embodiment, the present invention relates to upregulating CYP1A1, 1A2, 1B1, 2S1, UGT1A1, or UGT1A6 in hairy skin, hair follicles, and / or keratinocyte cells by applying a topical solution containing an agonist of the AhR nuclear receptor. In one embodiment, the present invention relates to upregulating the sulfonation ability of hairy skin, hair follicles, and / or keratinocyte cells by applying a topical solution containing an alkalizing agent or an alkalizing agent and a penetration enhancer together with an agent that upregulates CYP1A1, 1A2, 1B1, 2S1, UGT1A1 or UGT1A6. The topical solution contains an agonist of the AhR nuclear receptor. Examples of AhR agonists include, but are not limited to, PAH, TCDD (other PHAHs), -naphthoflavone, indigoid, tryptophan metabolites, omeprazole, and lansoprazole.

[0072] In one embodiment, the present invention relates to upregulating the concentration of CYP2A6, 2B6, 2C8, 2C9, 2Cl9, 3A4, UGT1A1, SULT1A1, ALAS, MRP2, or MRP3 in hairy skin, hair follicles, and / or keratinocyte cells by applying a topical solution containing an agonist of the CAR nuclear receptor. In one embodiment, the present invention relates to upregulating the sulfonation ability of hairy skin, hair follicles, and / or keratinocyte cells by applying a topical solution containing an alkalizing agent or an alkalizing agent and a penetration enhancer together with an agonist of the CAR nuclear receptor. Examples of CAR agonists include, but are not limited to, phenobarbital, phenytoin, carbamazepine, CITCO (human), TCPOBOP (mouse), clotrimazole, and Yin Zhi Wuang (many PXR agonists are also CAR agonists and vice versa).

[0073] In one embodiment, the present invention relates to upregulating the concentration of CYP2B6, 2C8, 2C9, 2Cl9, 3A4, 3A7, 7A1, SULT2A1, UGT1A1, 1A3, 1A4, PAPSS2, ALAS, MDR1, or AhR in hairy skin, hair follicles, and / or keratinocyte cells by applying a topical solution containing an agonist of the PXR nuclear receptor. In one embodiment, the present invention relates to upregulating the sulfonation ability of hairy skin, hair follicles, and / or keratinocyte cells by applying a topical solution containing an alkalizing agent or an alkalizing agent and a penetration enhancer together with an agonist of the PXR nuclear receptor. Examples of PXR agonists include, but are not limited to, amprenavir, abacimib, bosentan, bile acids, carbamazepine, clindamycin, clotrimazole, cortisol, cyproterone acetate, dicloxacillin, efavirenz, etoposide, dexamethasone, genistein, griseofulvin, guggulsterone, guggiferone G, galcinoal, isogalcinoal, hyperforin (St. John's wort), indinavir, lovastatin, mifepristone, nafcillin, nelfinavir, nifedipine, omeprazole, paclitaxel, PCB, phenobarbital, phthalic acid monoester, 5-pregnan-3,20-dione, rifabutin, rifampin, ritonavir, saquinavir, simvastatin, spironolactone, sulfinpyrazone, TAO, tetracycline, topotecan, transnanoclor, troglitazone, verapamil, vitamin E, vitamin K2, artemisinin, PCN, LCA, caffeic acid, SR-12813, rifaximin, mevastatin, TO901317, solomonsterol A, and meclizine.

[0074] In one embodiment, the present invention relates to upregulating the concentration of BSEP, 1-BABP, MDR3, UGT2B4, SULT2Al, OATP8, PPARa, or SHP in hairy skin, hair follicles, and / or keratinocyte cells by applying a topical solution containing an agonist of the FXR nuclear receptor. Examples of FXR agonists include, but are not limited to, bile acids, GW4064, AGN29, and AGN31.

[0075] In one embodiment, the present invention relates to upregulating the sulfonation ability of hairy skin, hair follicles, and / or keratinocyte cells by applying a topical solution containing an alkalizing agent or an alkalizing agent and a penetration enhancer together with an agonist of the RXR nuclear receptor. Examples of RXR agonists include, but are not limited to, 9-cis-retinoic acid, all-trans-retinoic acid, ATRA, retinal (or retinol or retinaldehyde), retinol A, (E)-5,8,11,14,17,20-docosahexaenoic acid, lithocholic acid, phytic acid, 9cUAB30, AGN194204, CD3254L, Gl00268, LG101305, methoprene acid, PA024, SR11217, SR11237 (BMS649), DEC1, DR511I, PRIC295, bexarotene, CD3254, docosahexaenoic acid, flurobexarotene, LG 100268, LG 100754, isotretinoin, etc.

[0076] In one embodiment, the present invention relates to upregulating the sulfonation ability of hairy skin, hair follicles and / or keratinocyte cells by applying a topical solution comprising an alkalizing agent or an alkalizing agent and a penetration enhancer together with an agonist of the RAR nuclear receptor. Examples of RAR agonists include, but are not limited to, all-trans-retinoic acid, ATRA, retinal (or retinol or retinaldehyde), retinol A, 9-cis-retinoic acid, all-trans-5,6-epoxyretinoic acid, DR5l11, isotretinoin, AC 261066, AC 55649, adapalene, AM 580, AM 80, BMS 753, BMS 961, BMS 453, CD 1530, CD 2314, CD 437, Ch 55, tazarotene, TTNPB, AR-7, FOXO1, SMRT, N-CoR, SMRTER, EC 19, etc.

[0077] In one embodiment, the present invention relates to upregulating the sulfonation ability of hairy skin, hair follicles and / or keratinocyte cells by applying a topical solution comprising an alkalizing agent or an alkalizing agent and a penetration enhancer together with an agonist of the FXR nuclear receptor. Examples of FXR agonists include, but are not limited to, bile acids, GW4064, AGN29, and AGN31.

[0078] In one embodiment, the present invention relates to increasing the activity of sulfotransferase by generating an embodiment of the composition disclosed herein and incorporating the composition into a solution. The method may further include adjusting the pH of the solution to be greater than 7. The method may include applying a solution containing the composition to human skin. By having a solution having an embodiment of the composition with a pH greater than 7, the activity of sulfotransferase can be increased, which may include an increase in the metabolic activity of the SULTIAI enzyme.

[0079] Nuclear receptor agonists can be administered to hair follicles or the scalp to increase the sulfonation ability of hairy skin, hair follicles, and / or keratinocyte cells, and to treat or prevent alopecia and other disorders described herein. It is particularly contemplated that nuclear receptor agonists known in the art or disclosed herein can be administered to hair follicles or the scalp in combination with an agent that delays systemic absorption of the agent passing through the dermis. In this way, alopecia or other disorders described herein can be treated, alleviated, or prevented while avoiding such systemic side effects using agents that may otherwise have undesirable systemic effects. One formulation of an agent for topical administration to avoid systemic absorption is described in detail in US Patent Application Publication No. 2009 / 0068287 (incorporated herein by reference in its entirety).

[0080] In one aspect, a nuclear receptor agonist or an alkalizing agent or a therapeutic agent such as an alkalizing agent and a penetration enhancer is applied to a skin piece such as a scalp piece containing at least one hair follicle.

[0081] In one aspect of the present invention, male pattern alopecia is diagnosed using a kit for measuring the pH of the hair follicles of a subject. In one aspect of the present invention, a minoxidil response is diagnosed using a kit for measuring the pH of the hair follicles of a subject. In another aspect, the proliferation of stem cells in the hair follicles is detected using a kit for measuring the pH of the hair follicles of a subject. In yet another embodiment, the effectiveness of a treatment for growing hair is evaluated by measuring the pH of the hair follicles of a subject at baseline using a kit for measuring the pH of the hair follicles of a subject using a treatment for growing hair for a predetermined time, and finally measuring the pH of the hair follicles of the subject after treatment use for comparison with the baseline.

[0082] In one aspect of the present invention, a kit for measuring the pH of the hair follicles of a subject is used. The kit includes a 20x stereomicroscope equipped with bromothymol blue (0.04%) and a 5MP color digital eyepiece microscope camera.

[0083] In one embodiment of the present invention, intracellular alkalization is, for example, Na + -H + exchanger (NHE), Na + -HCO3 - cotransporter (NBC), Na + -dependent Cl - -HCO3 - exchanger (NDCBE), Na + -K + -ATPase pump (NKA), and the like, but not limited thereto, by activating one or more ion channels that control cytoplasmic pH. Activation of the ion channels that bring about intracellular alkalization can be carried out by using one or more of the following agents: saxitoxin, neosaxitoxin, tetrodotoxin, oxcarbazepine, carbamazepine, quinidine, procainamide, disopyramide, lidocaine, mexiletine, tocainide, phenytoin, encainide, flecainide, moricizine, propafenone, aconitine, batrachotoxin, robustoxin, benthotoxin, sige-toxin, DDT, pyrethrin, fenvalerate, solnacid (AP301), ambroxol, bromhexine, articaine hydrochloride, articaine, benzamil, bupivacaine, camostat mesilate, carbamazepine, caliporide, 3',4'-dichlorobenzamil, disopyramide, encainide, flecainide acetate, GMQ, halofantrine, lappaconitine, levobupivacaine, lidocaine, lidocaine hydrochloride, lidocaine N-ethyl chloride, lorcainide, metrazone, mexiletine, ouabain octahydrate, PF-01247324, PF-04531083, PF-04856264, PF-05089771, PF-06305591, pilsicainide, α-pompilidotoxin, procaine, propafenone, ProTx-II, pyrethrum, quinidine, quinidine sulfate, ralfinamide, ralfinamide mesilate, rostafloxacin, safinamide, safinamide mesilate, tocainide, tolperisone, UCL2077, veratridine, zoniporide, and the like.

[0084] In one embodiment of the present invention, intracellular alkalization is, for example, Na + -H+ Exchanger (NHE), Na + -HCO3 - Co-transporter (NBC), Na + -dependent Cl - -HCO3 - Exchanger (NDCBE), Na + -K + It is achieved by upregulating one or more ion channels that control cytoplasmic pH, including but not limited to the exchanger (NHE), Na

[0085] In one embodiment of the present invention, intracellular alkalization is, for example, Cl - -HCO3 - Or an ion exchanger (AE), Ca2 +It is achieved by inhibiting one or more ion channels that control cytoplasmic pH, including but not limited to plasma membrane Ca2+-ATPase (PMCA). Inhibition of ion channels that result in intracellular alkalinization can be effected by using one or more of the following agents: cholestyramine, cholestipol, colesevelam, rifampicin, naltrexone, naloxone, sertraline, EIPA, acetazolamide, amlodipine (Norvasc), aranidipine (Sapresta), azelnidipine (Calblock), barnidipine (HypoCa), benidipine (Coniel), cilnidipine (Atelec, Cinalong, Siscard), clevidipine (Cleviprex), efonidipine (Landel), felodipine (Plendil), isradipine (DynaCirc, Prescal), lacidipine (Motens, Lacipil), lercanidipine (Zanidip), manidipine (Calslot, Madipine), nicardipine (Cardene, Carden SR), nifedipine (Procardia, Adalat), nilvadipine (Nivadil), nimodipine (Nimotop), nisoldipine (Baymycard, Sular, Syscor), nitrendipine (Cardif, Nitrepin, Baylotensin), pranidipine (Acalas), fendiline, gallopamil, verapamil (Calan, Isoptin), diltiazem (Cardizem), mibefradil, bepridil, flunarizine, fluspirilene, fendiline, gabapentinoid, gabapentin, pregabalin, ziconotide, niflumic acid, anthracene-9-carboxylic acid, and the like.

[0086] In one embodiment of the invention, intracellular alkalinization is, for example, Cl - -HCO3 - or an anion exchanger (AE), Ca 2+-By downregulating one or more ion channels that control cytoplasmic pH, including but not limited to plasma membrane Ca2+-ATPase (PMCA). Downregulation of ion channels that cause intracellular alkalinization can be achieved by using one or more of the following agents: angiotensin II, catecholamine, endothelin-1, glucocorticoid, NPY, thyroid hormone, etc.

[0087] In one embodiment of the present invention, intracellular acidification is, for example, Cl - -HCO3 - or anion exchanger (AE), Ca 2+ -By activating one or more ion channels that control cytoplasmic pH, including but not limited to plasma membrane Ca2+-ATPase (PMCA). Activation of ion channels that cause intracellular acidification can be achieved by using one or more of the following agents: Bay K8644, nifedipine, ambroxol, lubiprostone, amitiiza (Pro), 1,10-phenanthroline, or GABA-A receptor agonist (e.g., lorazepam), etc.

[0088] In one embodiment of the present invention, intracellular acidification is, for example, Cl - -HCO3 - or anion exchanger (AE), Ca 2+ -By upregulating one or more ion channels that control cytoplasmic pH, including but not limited to plasma membrane Ca2+-ATPase (PMCA). Upregulation of ion channels that cause intracellular acidification can be achieved by using one or more of the following agents: angiotensin II, catecholamine, endothelin-1, glucocorticoid, NPY, thyroid hormone, etc.

[0089] In one embodiment of the present invention, intracellular acidification is, for example, Na + -H + exchanger (NHE), Na + -HCO3 - cotransporter (NBC), Na + -dependent Cl - -HCO3 -Exchanger (NDCBE), Na + -K + -ATPase pump (NKA), and is achieved by inhibiting one or more ion channels that control cytoplasmic pH, including but not limited to these. Inhibition of ion channels that cause intracellular acidification can be achieved by using one or more of the following agents: S-(N-ethyl-N-isopropyl)amiloride, zoniporide, cariporide, KR-32568 [5-(2-methyl-5-fluorophenyl)furan-2-ylcarbonyl]guanidine, eniporide, EMD87580 [(2-methyl-4,5-di-(methylsulfonyl)-benzoyl)-guanidine], HMA [5-(N,N-hexamethylene)-amiloride], KR-33028 (4-cyano(benzo[b]thiophene-2-carbonyl)guanidine), S0859, [2-chloro-N-[[2'-[(cyanoamino)sulfonyl][1,1'-biphenyl]-4-yl]methyl]-N-[(4-methylphenyl)methyl]-benzamide, levetiracetam, hydrochlorothiazide (HCTZ), ouabain, dihydroouabain, lanatoside C, bufalin, digitoxin, digoxin, strophanthidin, ouabagenin, and the like.

[0090] In one embodiment of the present invention, intracellular acidification is, for example, Na + -H + exchanger (NHE), Na + -HCO3 - cotransporter (NBC), Na + -dependent Cl - -HCO3 - exchanger (NDCBE), Na + -K + -ATPase pump (NKA), and is achieved by downregulating one or more ion channels that control cytoplasmic pH, including but not limited to these. Downregulation of ion channels that cause intracellular acidification can be achieved by using one or more of the following agents: angiotensin II, catecholamine, endothelin-1, glucocorticoid, NPY, thyroid hormone, and the like.

[0091] In one embodiment of the present invention, intracellular alkalinization or acidification is achieved by activating endogenous pH sensors including, but not limited to, acid-sensing ion channels, pH-sensing ion channel-type receptors, pH-sensing metabotropic receptors, transient receptor potential ion channels, TRPV1, TRPC4, TRPC5, TRPP2, and purinceptors.

[0092] Formulation The therapeutic agents, particularly nuclear receptor agonists and / or alkalizing agents, described herein and used in the present method can be formulated according to the knowledge of those skilled in the art. In one embodiment, the nuclear receptor agonist and / or alkalizing agent or other inducer of sulfotransferase is formulated to provide local sustained or controlled release. As an example, in one embodiment, the inducer of sulfotransferase is encapsulated for sustained release.

[0093] The therapeutic agents, particularly nuclear receptor agonists and / or alkalizing agents, described herein and used in the present method can be formulated according to the knowledge of those skilled in the art. In one embodiment, the nuclear receptor agonist or other inducer of sulfotransferase is encapsulated to increase the water solubility of the therapeutic agent. In another embodiment, the nuclear receptor agonist or other inducer of sulfotransferase is encapsulated to reduce loss due to degradation of the therapeutic agent, for example, to reduce oxidation of the therapeutic agent.

[0094] In one embodiment, hyperforin is encapsulated to overcome its low water solubility and facile oxidative degradation.

[0095] In one embodiment of the present invention, a diagnostic test is used to determine whether a subject is likely to have upregulated sulfotransferase by a specific PXR agonist. For example, a genetic test of the PXR gene can identify whether human PXR has been made hyperforin-insensitive by mutagenesis of Leu308 to phenylalanine. Other methods are also possible.

[0096] In one embodiment of the present invention, the PXR agonist, CAR agonist, alkalizing agent and / or acidifying agent are secreted from a genetically modified organism (GMO) transplanted into human skin.

[0097] In one embodiment of the present invention, the PXR agonist, CAR agonist and / or alkalizing agent are secreted from bacterial organisms applied to human skin as probiotics.

[0098] In one embodiment of the present invention, the use of a topical composition applied to the scalp that upregulates the sulfonation ability of hair follicles is used to enhance the effectiveness of low-dose oral minoxidil. The method further includes the use of a topical composition applied to the scalp that upregulates the sulfonation ability of hair follicles, targeting the activation of minoxidil in the scalp of a subject receiving oral low-dose minoxidil. Examples of oral low-dose minoxidil include a dosage of less than 0.5 mg once a day. Other examples include 0.45 mg, 0.4 mg, 0.35 mg, 0.30 mg, 0.25 mg, 0.20 mg, 0.15 mg, 0.10 mg, 0.05 mg, 250 μM, 10 μM used once a day.

[0099] In another embodiment, the nuclear receptor agonist or other inducer of sulfotransferase or PAPS is formulated for shampoo, foam, ointment, spray, solution, gel, sustained-release capsule, oral tablet, dry shampoo, or any similar compound or delivery vehicle or means. Topical application is preferred. In one embodiment, the composition is formulated as a topical cream. In another embodiment, the composition is formulated as a hair styling product selected from the group consisting of styling gel, styling foam and hair conditioner.

[0100] In another embodiment, the composition may include an exfoliant to promote abrasion of the scalp surface. Examples of exfoliants include (1) inorganic and / or metal particles such as body-centered cubic boron nitride (borazon (registered trademark)); aluminosilicates (e.g., nepheline); zircon; mixed oxides of aluminum such as emery; zinc oxide; aluminum oxide such as alumina or corundum; titanium oxide; mica coated with titanium oxide; carbides, particularly silicon carbide (carborundum); or other metal oxides; metals, and metal alloys such as iron shot, steel shot, particularly pearlite; silicates such as glass, quartz, sand or vermiculite; calcium carbonate (e.g., volcanic sand or rose de brignol sand) or magnesium carbonate; sodium chloride; pumice; amorphous silica; diamond; ceramics, and (2) organic particles such as fruit stones, particularly apricot stones such as scrubami (registered trademark) apricot; wood cellulose such as ground bamboo stalks; coconut shells such as coconut exfoliant; polyamides, particularly nylon-6; saccharides; plastic microbeads such as polyethylene or polypropylene; ground walnuts; ground apricot seeds; ground shells, and (3) mixed particles combining organic and inorganic compounds, and particles coated with the above compounds. The exfoliant may be in the form of microbeads having a maximum dimension of less than 5 mm with an exfoliating effect.

[0101] In another embodiment, the composition may include an exfoliant to promote absorption of a nuclear receptor agonist and / or an alkalizing agent into the scalp. An example of the exfoliant is salicylic acid.

[0102] In one embodiment, a composition comprising a nuclear receptor agonist and / or an alkalizing agent can be formulated as a drug (which may include a drug with minoxidil). In one embodiment, a composition comprising a nuclear receptor agonist and / or an alkalizing agent can be formulated as a cosmetic. In one embodiment, a composition comprising a nuclear receptor agonist and / or an alkalizing agent can be formulated as a cosmetic for use before the use of minoxidil.

[0103] The amount of the therapeutic agent present in the composition can be determined by one skilled in the art using known methods. In certain embodiments, the nuclear receptor agonist and / or an alkalizing agent or other inducer of sulfotransferase or PAPS is present in the composition at a concentration of about 0.0020 - 0.0030% by weight, or about 0.0025% by weight. In another embodiment, the therapeutic agent, such as a nuclear receptor agonist and / or an alkalizing agent, is present in the composition at a concentration of about 0.0025% by weight, 0.0033% by weight, 0.005% by weight, 0.01% by weight, 0.02% by weight, 0.025% by weight, or 0.10% by weight.

[0104] In other embodiments, the therapeutic agent, such as a nuclear receptor agonist and / or an alkalizing agent, is present in a topical composition for use in the methods disclosed herein at concentrations of about 0.1 - 35% by weight, about 1.0 - 30% by weight, about 0.2 - 30% by weight, about 0.2 - 25% by weight, about 0.2 - 20% by weight, about 0.2 - 15% by weight, about 0.2 - 10% by weight, about 0.2 - 5% by weight, about 0.2 - 4% by weight, about 0.2 - 3% by weight, about 0.2 - 2% by weight, about 0.2 - 1% by weight, about 10.0 - 30% by weight, about 15.0 - 30% by weight, about 20.0 - 30% by weight, about 10 - 20% by weight, about 10 - 15% by weight, about 15 - 20% by weight, about 15 - 60% by weight, about 20 - 60% by weight, about 50 - 60% by weight, and about 45 - 55% by weight.

[0105] In one embodiment, the composition comprises a nuclear receptor agonist and / or an alkalizing agent at a concentration of about 0.025 wt%, about 0.033 wt%, about 0.05 wt%, about 0.1 wt%, about 0.2 wt%, about 0.25 wt%, about 0.30 wt%, about 0.40 wt%, about 1.0 wt%, about 1.5 wt%, about 2.0 wt%, or about 2.5 wt%.

[0106] The compositions used in the present disclosure, particularly those comprising a nuclear receptor agonist and / or an alkalizing agent, can be formulated with preservatives such as EDTA (0.1 - 0.5 wt% of the formulation) and / or sodium pyrosulfite (0.1 - 0.5 wt% of the formulation). In some embodiments, the penetration enhancer is selected from one or more of the group consisting of alcohols, glycols, fatty acids, fatty acid esters, fatty acid ethers, occlusive agents, surfactants, dimethylaminopropionic acid derivatives, terpenes, sulfoxides, cyclic ethers, amides, and amines. Other ingredients of the formulations used herein can be selected from cosmetically approved additives known in the art, including water, thickeners, and the like.

[0107] The composition can be packaged in a kit with an applicator for application to the skin. The invention also relates to a kit comprising a composition of a therapeutic agent such as a nuclear receptor agonist and an applicator, and a kit comprising a composition of a therapeutic agent such as a nuclear receptor agonist and a hairbrush or comb, particularly a brush or comb that provides a keratolytic effect on the scalp such that a light rubbing occurs after its use to enhance the penetration of the therapeutic agent into the AP muscle and / or hair follicles. In one embodiment, the therapeutic agent is provided with a metered applicator that provides a fixed volume of the composition administered per dose, for example, 1 ml of topical composition per administration.

[0108] The composition can be packaged in a kit containing a topical minoxidil formulation. For example, 2% minoxidil topical solution, 3% topical minoxidil solution, 5% topical minoxidil solution, 5% topical minoxidil foam, 10% topical minoxidil solution.

[0109] It should be understood that throughout the above ranges, and throughout this document, it is also intended to encompass single values included within these ranges. For example, for a formulation containing a specific component in the range of 1 - 50%, it is intended to disclose a proportion of 5% or 49% as well.

[0110] Therapeutic agent The methods of the present disclosure can be used in combination with nuclear receptor agonists, or other compounds that induce the induction of sulfotransferase or PAPSS. Suitable nuclear receptor agonists can be used, including but not limited to amprenavir, abaximibe, bosentan, bile acids, carbamazepine, clindamycin, clotrimazole, cortisol, cyproterone acetate, dicloxacillin, efavirenz, etoposide, dexamethasone, genistein, glycerolfulvin, guggulsterone, hyperforin (St. John's wort), indinavir, lovastatin, mifepristone, nafcillin, naringenin, nelfinavir, nifedipine, omeprazole, paclitaxel, PCB, phenobarbital, phthalic acid monoester, 5 - pregnane - 3,20 - dione, quercetin, rifabutin, rifampin, ritonavir, saquinavir, simvastatin, spironolactone, sulfinpyrazone, TAO, tetracycline, topotecan, transnanoclor, troglitazone, verapamil, vitamin E, vitamin K2, artemisinin, PCN, LCA, caffeic acid phenethyl ester, SR - 12813, rifaximin, mevastatin, TO901317, solomonsterol A, meclizine, fibrate, WY - 14,643, perfluorodecanoic acid, bile acids, GW4064, AGN29, AGN31, caffeic acid phenethyl ester, fexaramine, XL335, WAY - 362450, FXR - 450, obeticholic acid (OCA), PX 20350, and DY 268. Also, derivatives of nuclear receptor agonists including derivatives of the above - mentioned compounds can be used. In other embodiments, prodrugs that are activated to become nuclear receptor agonists can be used.

[0111] In one embodiment, the nuclear receptor agonist is hyperforin, or a pharmaceutically acceptable salt or hydrate thereof, at a concentration of 0.0025 to 40% by weight, 0.0025 to 25% by weight, or 0.005 to 22.5% by weight, or 0.0075 to 20% by weight, or 1 to 17.5% by weight, or 1.5 to 15% by weight, or 2 to 14.5% by weight, or 2.5 to 14% by weight, or 5 to 13.5% by weight, or 7.5 to 12.5% by weight, or 8 to 12% by weight, or 8.5 to 11.5% by weight, or 9 to 11% by weight, or 9.25 to 10.75% by weight, or 9.5 to 10.5% by weight, or 9.6 to 10.4% by weight, or 9.7 to 10.3% by weight, or 9.8 to 10.2% by weight, or 9.9 to 10.1% by weight, or 9.95 to 10.05% by weight, or 9.96 to 10.04% by weight, or 9.97 to 10.03% by weight, or 9.98 to 10.02% by weight, or 9.99 to 10.01% by weight, or 9.995 to 10.005% by weight, or 9.996 to 10.004% by weight, or 9.997 to 10.003% by weight, or 9.998 to 10.002% by weight, or 9.999 to 10.001% by weight in the composition.

[0112] In one embodiment, the nuclear receptor agonist is a St. John's wort extract containing hyperforin, or a pharmaceutically acceptable salt or hydrate thereof, at a concentration of 0.0025 to 40% by weight, 0.0025 to 25% by weight, or 0.005 to 22.5% by weight, or 0.0075 to 20% by weight, or 1 to 17.5% by weight, or 1.5 to 15% by weight, or 2 to 14.5% by weight, or 2.5 to 14% by weight, or 5 to 13.5% by weight, or 7.5 to 12.5% by weight, or 8 to 12% by weight, or 8.5 to 11.5% by weight, or 9 to 11% by weight, or 9.25 to 10.75% by weight, or 9.5 to 10.5% by weight, or 9.6 to 10.4% by weight, or 9.7 to 10.3% by weight, or 9.8 to 10.2% by weight, or 9.9 to 10.1% by weight, or 9.95 to 10.05% by weight, or 9.96 to 10.04% by weight, or 9.97 to 10.03% by weight, or 9.98 to 10.01% by weight, or 9.99 to 10.01% by weight in the composition.

[0113] In one embodiment, the nuclear receptor agonist is vitamin K2, or a pharmaceutically acceptable salt or hydrate thereof, at a concentration of 0.0025 to 40% by weight, 0.0025 to 25% by weight, or 0.005 to 22.5% by weight, or 0.0075 to 20% by weight, or 1 to 17.5% by weight, or 1.5 to 15% by weight, or 2 to 14.5% by weight, or 2.5 to 14% by weight, or 5 to 13.5% by weight, or 7.5 to 12.5% by weight, or 8 to 12% by weight, or 8.5 to 11.5% by weight, or 9 to 11% by weight, or 9.25 to 10.75% by weight, or 9.5 to 10.5% by weight, or 9.6 to 10.4% by weight, or 9.7 to 10.3% by weight, or 9.8 to 10.2% by weight, or 9.9 to 10.1% by weight, or 9.95 to 10.05% by weight, or 9.96 to 10.04% by weight, or 9.97 to 10.03% by weight, or 9.98 to 10.02% by weight, or 9.99 to 10.01% by weight in the composition.

[0114] In one embodiment, the nuclear receptor agonist is genistein, or a pharmaceutically acceptable salt or hydrate thereof, at a concentration in the range having a lower limit of 0.25% by weight, 0.5% by weight, 0.75% by weight, 1% by weight, 1.5% by weight, 2% by weight, 2.5% by weight, 5% by weight, 7.5% by weight, 8% by weight, 8.5% by weight, 9% by weight, 9.25% by weight, 9.5% by weight, 9.6% by weight, 9.7% by weight, 9.8% by weight, 9.9% by weight, 9.95% by weight, 9.96% by weight, 9.97% by weight, 9.98% by weight, or 9.99% by weight and an upper limit of 10.01% by weight, 10.02% by weight, 10.03% by weight, 10.04% by weight, 10.05% by weight, 10.1% by weight, 10.2% by weight, 10.3% by weight, 10.4% by weight, 10.5% by weight, 10.75% by weight, 11% by weight, 11.5% by weight, 12% by weight, 12.5% by weight, 13.5% by weight, 14% by weight, 14.5% by weight, 15% by weight, 17.5% by weight, 20% by weight, 22.5% by weight, 25% by weight, 30% by weight, 35% by weight, 40% by weight, 45% by weight, or 50% by weight in the composition (for example, ranges such as 0.25% by weight to 10.01% by weight, 0.25% by weight to 10.02% by weight, 0.5% by weight to 10.01% by weight, 0.5% by weight to 10.02% by weight, etc.).

[0115] In some embodiments, provided herein is a nuclear receptor agonist formulated with a carrier or delivery vehicle optimized for delivery of the nuclear receptor agonist to the scalp. The nuclear receptor agonist can be released using several different formulations or release methods, including sustained release, creams, ointments, sprays, capsules, or other release methods. For example, the nuclear receptor agonist can be incorporated into a shampoo for use in the shower. In other embodiments, the nuclear receptor agonist can be included in an ointment or other topical cream that can be applied to the scalp such that it can be slowly absorbed through the skin. In other embodiments, the nuclear receptor agonist can be included in a liquid spray or aerosol vehicle applied to the scalp. In other embodiments, the nuclear receptor agonist can be incorporated into a capsule or other sustained release vehicle that allows the chemical or agent to be slowly released into the dermis of the scalp. Capsules or vehicles encapsulating the nuclear receptor agonist can include, but are not limited to, liposomes, nonionic liposomes, niosomes, novasomes I, erythromycin-Zn complexes, microspheres, nanoparticles, solid lipid nanoparticles, and nanoemulsions. In some embodiments, this can include gels or foams applied to the scalp. It is particularly contemplated that the nuclear receptor agonist can be formulated into hair care products, such as shampoos, styling gels, styling foams, hair conditioners, hair serums, hair masks, and the like.

[0116] Provided herein are alkalizing agents or combinations of alkalizing agents and penetration enhancers formulated with a carrier or delivery vehicle optimized for delivery of the alkalizing agent to the scalp. The alkalizing agent can be released using several different formulations or release methods, including sustained release, creams, solutions, lotions, beauty liquids, ointments, sprays, capsules, or other release methods. For example, the alkalizing agent can be incorporated into a shampoo for use during a shower. In other embodiments, the alkalizing agent can be included in an ointment or other topical cream that can be applied to the scalp such that it can be slowly absorbed by the skin. In other embodiments, the alkalizing agent can be included in a liquid spray or aerosol vehicle applied to the scalp. In other embodiments, the alkalizing agent can be incorporated into a capsule or other sustained release vehicle that allows the chemical or agent to be slowly released into the dermis of the scalp. Capsules or vehicles encapsulating the alkalizing agent or combinations of alkalizing agents and penetration enhancers can include, but are not limited to, liposomes, nonionic liposomes, niosomes, novasomes I, erythromycin-Zn complexes, microspheres, nanoparticles, solid lipid nanoparticles, and nanoemulsions. In some embodiments, this can include gels or foams applied to the scalp. It is particularly contemplated that the alkalizing agent or combinations of alkalizing agents and penetration enhancers can be formulated into hair care products such as shampoos, styling gels, styling foams, hair conditioners, hair serums, hair masks, and the like.

[0117] In some embodiments, provided herein is an acidifying agent formulated with a penetration enhancer and a carrier or delivery vehicle optimized for delivering the acidifying agent to the scalp. The acidifying agent can be released using several different formulations or release methods, including sustained release, creams, ointments, sprays, capsules, solutions, deodorants (solid or liquid), antiperspirants (solid or liquid), emollients, shaving creams, shaving gels, lotions, or other release methods. For example, the acidifying agent can be incorporated into an antiperspirant for use under the arms. In other embodiments, the acidifying agent can be included in a moisturizing lotion or other topical cream that can be applied to the legs such that it can be slowly absorbed into the skin. In other embodiments, the acidifying agent can be included in a shaving gel that can be applied to the beard. In other embodiments, the acidifying agent can be incorporated into a capsule or other sustained release vehicle that allows a chemical or agent to be slowly released into the dermis of the skin. The capsule or vehicle encapsulating the acidifying agent or the acidifying agent and the penetration enhancer can include, but is not limited to, liposomes, nonionic liposomes, niosomes, novasomes I, erythromycin-Zn complexes, microspheres, nanoparticles, solid lipid nanoparticles, and nanoemulsions. In some embodiments, this can include a gel or foam applied to the skin. It is particularly contemplated that the acidifying agent or the acidifying agent and the penetration enhancer can be formulated into skin care products such as moisturizing lotions, deodorants, antiperspirants, emollients, shaving creams, shaving gels, and the like.

[0118] Any of the above formulations can be used daily, for example, once a day, twice a day, once every two days, or once a week. The daily use of an alkalizing agent, with or without a nuclear receptor agonist and / or a penetration enhancer, has been shown as an adjuvant therapy for minoxidil in patients with androgenetic alopecia. It is specifically contemplated that any composition (e.g., shampoo) of the above nuclear receptor agonist, alkalizing agent, and / or alkalizing agent can be used once a day by a person using minoxidil to enhance the effectiveness of minoxidil.

[0119] When the encapsulation technology is implemented with the formulations exemplified above (e.g., liposomes, micelles, nanogels, lipid nanoparticles, selenium nanoparticles, virosomes, dendrimers, and / or carbon nanotubes), the stability of the formulation needs to be optimized to prevent degradation. For example, a liposome is a vesicular structure made from one (single layer) or multiple bilayers of amphiphilic lipids. In such a system, the lipids are often in direct contact with the aqueous solution and are subject to hydrolysis (degradation of lipids by water) and oxidation (degradation of lipids by loss of electrons). Similarly, delivery systems using encapsulation technology are optimized for stratum corneum penetration depending on the size of the encapsulated structure. For example, structural instabilities such as aggregation in solution or conversion from a single-layer structure to a multi-layer structure or other liposome structures reduce the effectiveness of payload delivery through the skin.

[0120] To optimize the stability of the formulation, many measurement techniques for tracking the degradation of the encapsulated structure have been described. For example, following hydrolysis, free fatty acids are generated and can be detected by ultraviolet-visible (UV / Vis) spectroscopy. When oxidative degradation occurs in the formulation, peroxidized lipids can also be detected using UV / Vis spectroscopy. The instability of the vesicular structure can be monitored by examining the hydrodynamic radius of the liposomes using techniques such as dynamic light scattering, cryogenic transmission electron microscopy, and small-angle neutron scattering.

[0121] Formulations utilizing encapsulation technology to increase skin penetration can be optimized by adjusting pH, temperature, and particle size (extrusion). In one embodiment of the present invention, the liposome solution is stabilized by adjusting the pH to a range of 7 to 11. In another embodiment, the pH is adjusted to a range of 7.5 to 10. In yet another embodiment, the liposome solution is stabilized by adjusting the pH to a range of 8.0 to 8.7. In one embodiment, a buffer solution, such as acetate, citrate, or HEPES, is used to stabilize the pH of the liposome solution. In another embodiment, Tris buffer is used. In another embodiment, a carbonate buffer system or a phosphate buffer system is used. In one embodiment of the present invention, the liposome solution is stabilized by adjusting the pH to a range of 8.0 to 9.0 using Tris buffer.

[0122] In one embodiment of the present invention, the buffer system for extending the shelf life of the liposome solution is optimized using ultraviolet-visible (UV / Vis) spectroscopy over time. In yet another embodiment, samples of the optimized liposome solution are stored at high temperature to accelerate degradation prior to ultraviolet-visible (UV / Vis) spectroscopy over time.

[0123] In one embodiment of the present invention, the oxidative degradation of the liposome solution is prevented by the addition of an antioxidant. In one embodiment, the oxidative degradation of the liposome solution is prevented by the addition of ascorbic acid, monothioglycerol, potassium pyrosulfite, sodium bisulfite, sodium formaldehyde sulfoxylate, sodium sulfite, sodium thiosulfate, tocopherol, sodium pyrosulfite, butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), ascorbyl palmitate, or propyl gallate. In one embodiment, the oxidative degradation of the liposome solution is prevented by the addition of acai oil, alpha-lipoic acid, green tea extract, retinal, vitamin C, coenzyme Q10 (CoQ-10), isoflavone, polyphenol, curcumin, turmeric, pomegranate, rosemary extract, glutathione, selenium, or zinc. In yet another embodiment of the present invention, the composition comprises a chelating molecule such as ethylenediaminetetraacetic acid (EDTA), disodium EDTA, tetrasodium EDTA, pentasodium pentetate, sodium metasilicate and sodium phosphate derivatives, etidronic acid and its derivatives, or galactaric acid. These chelating agents can be added to scavenge free radicals in the solution and prevent the oxidation of lipids in the liposome-containing formulation.

[0124] In one embodiment of the present invention, the pH range is selected to be optimal for preventing the degradation of the liposome solution while being within the pH range that is optimal for inducing upregulation of SULT1A1. In another embodiment of the present invention, a pH range of 8.0 to 9.0 is used for both stabilizing the liposome solution and inducing the expression of SULT1A1. In one embodiment of the present invention, a stable liposome solution of encapsulated Tris buffer is used to induce the expression of SULT1A1 in the outer root sheath of the hair follicle. In another embodiment, a stable liposome solution of encapsulated Tris buffer is produced using phosphatidylcholine (Phospholipon 90G). In another embodiment, a stable liposome solution of encapsulated Tris buffer is produced using phosphatidylcholine (Phospholipon 90G) in an amount of 1 to 15% (w / w). In yet another embodiment, a stable liposome solution of encapsulated Tris buffer is produced using 2% (w / w) phosphatidylcholine (Phospholipon 90G). In one embodiment of the present invention, a liposome solution containing phosphatidylcholine (Phospholipon 90G) is protected from hydrolysis and oxidation by adding a Tris buffer in the pH range of 8.0 to 8.7. In yet another embodiment of the present invention, a liposome solution containing phosphatidylcholine (Phospholipon 90G) is stabilized using a Tris buffer at a concentration of 100 to 500 mM. In another embodiment, a Tris buffer at a concentration of 500 mM to 1 M is used. In another embodiment of the present invention, a liposome solution containing phosphatidylcholine (Phospholipon 90G) is stabilized using a Tris buffer at a concentration of 250 mM or 3% (w / w). In another embodiment, a liposome solution containing phosphatidylcholine (Phospholipon 90G) and 250 mM or 3% (w / w) Tris is used to induce the expression of SULT1A1 in the outer root sheath of the hair follicle.

[0125] In one embodiment, liposomes comprising or consisting of phosphatidylcholine (available under the trade name Phospholipon 90G) are used to encapsulate sodium bicarbonate (e.g., pH 10) or TRIS (e.g., pH 8). In some embodiments, sodium bicarbonate and / or TRIS are used, for example at pH 8, to upregulate SULT1A1 in vivo.

[0126] In some embodiments, the present disclosure provides a composition for increasing the sulfonation ability of hair follicle cells and / or keratinocyte cells, inducing sulfotransferase in hair follicles, inducing the expression of sulfotransferase, increasing sulfotransferase activity, upregulating sulfotransferase, converting non-responders to minoxidil responders, and / or improving minoxidil response, the composition comprising: (i) an agent configured to increase the sulfonation ability of hairy skin, hair follicles and / or keratinocyte cells in humans; (ii) an alkalizing agent; (ii) liposomes encapsulating at least a portion of the alkalizing agent; (iii) an antioxidant configured to prevent oxidative degradation of the liposomes; and (iv) a buffer system configured to increase skin penetration of the liposomes and / or stabilize the liposome solution; and (v) a solvent; comprising, wherein the liposomes comprise phosphatidylcholine and / or lecithin; and optionally, the alkalizing agent and the buffer system are the same and / or contain the same components, providing a composition.

[0127] In some embodiments, an agent configured to increase the sulfonation ability of hairy skin, hair follicles, and / or keratinocyte cells is an inorganic sulfur source such as cysteine, L-cysteine, hydrogen sulfide, elemental sulfur, sulfite, thiosulfate, polythionate, magnesium sulfate, sodium sulfate, or sodium metabisulfite; for example, sodium metabisulfite. In some embodiments, the alkalizing agent is a buffer system selected from pH regulators such as bicarbonate, acetate, citrate, Tris, or HEPES; for example, a TRIS / TRIS HCl buffer at pH 8-9.

[0128] In some embodiments, the buffer system is selected from carbonate such as sodium bicarbonate / sodium carbonate; acetate such as acetic acid / sodium acetate; citrate such as monosodium, disodium, or trisodium citrate; TRIS such as TRIS / TRIS HCl; or HEPES. Preferably, the buffer system provides a solution pH of 7.5-10; for example, 8.0-9.0; for example, 8.0-8.7. In some embodiments, the buffer system contains TRIS / TRIS HCl at pH 8-9.

[0129] In some embodiments, the alkalizing agent and the buffer system are the same and / or contain the same components; for example, both contain TRIS such as TRIS / TRIS HCl.

[0130] In some embodiments, the antioxidant is selected from ascorbic acid, monothioglycerol, potassium pyrosulfite, sodium bisulfite, sodium formaldehyde sulfoxylate, sodium sulfite, sodium thiosulfate, tocopherol, sodium pyrosulfite, butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), ascorbyl palmitate, propyl gallate, acai oil, alpha-lipoic acid, green tea extract, retinal, vitamin C, coenzyme Q10 (CoQ-10), isoflavones, polyphenols, curcumin, turmeric, pomegranate, rosemary extract, glutathione, selenium, zinc, chelating molecules, ethylenediaminetetraacetic acid (EDTA), disodium EDTA, tetrasodium EDTA, pentasodium pentetate, sodium metasilicate and sodium phosphate derivatives, etidronic acid and / or its derivatives, and / or galactaric acid; for example tocopherol, for example tocopherol acetate ester. In some embodiments, the composition may further comprise one or more penetration enhancers.In some embodiments, the penetration enhancer is alcohol, glycol (e.g., diethylene glycol and tetraethylene glycol), fatty acid (e.g., lauric acid, myristic acid, and capric acid), fatty acid ester, fatty acid ether, cyclodextrin, occlusive agent, surfactant, dimethylaminopropionic acid derivative, terpene, sulfoxide, cyclic ether, amide, and amine, sulfoxide (e.g., dimethyl sulfoxide, DMSO, decyl methyl sulfoxide), azone (e.g., 1-dodecylazacycloheptan-2-one, laurocapram, or laurocaprum), pyrrolidone (e.g., 2-pyrrolidone, 2P, N-methylpyrrolidone, N-methyl-2-pyrrolidone, NMP, 1-propyl-3-dodecyl-2-pyrrolidone, 1-butyl-3-dodecyl-2-pyrrolidone), alcohol and alkanol (ethanol, or decanol), glycol (e.g., propylene glycol), surfactant (e.g., polyoxyethylene-2-oleyl ether, polyoxyethylene-2-stearyl ether, sodium dodecyl sulfate, SDS, sodium lauryl sulfate, SLS), oxazolidinone (e.g., 4-decyloxazolidin-2-one), urea, 2-(1-nonyl)-1,3-dioxolane, terpene, polyester nanosponge, liposome, phospholipid, cyclopentadecalactone, pentadecalactone, SNAC, sodium N-[8-(2-hydroxybenzoyl)amino]caprylate, CNAC, 5-CNAC, 8-(N-2-hydroxy-5-chloro-benzyl)-amino-caprylic acid, sodium caprate, glyceryltriglyceride, and peptide. In some preferred embodiments, the penetration enhancer is a polyethylene glycol derivative of a mixture of mono-, di-, and tri-glycerides of capric acid and caprylic acid containing an average of 6 molecules of ethylene oxide; for example, Accanon-CC6 or consisting of them. In some preferred embodiments, the penetration enhancer comprises or consists of one or more of carbitol, diethylene glycol monoethyl ether, ethyl carbitol, ethyl carbitol, transcutol, transcutol HP, or transcutol P.

[0131] In some preferred embodiments, the penetration enhancer is a mixture of polyethylene glycol derivatives of mono-, di- and tri-glycerides of caprylic acid and capric acid containing on average 6 molecules of ethylene oxide in an amount of 0.10 wt% to 3.00 wt%; for example 0.50 wt% to 2.00 wt%; for example 0.75 wt% to 1.25 wt%; for example 1.00 wt%; for example Accanon-CC6, in combination with or consisting of a second penetration enhancer, such as diethylene glycol monoethyl ether, in an amount of 0.10 wt% to 7.00 wt%; for example 0.50 wt% to 5.00 wt%; for example 0.75 wt% to 4.0 wt%; for example 2.6 wt%.

[0132] In some embodiments, the composition may further comprise one or more chelating agents, such as ethylenediaminetetraacetic acid (EDTA), disodium EDTA, tetrasodium EDTA, pentasodium pentetate, sodium metasilicate and sodium phosphate derivatives, etidronic acid and its derivatives, or galactaric acid. In some preferred embodiments, the chelating agent is tetrasodium EDTA.

[0133] In some embodiments, the composition may further comprise one or more preservatives, such as antibacterial / antifungal agents. In some preferred embodiments, the preservative is phenoxyethanol and ethylhexylglycerin, such as EUXYL PE 9010. In another embodiment, the preservative is caprylic hydroxamic acid and 1,2-hexanediol and propanediol, such as Spectrastat PHL.

[0134] In some embodiments, the composition may further comprise one or more aromatic compounds and / or surfactants, particularly when the aromatic compound or another component described herein does not dissolve completely in the composition. Suitable surfactants include anionic, cationic, nonionic, and amphoteric surfactants. In some examples, the surfactant is a nonionic surfactant such as polyoxyethylene-2-oleyl ether, polyoxyethylene-2-stearyl ether, or polysorbate 80, or an anionic surfactant such as sodium dodecyl sulfate (SDS; sodium lauryl sulfate (SLS)).

[0135] In some embodiments, the composition may contain one or more additional solvent or lipid components to help obtain an optimal viscosity of the solution and / or to help provide an optimal lipid environment for the formation and stability of liposomes. Examples of such suitable solvents or lipid components include poly-hydroxyl compounds such as glycerol, cetyl alcohol, stearic acid, carnauba wax, hydroxyethyl cellulose, guar gum, xanthan gum, gelatin, magnesium aluminum silicate, silica, bentonite, carbomer (acrylic acid polymer), cetyl palmitate, and acryloyldimethyltaurine ammonium.

[0136] In some embodiments, the agent configured to increase the sulfonation ability of hairy skin, hair follicles, and / or keratinocyte cells is an inorganic sulfur source such as sodium pyrosulfite; the alkalizing agent and buffer system each contain TRIS / TRIS HCl; the antioxidant contains tocopherol; for example, tocopherol acetate; the solvent is water; and the liposome contains phosphatidylcholine. In some such embodiments, the composition may further contain a chelating agent such as EDTA tetrasodium; an antibacterial / antifungal agent such as EUXYL PE 9010; an aromatic compound; a surfactant such as polysorbate 80; and glycerol.

[0137] In some embodiments, the composition has the following Composition A:

Table 1

[0138] Composition A In some embodiments, the composition of the present disclosure is configured to be administered by applying the composition at a predetermined frequency and / or by administering the composition prior to the application of topical minoxidil.

[0139] In some embodiments, the composition of the present disclosure is formulated as a cosmetic.

[0140] In some embodiments, the composition of the present disclosure is formulated as any one or a combination of a sustained-release vehicle, a cream, a solution, a lotion, a beauty liquid, an ointment, a spray, an aerosol medium, a capsule, a shampoo, a gel, a foam, a cosmetic, a hair conditioner, a hair care product, a hair mask, a deodorant, an antiperspirant, a moisturizer, or a shaving cream or gel.

[0141] In some embodiments, the present disclosure provides a kit for increasing the sulfonation ability of hair follicle cells and / or keratinocyte cells, inducing sulfotransferase in hair follicles, inducing the expression of sulfotransferase, increasing sulfotransferase activity, upregulating sulfotransferase, converting non-responders to minoxidil responders, and / or improving minoxidil response, the kit comprising a composition and a dispenser, implant or pill; the composition comprising a composition according to the present disclosure, such as the composition according to Composition A above. In some such embodiments, the composition is formulated as any one or a combination of a sustained-release vehicle, a cream, a solution, a lotion, a beauty liquid, an ointment, a spray, an aerosol medium, a capsule, a shampoo, a gel, a foam, a cosmetic, a hair conditioner, a hair care product, a hair mask, a deodorant, an antiperspirant, a moisturizer, or a shaving cream or gel. In some embodiments, the kit further comprises minoxidil.

[0142] The present disclosure also relates to a method for producing a composition for increasing the sulfonation ability of hair follicle cells and / or keratinocyte cells, inducing sulfotransferase in hair follicles, inducing the expression of sulfotransferase, increasing sulfotransferase activity, upregulating sulfotransferase, converting non-responders to minoxidil responders, and / or improving minoxidil response, wherein the composition comprises: (i) an agent configured to increase the sulfonation ability of hairy skin, hair follicles and / or keratinocyte cells in humans; (ii) an alkalizing agent; (ii) liposomes encapsulating at least a portion of the alkalizing agent; (iii) an antioxidant configured to prevent oxidative degradation of the liposomes; and (iv) a buffer system configured to increase skin penetration of the liposomes and / or stabilize the liposome solution; and (v) a solvent; Optionally, a penetration enhancer; Optionally, a chelating agent; comprising, wherein the liposomes comprise phosphatidylcholine and / or lecithin; and optionally, the alkalizing agent and the buffer system are the same or contain the same components; the method comprising: a) encapsulating at least a portion of each of an agent configured to increase sulfonation ability, an alkalizing agent, an antioxidant, a penetration enhancer (if present) and a chelating agent (if present) into liposomes to form a liposome solution; and b) adding a preservative, and optionally a fragrance and optionally a surfactant to the liposome solution; comprising, wherein the liposomes comprise phosphatidylcholine and / or lecithin, providing a method.

[0143] In some embodiments, the product of the method is a composition according to the present disclosure, such as composition A above.

[0144] In a further embodiment, the present disclosure also provides a method for increasing the sulfonation ability of hair follicle cells and / or keratinocyte cells, inducing sulfotransferase in hair follicles, inducing the expression of sulfotransferase, increasing sulfotransferase activity, upregulating sulfotransferase, converting non-responders to minoxidil responders, and / or stabilizing a composition for improving minoxidil response; the method comprising encapsulating the composition in a solution comprising liposomes, nonionic liposomes, niosomes, novasomes I, erythromycin-Zn complex, microspheres, nanoparticles, solid lipid nanoparticles, nanoemulsions, micelles, nanogels, selenium nanoparticles, virosomes, dendrimers or carbon nanotubes; wherein the encapsulation increases the water solubility of the composition, decreases the water solubility of the composition, reduces loss by degradation, or promotes penetration through the stratum corneum.

[0145] In certain cases, it is understood that a component may have multiple functions. For example, a buffer system (e.g., TRIS / TRIS HCl at basic pH) can also act as an alkalizing agent and a chelating agent (e.g., EDTA), and an inorganic sulfur source (e.g., sodium metabisulfite) can also function as a preservative.

[0146] Use of RXR, RAR and other NR agonists Embodiments of the present invention may include the use of a retinoid X receptor (RXR) agonist, a retinoic acid receptor (RAR) agonist, and / or an agonist of another nuclear receptor (NR) in an RXR-NR heterodimer. For example, any one or a combination of an RXR agonist, an RAR agonist and / or an agonist of another NR in an RXR-NR heterodimer may treat or prevent hair loss (e.g., the formation of alopecia), increase or improve hair growth, induce sulfotransferase, increase the effectiveness of minoxidil, and / or convert male pattern alopecia in non-responders to minoxidil to responders. This can be achieved by using an RXR agonist, an RAR agonist and / or an agonist of another NR in an RXR-NR heterodimer according to any of the methods described herein. As a non-limiting example, embodiments may include the use of an RXR agonist, an RAR agonist and / or an RXR agonist with an agonist of another NR in an RXR-NR heterodimer to induce the expression of SULT1A1.

[0147] The retinoid X receptor (RXR) is an essential member of the steroid / thyroid hormone superfamily of nuclear receptors (NRs) that mainly functions as a transcription factor. The natural ligand of RXR was first proposed to be 9-cis-retinoic acid (9-cis-RA). However, many groups were unable to detect endogenous 9-cis-RA in cells. All-trans-retinoic acid (ATRA) has been found to be a ligand for RXR. Polyunsaturated fatty acids (PUFAs), such as docosahexaenoic acid (DHA), and the phytanic acid, a saturated metabolite of chlorophyll, have also been identified as RXR ligands.

[0148] In the nucleus, RXR functions as a transcription factor. It binds to a specific 6-base pair sequence of DNA in the promoter region of a gene. RXR functions as a dimer, either by itself (homodimer) or with another NR (heterodimer). Binding of a ligand to the NR partner defines a promoter site response element (RE) composed of two 6-base pair sequences (half-sites) separated by a distinct number of bases to which the RXR-NR heterodimer binds.

[0149] Transcriptional activation by RXR-NR can be classified into three categories: non-permissive, permissive, and conditionally permissive heterodimers of RXR and another nuclear receptor (NR).

[0150] Examples of transcriptional activation by non-permissive heterodimer partners include the thyroid hormone receptor (TR) or the vitamin D receptor (VDR). Since the non-permissive NR is dominant, binding of its agonist controls the transcription complex to initiate gene transcription from the non-permissive-ligand responsive gene transcription start site. Binding of an RXR agonist does not enhance the response induced by the NR agonist.

[0151] Examples of transcriptional activation by permissive RXR heterodimer partners include the pregnane X receptor (PXR), constitutive androstane receptor (CAR), farnesoid (bile acid) X receptor (FXR), liver (oxysterol) X receptor (LXR), and peroxisome proliferator-activated receptor (PPAR). An agonist of either partner in a heterodimer pair, e.g., RXR-PPAR, can bind to its own NR and initiate gene transcription. Binding of an agonist to the second NR in the dimer enhances the transcriptional response induced by the first NR-agonist complex, either additively or synergistically.

[0152] As an example of transcriptional activation by a conditional permissive heterodimer partner, the retinoic acid receptor (RAR) can be mentioned. The binding of an RAR agonist controls the transcriptional response and also permits the binding of an RXR agonist. Thus, the RAR-agonist complex is permissive. The RXR-agonist complex enhances the transcriptional response induced by the RAR agonist.

[0153] Therefore, a ligand of either RXR or NR can be used to initiate the transcription of a gene. Also, in the case of permissive and conditional permissive transcriptional activation, a ligand of RXR or NR can act synergistically to activate transcription.

[0154] In one embodiment of the present invention, an RXR agonist is used to induce the expression of SULT1A1. Examples of RXR agonists include, but are not limited to, 9-cis-retinoic acid, all-trans-retinoic acid, ATRA, retinal (or retinol or retinaldehyde), retinoic A, (E)-5,8,11,14,17,20-docosahexaenoic acid, lithocholic acid, phytic acid, 9cUAB30, AGN194204, CD3254L, Gl00268, LG101305, methoprene acid, PA024, SR11217, SR11237 (BMS649), DEC1, DR5III, PRIC295, bexarotene, CD3254, docosahexaenoic acid, flurobexarotene, LG 100268, LG 100754, isotretinoin, and the like.

[0155] In another embodiment of the present invention, an RAR agonist is used to induce the expression of SULT1A1. Examples of RAR agonists include, but are not limited to, all-trans-retinoic acid, ATRA, retinal (or retinol or retinaldehyde), retinol A, 9-cis-retinoic acid, all-trans-5,6-epoxy retinoic acid, DR5III, isotretinoin, AC 261066, AC 55649, adapalene, AM 580, AM 80, BMS 753, BMS 961, BMS 453, CD 1530, CD 2314, CD 437, Ch 55, tazarotene, TTNPB, AR-7, FOXO1, SMRT, N-CoR, SMRTER, EC 19, etc.

[0156] In yet another embodiment of the present invention, a compound that can be metabolized by an enzyme in the skin to become an RAR or RXR agonist is used to induce the expression of SULT1A1. Examples of compounds that can be metabolized to become agonists include, but are not limited to, retinyl propionate, retinyl palmitate or retinyl acetate.

[0157] In yet another embodiment of the present invention, an RXR agonist is used in combination with an agonist of another NR in an RXR-NR heterodimer to induce the expression of SULT1A1. Examples of other NRs include, but are not limited to, thyroid hormone receptor (TR), vitamin D receptor (VDR), pregnane X receptor (PXR), constitutive androstane receptor (CAR), farnesoid (bile acid) X receptor (FXR), liver (oxysterol) X receptor (LXR), peroxisome proliferator-activated receptor (PPAR), retinoic acid receptor (RAR), aryl hydrocarbon receptor (AhR), Nrf2, GR, etc.

[0158] In one embodiment, the present invention relates to upregulating the sulfonation ability of hairy skin, hair follicles, and / or keratinocyte cells by applying a topical solution containing a salt of minoxidil such that one ion of the salt is an alkalizing agent that raises the intracellular pH of cells in the outer root sheath of the hair follicle and the counter ion is minoxidil. Examples of alkalizing salts of minoxidil include, but are not limited to, minoxidil bicarbonate, minoxidil citrate, minoxidil carbonate, minoxidil lactate, and minoxidil acetate. In one embodiment, the salt is formulated with a penetration enhancer.

[0159] The therapeutic agents, particularly alkalizing agents, described herein and used in the methods can be formulated according to the knowledge of those skilled in the art. In one embodiment, the alkalizing agent or other inducer of sulfotransferase is encapsulated to increase the water solubility of the therapeutic agent. In one embodiment, the alkalizing agent or other inducer of sulfotransferase is encapsulated to decrease the water solubility of the therapeutic agent. In another embodiment, the alkalizing agent or other inducer of sulfotransferase is encapsulated to reduce loss due to degradation of the therapeutic agent, e.g., to reduce oxidation of the therapeutic agent. In another embodiment, the alkalizing agent or other inducer of sulfotransferase is encapsulated to promote penetration through the stratum corneum. In some examples, the alkalizing agent is incorporated into liposomes containing lecithin.

[0160] The effectiveness of a treatment for treating or preventing male pattern baldness can be determined by monitoring the hair density in a predetermined area of the subject's body, e.g., a predetermined area of the scalp. If the percentage of hair loss decreases by, for example, 10% or more after treatment, the treatment is effective for preventing male pattern baldness. Similarly, if the hair density is the same, it is effective for preventing male pattern baldness. If the hair density increases by, for example, 5% or more, e.g., 10% or more, after treatment, the treatment is considered effective for treating and / or preventing male pattern baldness.

[0161] The effectiveness of a treatment for treating or preventing male pattern hair loss can be determined by monitoring full body photographs. For example, a patient or an expert can evaluate the treatment response using the full body photographs before and after.

[0162] As described above, it is contemplated that all forms of hair loss can benefit from the techniques described herein. For example, the techniques described herein are applicable to the prevention or treatment of male pattern hair loss.

[0163] Any of the activators, inducers and / or inhibitors disclosed herein can be formulated as a medicament (e.g., a therapeutic agent) for use as an embodiment of a composition for carrying out the embodiments of the treatment disclosed herein.

[0164] Any of the compositions, activators, inducers, inhibitors and / or medicaments disclosed herein can be configured to be topically administered in the form of a shampoo, solution, foam, lotion, gel, spray or gas. In addition or alternatively, any of the compositions and / or medicaments disclosed herein can be administered orally, sublingually, by injection, as an implant, or by the use of bacteria that secrete an embodiment of the medicament.

[0165] Embodiments of the treatment disclosed herein can include administering an embodiment of the compositions, activators, inducers, inhibitors and / or medicaments disclosed herein at any frequency (e.g., once a day, twice a day, once every two days, once a week, once a month, etc.).

[0166] Any embodiment of the compositions or medicaments disclosed herein can be applied, orally administered, injected (e.g., injected as a sustained release formulation), or provided as an implant at a predetermined frequency (e.g., once or twice a day, once every 24 hours, once every 12 hours, once every 6 hours, etc.).

[0167] In one embodiment of the present invention, embodiments of a composition or therapeutic agent (e.g., any of the agents or compounds disclosed herein) that upregulates the sulfonation ability of hairy skin are delivered as a sustained-release injection or implant. Examples of the type of delivery system include, but are not limited to, microparticle-based depot formulations, nanoparticle-based depot formulations, transdermal systems, or implants.

[0168] In one embodiment of the present invention, embodiments of a composition or therapeutic agent (e.g., any of the agents or compounds disclosed herein) that upregulates the sulfonation ability of hairy skin are delivered as a microparticle-based depot formulation. The formulation may include a polymeric material (e.g., biodegradable) that enables protection of the drug load and control of drug release. Examples of polymer selection include, but are not limited to, polylactic-co-glycolic acid (PLGA), polylactic acid (PLA), and polyglycolic acid (PGA).

[0169] In one embodiment of the present invention, embodiments of a composition or therapeutic agent (e.g., any of the agents or compounds disclosed herein) that upregulates the sulfonation ability of hairy skin are delivered as a nanoparticle-based depot formulation. Nanoparticle-based depot formulations may include biocompatible and biodegradable materials, polymers made from gelatin, albumin, synthetic polymers (polylactide, polyalkylcyanoacrylate), or liposomes. The nanoparticles can be synthesized from a variety of available polymers including, but not limited to, polylactide-polyglycolide copolymer, polyacrylate, polycaprolactone, albumin, gelatin, alginic acid, collagen, chitosan, polylactide, and DL-lactic-co-glycolic acid copolymer polymers. The nanoparticles may also include silica nanoparticles, quantum dots, metal nanoparticles (e.g., gold, Cd, Se, ZnS, or iron oxide), or lanthanoid nanoparticles.

[0170] In one embodiment of the present invention, embodiments of a composition or therapeutic agent (e.g., any of the agents or compounds disclosed herein) that upregulates the sulfonation ability of hairy skin are delivered as an implant, which can be either passive or active. In one embodiment, an active drug delivery system can adjust drug release from a reservoir by controlling the diffusion rate, penetration rate, or concentration gradient. In one embodiment, a passive drug delivery system (implant) can control drug release using a pump that can be operated by many methods ranging from simple manual actuation by physical pressure to an electrochemically driven mechanism that can vary the drug delivery rate.

[0171] In one embodiment of the present invention, embodiments of a composition or therapeutic agent (e.g., any of the agents or compounds disclosed herein) that upregulates the sulfonation ability of hairy skin are delivered as a sustained-release suspension, liposome, in-situ gel-forming system, microsphere, non-aqueous solution / suspension, or implant.

[0172] In one embodiment of the present invention, embodiments of a composition or therapeutic agent (e.g., any of the agents or compounds disclosed herein) that upregulates the sulfonation ability of hairy skin are delivered as a sustained-release injection or implant once a day, once a week, once a month, or once a quarter.

[0173] In one embodiment of the present invention, embodiments of a composition or therapeutic agent (e.g., any of the agents or compounds disclosed herein) that upregulates the sulfonation ability of hairy skin are manufactured as a sustained-release agent by acylation (albumin binder), binding of carbohydrate analogs, fusion of polyamino acids, PEGylation, fusion of albumin or Fe (FcRn recycling).

[0174] In yet another embodiment of the present invention, minoxidil and embodiments of a composition or therapeutic agent (e.g., any of the agents or compounds disclosed herein) that upregulates the sulfonation ability of hairy skin are delivered together as a sustained-release injection or implant.

[0175] In yet another embodiment, embodiments of minoxidil and a composition or therapeutic agent (e.g., any of the agents or compounds disclosed herein) that upregulates the sulfonation ability of the hairy skin are delivered together as a microparticle-based depot formulation, a nanoparticle-based depot formulation, a transdermal system, or an implant.

[0176] Embodiments of the treatments disclosed herein include administration of embodiments of the compositions, activators, inducers, inhibitors, and / or agents disclosed herein to upregulate the sulfonation ability of the hairy skin, hair follicles, and / or keratinocyte cells, increase the minoxidil response, convert minoxidil non-responders to responders, and / or accelerate the minoxidil response.

[0177] One of ordinary skill in the art will understand, by the benefit of this disclosure, that any one or combination of the treatment methods disclosed herein can be used in combination with other treatment methods. Further, the treatment methods can be used in various combinations. For example, the treatment method can include administration of a first composition selected to upregulate the sulfonation ability of the hairy skin, hair follicles, and / or keratinocyte cells by a first technique (e.g., inhibiting Keap1); increase the minoxidil response; convert minoxidil non-responders to responders; and / or accelerate the minoxidil response, and subsequent administration of a second composition selected to upregulate the sulfonation ability of the hairy skin, hair follicles, and / or keratinocyte cells by a second technique (e.g., increasing the activity of p300 / CBP); increase the minoxidil response; convert minoxidil non-responders to responders; and / or accelerate the minoxidil response. By way of non-limiting example, the treatment method can include administering a composition comprising a Keap1 inhibitor for a first period (e.g., one week, one month, etc.), and then administering a composition comprising an agent for increasing the activity of p300 / CBP for a second period (e.g., one week, one month, etc.). One of ordinary skill in the art can understand that other treatment methods, periods, frequencies of administration, methods of administration, etc. can be used as variables in the combinations and permutations that make up the overall treatment method.

[0178] In the present disclosure, the terms optical density (OD) and absorbance unit (AU) are used interchangeably.

[0179] The various methods and techniques described above provide many ways to implement the present invention. It should be understood, of course, that not all of the described objectives or advantages can necessarily be achieved in accordance with any particular embodiment described herein. Thus, for example, one skilled in the art will recognize that the methods can be implemented in a manner that achieves or optimizes one advantage or group of advantages taught herein without necessarily achieving other objectives or advantages taught or suggested herein. Various alternative means are described herein. Some embodiments specifically include one, another, or several features, other embodiments specifically exclude one, another, or several features, and still other embodiments mitigate certain features by including one, another, or several advantageous features.

[0180] Furthermore, one skilled in the art will recognize the applicability of various features from different embodiments. Similarly, one skilled in the art can use various combinations of the above-described elements, features, and steps, and other known equivalents for each such element, feature, or step, to implement methods in accordance with the principles described herein. In various embodiments, some of the various elements, features, and steps are specifically included and others are specifically excluded.

[0181] Although this application is disclosed in connection with specific embodiments and examples, it will be understood by those skilled in the art that the embodiments of this application extend beyond the specifically disclosed embodiments to other alternative embodiments and / or their uses and modifications and equivalents.

[0182] The recitation of a range of values herein is merely intended to serve as a concise way of referring individually to each of the individual values within that range. Unless otherwise indicated herein, each individual value is incorporated herein as if it were individually recited herein. All of the methods described herein can be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by the context. The use of any examples or exemplary presentations provided herein with respect to particular embodiments of the application (e.g., "such as") is merely intended to better understand the application and does not impose a limitation on the scope of the application as claimed separately. No language in the specification should be construed as indicating any non-claimed element as essential to the practice of the application.

[0183] Particular embodiments of the present application are described herein. Variations of these embodiments will be apparent to those skilled in the art upon reading the foregoing description. It is contemplated that those skilled in the art can adopt such variations as needed and practice the application in ways other than those specifically described herein. Accordingly, many embodiments of the present application include all modifications and equivalents of the subject matter recited in the claims appended hereto that are permitted by applicable law. Further, unless otherwise indicated herein or otherwise clearly contradicted by the context, any combination of the above-described elements in all possible variations is included in the present application.

[0184] All patents, patent applications, publications of patent applications, and other materials such as articles, books, specifications, publications, documents, articles, etc., referred to herein are hereby incorporated by reference in their entirety for all purposes, except for those related to the prosecution history of the application, the same that are inconsistent or conflicting with the present document, or the same that may have a limiting effect on the broadest scope of the present or future claims related to the present document. By way of example, if there is a conflict or contradiction between the descriptions, definitions, and / or use of terms related to any of the incorporated materials and those related to the present document, the descriptions, definitions, and / or use of terms in the present document shall prevail.

Examples

[0185] Example 1: In Vitro Evaluation of Upregulation of Sulfotransferase

[0186] The following experiments were conducted to evaluate the upregulation of sulfotransferase in hair follicles by candidate compounds known to interact with human nuclear receptors (e.g., PXR and CAR).

[0187] Method: For each compound tested, 24 hairs were plucked from human subjects. The hairs were visually inspected to confirm the presence of hair bulbs. Two hairs were placed into 12 clean tubes containing 100 μL of Williams E medium containing 0.292 g / L L-glutamine (i.e., 2 hairs per reaction). 1 μL of DMSO without compound was added to the control sample. The hairs were incubated with the candidate compound at room temperature for 24 hours. All samples were performed in triplicate, i.e., the data described in the Results section are the average of three tested samples.

[0188] After 24 hours of incubation, the hairs were removed from the sample medium and briefly washed with clean water. The hairs were trimmed to approximately 1 cm in length and first immersed into 100 μL of assay solution containing 50 mM phosphate buffer (pH 8), 5 mM 4-nitrophenyl potassium sulfate, 20 μM adenosine 3',5'-diphosphate, 100 μM minoxidil, and 5 mM MgCl2 starting from the hair bulbs. The hairs were reacted with the solution at room temperature for 24 hours. After incubation, the hairs were removed and the optical absorbance of the solution at 405 nm was determined using a spectrophotometer with a single scan and a 1 cm optical path length.

[0189] Results: [Table 2] [Table 3]

[0190] Conclusion: All of hyperforin, genistein, and vitamin K2 induced sulfotransferase in the plucked hair follicles.

[0191] Example 2

[0192] The test was conducted on 30 human subjects (30 males) with low sulfotransferase determined by the colorimetric enzyme test described by Goren et al. Subjects were recruited based on enzyme test results with OD < 0.4. The subjects were randomly assigned to the active group and the placebo group at a ratio of 1:1. All subjects were applied with 5% topical minoxidil once a day. The active group was applied with a shampoo containing hyperforin once a day before using minoxidil. The placebo group was applied with a vehicle shampoo. At the end of one week, the average sulfotransferase activity of all subjects increased by about 3-fold (287%). The average sulfotransferase activity remained high during the 6-month follow-up period. At 4 months, the average increase in the number of hairs in the active group was 166% higher than that in the placebo. Also, 60% of the subjects in the active group responded to minoxidil compared to 0% in the placebo group. This indicates that the embodiments of the methods and compositions disclosed herein can convert male pattern baldness patients who are non-responders to minoxidil into responders.

[0193] Example 3

[0194] The test was conducted on 30 human subjects (30 women) with low sulfotransferase determined by the colorimetric enzyme test described by Goren et al. Subjects were recruited based on enzyme test results with OD < 0.4. The subjects were randomly assigned to the active group and the placebo group at a ratio of 1:1. All subjects applied 5% topical minoxidil once a day. The active group applied a shampoo containing hyperforin once a day before using minoxidil. The placebo group applied a vehicle shampoo. At the end of one week, the average sulfotransferase activity of all subjects increased by about 3-fold (279%). The average sulfotransferase activity remained high during the 6-month follow-up period. At 6 months, the average increase in hair count in the active group was 151% higher than that in the placebo. Also, 60% of the subjects in the active group responded to minoxidil compared to 0% in the placebo group. This indicates that the embodiments of the methods and compositions disclosed herein can convert patients with male pattern hair loss who are non-responders to minoxidil into responders.

[0195] Example 4

[0196] The test was conducted on 30 human subjects (30 men) with low sulfotransferase determined by the colorimetric enzyme test described by Goren et al. Subjects were recruited based on enzyme test results with OD < 0.4. The subjects were randomly assigned to the active group and the placebo group at a ratio of 1:1. All subjects applied 5% topical minoxidil once a day. The active group applied a shampoo containing St. John's wort once a day before using minoxidil. The placebo group applied a vehicle shampoo. At the end of one week, the average sulfotransferase activity of all subjects increased by about 3-fold (175%). The average sulfotransferase activity remained high during the 6-month follow-up period. At 4 months, the average increase in hair count in the active group was 123% higher than that in the placebo. Also, 60% of the subjects in the active group responded to minoxidil compared to 0% in the placebo group. This indicates that the embodiments of the methods and compositions disclosed herein can convert patients with male pattern hair loss who are non-responders to minoxidil into responders.

[0197] Example 5

[0198] The test was carried out on 30 human subjects (30 women) with low sulfotransferase determined by the colorimetric enzyme test described by Goren et al. Subjects were recruited based on enzyme test results with OD < 0.4. The subjects were randomly assigned to the active group and the placebo group at a ratio of 1:1. All subjects were applied with 5% topical minoxidil once a day. The active group was applied with a shampoo containing St. John's wort once a day before using minoxidil. The placebo group was applied with a vehicle shampoo. At the end of one week, the average sulfotransferase activity of all subjects increased by about 3-fold (302%). The average sulfotransferase activity remained high during the 6-month follow-up period. At 6 months, the average increase in hair count in the active group was 142% higher than that in the placebo. Also, 60% of the subjects in the active group responded to minoxidil compared to 0% in the placebo group. This indicates that the embodiments of the methods and compositions disclosed herein can convert patients with male pattern hair loss who are non-responders to minoxidil into responders.

[0199] Example 6

[0200] A test was carried out to evaluate the effectiveness of AB-103 (the AB-103 formulation is a combination of RXR + NR (nuclear receptor)) as an adjuvant therapy with 5% topical minoxidil solution in the treatment of male pattern hair loss (MPHL). Method: Double-blind direct comparison prospective study. Number of patients: 48 male subjects Diagnosis and inclusion criteria: · The subjects were diagnosed with androgenetic alopecia (AGA) by a dermatologist · Age: 18 years old or above · The subjects were able to give informed consent Test article: AB-103 shampoo once a day was administered together with topical 5% minoxidil solution once every two days. Treatment period: 16 weeks Reference treatment, dosage, and administration method: Administer vehicle shampoo once every two days together with topical 5% minoxidil solution. Evaluation criteria: Efficacy: · Full-body photos of each subject before and after treatment were evaluated for hair growth by blinded experts. Evaluation was performed using a standardized 7-point evaluation scale (baseline, 8 weeks, 16 weeks). · The activity of sulfotransferase in the plucked hair of each subject was measured using a minoxidil response test (baseline, 1 week, 16 weeks). Safety: · The scalp of each subject was evaluated by the site investigator for irritation, sensitization, erythema, or other skin abnormalities (baseline, 1 week, 8 weeks, 16 weeks). Statistical method: The statistical method selected to describe the data is the Mann-Whitney U test.

[0201] Summary - Conclusion:

[0202] Results of efficacy

[0203] The purpose of the study was to evaluate the efficacy of AB-103 as an adjuvant therapy with 5% topical minoxidil solution in the treatment of MPHL. A prospective clinical trial with direct comparison of 48 subjects treated for at least 16 weeks was conducted. Subjects were randomly assigned to two treatment groups: AB-103 was administered together with topical minoxidil (treatment group) or vehicle shampoo was administered together with topical minoxidil (comparison group). Full-body photos were evaluated by blinded experts. Treatment response was ranked on the following 7-point scale: -3 (significantly worsened), -2 (moderately worsened), -1 (slightly worsened), 0 (no change), +1 (slightly improved), +2 (moderately improved), and +3 (significantly improved). The raw data of the CRF were summarized in a table and graphed by experts (see Figure 1).

[0204] Eight subjects in the treatment group and five subjects in the control group did not complete the trial. The reason for discontinuation was not specified, but no adverse events were observed in any of these subjects during the one-week follow-up after discontinuation. A total of 35 subjects completed the trial.

[0205] The effect of AB-103 as an adjuvant minoxidil treatment compared to vehicle in the control group was determined using the Mann-Whitney U test (MedCalc v18.2.1). The null hypothesis and alternative hypothesis were as follows: H0: The distribution of treatment responses of subjects in the treatment group and the control group is equal H A : The distribution of treatment responses of subjects in the treatment group and the control group is not equal

[0206] The results are shown below: Mann-Whitney U test (two-sided) * Mann-Whitney U = 93.5, p-value = 0.0432; therefore, the null hypothesis is rejected. * Safety results: No adverse events were observed in any group.

[0207] Conclusion:

[0208] The distribution of treatment responses of subjects in the AB-103 + minoxidil group and the vehicle shampoo + minoxidil group was significantly different (p-value = 0.0432). In the AB-103 + minoxidil group, 75% of the subjects experienced hair growth, while in the vehicle shampoo + minoxidil group, it was 48%.

[0209] Note: In this sample population, the response rate in the control group (48%) was higher than that expected from previous clinical trials (39%). It is possible that the response of some subjects in the vehicle part was improved, but the higher observed response rate is likely due to the small size of the trial population.

[0210] Example 7

[0211] A study was conducted to evaluate the efficacy of AB-103 in the upregulation of minoxidil sulfotransferase in human hair follicles in vivo. Methods: Double-blind, placebo-controlled, forward-looking study. Number of patients: 20 female subjects Diagnosis and inclusion criteria: · Subjects were diagnosed with female pattern hair loss by a dermatologist · Age: 18 years or older · Subjects were able to give informed consent Test article: AB-103 shampoo to be rinsed once a day, once a day. Treatment period: 7 days Reference treatment, dosage and administration mode: Vehicle shampoo (placebo), once a day. Evaluation criteria: Efficacy: · The activity of sulfotransferase in the plucked hair of each subject was measured using a minoxidil response test (baseline, day 7). Safety: · The scalp of each subject was evaluated by the facility investigator for irritation, sensitization, erythema or other skin abnormalities (baseline, day 7). Statistical method: The statistical method selected to describe the data was the independent samples t-test.

[0212] Summary - Conclusion:

[0213] Results of efficacy

[0214] The purpose of the study was to evaluate the efficacy of AB-103 in the upregulation of minoxidil sulfotransferase in human hair follicles in vivo. A double-blind, placebo-controlled, forward-looking clinical trial of 20 subjects treated for 7 days was conducted. Subjects were randomly assigned to two treatment groups: AB-103 shampoo or shampoo vehicle. Sulfotransferase activity levels were determined using a minoxidil response test. Analyses were performed on a spectrophotometer (Shimadzu UV-1700, Kyoto, Japan). The raw data of the CRF were summarized in a table and graphed by an expert (see Figure 2).

[0215] The independent samples t-test (MedCalc v18.2.1) was used to determine the effect of AB-103 compared to vehicle shampoo on hair follicle sulfotransferase activity. The null and alternative hypotheses were as follows: H0: The mean change in sulfotransferase activity after 7 days of treatment with AB-103 is equal to the change in sulfotransferase activity after 7 days of treatment with vehicle shampoo H A : The mean change in sulfotransferase activity after 7 days of treatment with AB-103 is greater than the change in sulfotransferase activity after 7 days of treatment with vehicle shampoo Mathematically, it is described as follows: H0: μ1 = μ2 H A : μ1 > μ2

[0216] The results are shown below: Independent samples t-test (two-sided) *The D'Agostino-Pearson test for normality (MedCalc v18.2.1) allowed the normality of the difference with p = 0.4278. *Analysis of the dataset yielded t(18) = -2.839, p = 0.0109; thus, the results of the t-test indicate that the null hypothesis is rejected, and it was concluded that there is a significant difference in the mean change in sulfotransferase activity between the AB-103 group (μ = 0.2413, sd = -0.2562) [95% CI: 0.05807 to 0.4246] and the placebo group (μ = -0.008420, sd = -0.1085) [95% CI: -0.08602 to 0.06918]. *The 95% CI for the difference in means is 0.06492 ≤ μ b ~μ a ≤ 0.4346, and the best estimate is the mean difference = 0.2497. Safety results: No adverse events were observed in any of the groups.

[0217] Conclusion:

[0218] The mean change in sulfotransferase activity after 7 days of treatment with AB-103 was significantly greater than the mean change after placebo treatment (p value <0.0109). Also, using data from the report submitted to the regulatory authorities (FI-IVD-001), it was concluded that the increase in sulfotransferase activity was partially greater than the within-subject variability of the MRT assay.

[0219] Example 8

[0220] A study was conducted to evaluate the efficacy of AB-103 as an adjuvant therapy with 5% topical minoxidil foam in the treatment of female pattern hair loss (FPHL). Method: Double-blind direct comparison prospective study. Number of patients: 30 female subjects Diagnosis and inclusion criteria: · Subjects were diagnosed with female pattern hair loss by a dermatologist · Age: 18 years or older · Subjects were able to give informed consent Test article: AB-103 rinse-off shampoo once daily, administered together with topical 5% minoxidil foam, once daily. Treatment period: 24 weeks Reference treatment, dose and administration method: Topical 5% minoxidil foam, once daily. Evaluation criteria: Efficacy: · Full-body photographs of each subject before and after treatment were evaluated for hair growth by blinded experts. Evaluation was performed using a standardized 7-point rating scale (baseline, 12 weeks, 24 weeks). · The activity of sulfotransferase in the plucked hair of each subject was measured using a minoxidil response test (baseline, 1 week, 24 weeks). Safety: · The scalp of each subject was evaluated by the study investigator for irritation, sensitization, erythema or other skin abnormalities (baseline, 4 weeks, 8 weeks, 12 weeks, 24 weeks). Statistical method: The statistical method selected to describe the data was the Mann-Whitney U test.

[0221] Summary - Conclusion:

[0222] Results of efficacy

[0223] The purpose of the study was to evaluate the efficacy of AB-103 as an adjuvant therapy with 5% topical minoxidil foam in the treatment of FPHL. A prospective clinical trial with direct comparison of 30 subjects treated for at least 24 weeks was conducted. The subjects were randomly assigned to two treatment groups: AB-103 administered with topical minoxidil or topical minoxidil monotherapy. Whole photographs were evaluated by blinded experts. Treatment response was ranked on a 7-point scale as follows: -3 (significantly worsened), -2 (moderately worsened), -1 (slightly worsened), 0 (no change), +1 (slightly improved), +2 (moderately improved), and +3 (significantly improved). The raw data of the CRF were tabulated and graphed by experts (see Figure 3).

[0224] The effect of the AB-103 + minoxidil treatment compared to minoxidil monotherapy was determined using the Mann-Whitney U test (MedCalc v18.2.1). The null hypothesis and alternative hypothesis were as follows: H0: The distributions of the AB-103 + minoxidil group and the minoxidil monotherapy group are equal H A : The distributions of the AB-103 + minoxidil group and the minoxidil monotherapy group are not equal

[0225] The results are shown below: Mann-Whitney U test (two-sided) *Combined dataset (all sites): p-value of the Mann-Whitney U test < 0.0357; therefore, the null hypothesis is rejected. *Safety results: No adverse events were seen in either group.

[0226] Conclusion:

[0227] The treatment difference between AB-103 + minoxidil and minoxidil monotherapy was statistically significant (p-value < 0.0357). In the AB-103 + minoxidil group, 66% of the subjects experienced hair growth, compared with 33% in the minoxidil monotherapy group.

[0228] Despite the small test population, this study provides initial evidence for the use of AB-103 as an adjuvant therapy to 5% topical minoxidil foam in the treatment of FPHL.

[0229] Example 9

[0230] The study was to evaluate the efficacy of AB-103 as an adjuvant therapy to 5% topical minoxidil foam in the treatment of FPHL patients who were non-responders to 5% topical minoxidil. Method: Double-blind placebo-controlled prospective study. Number of patients: 30 female subjects Diagnosis and inclusion criteria: · Subjects were diagnosed with female pattern hair loss by a dermatologist · Age: 18 years or older · Subjects had negative minoxidil response test results (OD < 0.4) · Subjects were able to give informed consent Test article: AB-103 rinse-off shampoo once daily, administered together with topical 5% minoxidil foam once daily. Treatment period: 24 weeks Reference treatment, dose and administration mode: Vehicle shampoo, administered together with topical 5% minoxidil foam once daily. Evaluation criteria: Efficacy: · Mean change in the number of hairs in the target area (TAHC) [baseline, week 24). · The activity of sulfotransferase of the plucked hairs of each subject was measured using the minoxidil response test (baseline, week 1, week 24). Safety: · The scalp of each subject was evaluated by the facility investigator for irritation, sensitization, erythema, or other skin abnormalities (baseline, week 24). Statistical method: The statistical method selected to describe the data is the independent samples t-test.

[0231] Summary - Conclusion:

[0232] Results of efficacy

[0233] The purpose of the study was to evaluate the efficacy of AB-103 as an adjuvant therapy with 5% topical minoxidil in the treatment of FPHL patients who are non-responders to 5% topical minoxidil. A double-blind, placebo-controlled, prospective clinical trial was conducted on 30 subjects treated for at least 24 weeks. The subjects were randomly assigned to two treatment groups: AB-103 was administered together with topical minoxidil or vehicle shampoo was administered together with topical minoxidil (placebo group). TAHC was evaluated in an area of 1 cm on the shaved and tattooed scalp. 2 The data of the CRF were summarized in a table and graphed by an expert (see Figure 4). Three subjects in the placebo group did not complete the study, and one subject in the treatment group did not complete the study. No adverse events were observed in any of the subjects. Two of the subjects who discontinued the study cited lack of visible results as the reason for discontinuation. A total of 26 subjects completed the study.

[0234] The mean change in TAHC in the AB-103 + minoxidil group was determined using the independent samples t-test (MedCalc v18.2.1) and compared with the mean change in TAHC in the vehicle shampoo + minoxidil group. The null hypothesis and the alternative hypothesis are as follows: H0: The mean change in TAHC after 24 weeks of treatment with AB-103 + minoxidil is equal to the mean change in TAHC after 24 weeks of treatment with vehicle shampoo + minoxidil H A: The mean change in TAHC after 24 weeks of treatment with AB-103 + minoxidil was greater than the mean change in TAHC after 24 weeks of treatment with vehicle shampoo + minoxidil. Mathematically, it is described as follows: H0: μ1 = μ2 H A : μ1 > μ2

[0235] The results are shown below: Independent samples t-test (two-sided) * The D'Agostino-Pearson test for normality (MedCalc v18.2.1) tolerated the normality of the difference with p = 0.4063. * Analysis of the dataset yielded t(24) = -2.862, p = 0.0086; thus, the results of the t-test indicate that the null hypothesis is rejected, and it was concluded that there was a significant difference in the mean change in TAHC between the AB-103 group (μ = 12.9571, sd = 9.4802) [95% CI: 7.4835 - 18.4308] and the placebo group (μ = 3.0083, sd = 8.0062) [95% CI: -2.0786 - 8.0952]. * The 95% CI for the difference in means was -17.1224 ≤ μ b ~μ a ≤ -2.7752, and the best estimate was the mean difference = -9.9488. Safety results: No adverse events were observed in either group.

[0236] Conclusion:

[0237] The mean change in TAHC after 24 weeks of treatment with AB-103 + minoxidil was greater than the mean change in TAHC in the placebo group (p = 0.0086). Also, in the AB-103 + minoxidil group, 57% of the subjects experienced hair growth, while it was 0% in the placebo group.

[0238] This study provides initial evidence for the use of AB-103 as an adjuvant therapy to 5% topical minoxidil in the treatment of FPHL patients who are non-responders to 5% topical minoxidil.

[0239] Example 10

[0240] Evaluation of the effectiveness of alkaline pH on the increase in sulfate transferase in hair follicles

[0241] Test 001

[0242] An in vitro test was conducted to evaluate the effectiveness of an alkaline pH solution on the increase in sulfate transferase in hair follicles. Twenty hairs were plucked from each subject. The baseline sulfate transferase activity of each subject was measured by analyzing ten of the plucked hairs using the minoxidil response test devised by Goren et al. The remaining ten hairs were incubated with an alkaline solution (pH 8.5) at 37°C for 24 hours. Thereafter, the remaining ten hairs were analyzed using the minoxidil response test devised by Goren et al. The data were summarized in Table 3 below. The average increase was approximately 100%.

Table 4

[0243] Test 002

[0244] The test was conducted in 30 human subjects (30 males) with low sulfate transferase determined by the colorimetric enzyme test described by Goren et al. Subjects were recruited based on enzyme test results with OD < 0.4. The subjects were randomly assigned to the active group and the placebo group at a 1:1 ratio. All subjects were applied with 5% topical minoxidil once a day. The active group was applied with an alkaline solution (pH 8.5) once a day before using minoxidil. The placebo group was applied with a vehicle solution (pH 7.0). At the end of one week, the average sulfate transferase activity of all subjects increased by approximately 2-fold (95%). The average sulfate transferase activity remained high during the 6-month follow-up period. At 4 months, the average increase in the number of hairs in the active group was 192% higher than that in the placebo. Also, approximately 50% of the subjects in the active group responded to minoxidil as compared to 0% in the placebo group.

[0245] Test 003

[0246] The test was conducted in 30 human subjects (30 women) with low sulfotransferase determined by the colorimetric enzyme test described by Goren et al. Subjects were recruited based on enzyme test results with OD < 0.4. The subjects were randomly assigned to the active group and the placebo group at a ratio of 1:1. All subjects were applied with 5% topical minoxidil once a day. The active group was applied with an alkaline solution (pH 8.5) once a day before using minoxidil. The placebo group was applied with a vehicle solution (pH 7.0). At the end of one week, the average sulfotransferase activity of all subjects increased by about 2-fold (115%). The average sulfotransferase activity remained high during the 6-month follow-up period. At 6 months, the average increase in hair count in the active group was 173% higher than that in the placebo. Also, about 50% of the subjects in the active group responded to minoxidil compared to 0% in the placebo group.

[0247] Example 11

[0248] pHi assay

[0249] An aqueous solution of 0.04% bromothymol blue was used as a pH indicator to visualize the intracellular pH (pHi) of the cells located in the hair follicle stem cell (HFSC) niche. A neutral solution of bromothymol blue with pH 6.0 - 7.6 appears green, pH 6.0 appears yellow, and above pH 7.6 appears blue. The hair follicles were immersed in the assay solution for about 5 minutes until the HFSCs were stained. The cells were visualized using a 20x stereomicroscope equipped with a 5MP color digital eyepiece microscope camera. [Table 5]

[0250] pHi of HFSC

[0251] The following experiment was conducted to evaluate the intracellular pH of the HFSC niche in hair.

[0252] Method:

[0253] One hair was plucked from each human subject. The hair was visually inspected to confirm the presence of the hair bulb and the hair was briefly rinsed with clean water. The hair was then immersed in 100 μL of assay solution starting from the hair bulb. The hair was reacted with the solution at room temperature for 5 minutes. After incubation, the hair was removed and placed on a clean slide glass and visualized using a 20x stereomicroscope equipped with a 5MP color digital eyepiece microscope camera.

[0254] Results: See Table 5 in Figure 5.

[0255] Conclusion: The intracellular pH of the cells contained in the HFSC niche was less than pH 6.0.

[0256] In vitro upregulation of SULT1A1 by pH increase (24 h)

[0257] The following experiment was conducted to evaluate the upregulation of sulfotransferase in hair follicles by an increase in pHi.

[0258] Method:

[0259] For each pH tested, 36 hairs were plucked from human subjects. The hair was visually inspected to confirm the presence of the hair bulb. Two hairs were placed into 9 wells of a sterile flat-bottom tissue culture plate containing 250 μL of Williams' E medium containing 0.292 g / L L-glutamine at pH 5.9, 7.4 and 8.1 (i.e., 3 wells per pH) (i.e., 2 hairs per reaction). The hairs were incubated at 5% CO2, 100% relative humidity for 6 hours and 24 hours. All samples were performed in triplicate, i.e., the data described in the results section are the average of three tested samples for the pH.

[0260] After 24 hours of incubation, the hair was removed from the sample medium and simply washed with clean water. The hair was trimmed to a length of approximately 1 cm and first immersed from the hair bulb in 100 μL of an assay solution containing 50 mM phosphate buffer (pH 8), 5 mM 4-nitrophenyl potassium sulfate, 20 μM adenosine 3',5'-diphosphate, 100 μM minoxidil, and 5 mM MgCl2. The hair was reacted with the solution at room temperature for 24 hours. After incubation, the hair was removed, and the optical absorbance of the solution at 405 nm was determined using a spectrophotometer with a single scan and a 1 cm optical path length.

[0261] Results: See Tables 6 - 7 below.

Table 6

Table 7

[0262] Conclusion: Incubating hair in a growth medium with a pH above 7.0 significantly upregulated the sulfotransferase response within 24 hours, but not within 6 hours.

[0263] In vivo changes in HFSC niche pHi

[0264] The following experiment was conducted to evaluate the ability to change the pHi of HFSCs by applying a topical solution to the scalp.

[0265] Method:

[0266] 1 mL of a 10% solution of sodium bicarbonate in dimethyl sulfoxide (DMSO) was applied to the scalp of each subject in a small quarter-sized area. One hair within the area was plucked from each subject at time 0 (zero), 15, and 30 minutes. The hair was visually inspected to confirm the presence of the hair bulb, and the hair was briefly rinsed with clean water. The hair was first immersed from the hair bulb into 100 μL of assay solution. The hair was reacted with the solution at room temperature for 5 minutes. After incubation, the hair was removed and placed on a clean slide glass and visualized using a 20x stereomicroscope equipped with a 5MP color digital eyepiece microscope camera.

[0267] Results: See Tables 8 - 10 in Figures 6 - 8.

[0268] Conclusion: Topical application of 10% sodium bicarbonate in DMSO was able to change the pHi of cells located in the HFSC niche within 30 minutes of application.

[0269] Example 12

[0270] Upregulation of sulfotransferase by an alkalizing agent in human hair follicles

[0271] Twenty-four hairs were plucked from each human subject. The hair was visually inspected to confirm the presence of the hair bulb. Two hairs were placed into a capped 1.5 mL tube containing 400 μL of Dulbecco's Modified Eagle Medium / Nutrient Mixture F-12 Ham medium containing 0.365 g / L L-glutamine, 1.2 g / L NaHCO3, and 5.18 g / L CHES at pH 9.5 (i.e., 2 hairs per reaction). The hair was incubated at 37 °C and 100% relative humidity for 0 (baseline), 4, 8, 16, 20, and 24 hours. All samples were performed 4 times and the experiment was repeated 4 times, i.e., the data described in the results section are the average of 4 experiments using 4 samples tested at each time point.

[0272] After incubation at each time point, the hair was removed from the sample medium and briefly washed with clean water. The hair was trimmed to approximately 1 cm in length and first immersed from the hair bulb in 100 μL of an assay solution containing 50 mM phosphate buffer (pH 8), 5 mM 4-nitrophenyl potassium sulfate, 20 μM adenosine 3',5'-diphosphate, 100 μM minoxidil, and 5 mM MgCl2. The hair was reacted with the solution at room temperature for 24 hours. Referring to Figure 9, after incubation, the hair was removed and the optical absorbance of the solution at 405 nm was determined using a spectrophotometer with a single scan and a 1 cm optical path length.

Table 8

[0273] Example 13

[0274] Alkalinized topical formulations with and without minoxidil

[0275] Table 9 shows various topical formulations containing salts of minoxidil (e.g., alkalinized salts of minoxidil) with and without minoxidil that can be used in embodiments of the present invention.

Table 9

[0276] Example 14

[0277] Human hair follicle pH change over time using topical application of alkalinized topical formulations

[0278] Various topical formulations were applied to the scalp of subjects. Hair from the application site was plucked every hour over a 24-hour period. The hair after each plucking was imaged to detect the pH change caused by each formulation over the experimental period. The pHi assay described in Example 11 was used to detect an increase in pH. Hair was plucked once per hour for 8 hours and then again the next day (24 hours).

Table 10

[0279] Example 15

[0280] Accelerated stability of liposome-containing solution

[0281] Various topical liposome formulations were manufactured and monitored for oxidative and hydrolytic degradation. Two validation batches (lots) of the liposome-containing formulations were made and stored at elevated temperature. During the accelerated stability testing process, samples from each lot were removed from the elevated temperature and visually inspected for yellowness. [Table 11] [Table 12]

[0282] Subjecting the test device to extreme temperature conditions is intended to simulate the degradation of the formulation over time, but it is accelerated. Using the Arrhenius equation, data on the shelf life can be estimated as predictive measures of the performance of the formulation. The Arrhenius equation relates the reaction rate (k) of a chemical reaction to the absolute temperature (T): d(Ink) / dT = ΔE a / RT 2

[0283] where Ea is the activation energy and R is the universal gas constant. [Table 13]

[0284] Using the Arrhenius model at 20 kcal, if the specifications are met after 56.2 days at 50 °C or 112.3 days at 40 °C, the test formulation is theoretically expected to perform satisfactorily for one year.

[0285] The purpose of the stability tests at 50 °C and 40 °C is to generate data to determine the shelf life of the formulation. The data are used as predictors of the stability of the final formulation form.

[0286] Test Kit Storage Conditions Store the test preparation at 50 °C and 40 °C (±2 °C for all temperatures). [Table 14]

[0287] Stability Criteria The accelerated test must first meet the acceptance criteria described in Table 15. [Table 15] [Table 16] Results [Table 17] [Table 18]

[0288] Example 16

[0289] In Vivo Evaluation of SULT1A1 Expression after Application of Formulations G1 and G2 (Liposome-Containing Solutions)

[0290] An in vivo test was conducted to evaluate the effectiveness of the liposome-containing solution in increasing the sulfotransferase of hair follicles. Twenty-four female subjects were recruited for the test. At baseline (day 0), 10 hairs were plucked from each subject. After the baseline evaluation of sulfotransferase, each subject was instructed to apply the liposome-containing solution to the scalp once a day for 7 days. Twelve subjects applied formulation GI (Table 11), and twelve subjects applied formulation G2 (Table 12).

[0291] After 7 days of treatment, 10 hairs removed from each subject were analyzed using the minoxidil response test devised by Goren et al. The data were summarized in Table 18 below. The average increase was approximately 145% for formulation GI and approximately 135% for formulation G2.

Table 19

[0292] Example 17 Liposome formulation A liposome formulation having the following composition was produced:

Table 20

[0293] The components of phase A were mixed together at 55 - 70 °C until the solution became homogeneous and all the powder had dissolved. The components of phase B were added and the solution was mixed until most of the B component had dissolved. The solution was then mixed with a rotor - stator homogenizer and cooled to room temperature. Component C was then mixed together in a separate container and then added to the A - B liposome solution.

[0294] Subjecting the test device to extreme temperature conditions is intended to simulate the degradation of the formulation over time, but it is accelerated. Using the Arrhenius equation, the data for the shelf life can be estimated as predictive measures of the formulation's performance. The Arrhenius equation relates the chemical reaction rate (k) to the absolute temperature (T): d(Ink) / dT = ΔE a / RT 2

[0295] In the equation, Ea is the activation energy and R is the universal gas constant.

Table 21

[0296] Using the Arrhenius model at 20 kcal, if the test formulation meets the specifications after 56.2 days at 50°C or 112.3 days at 40°C, the test formulation theoretically exhibits satisfactory performance for one year.

[0297] The purpose of the stability tests at 50°C and 40°C is to generate data for determining the shelf life of the formulation. The data is used as a stability predictor for the final formulation form.

[0298] Test Kit Storage Conditions Store the test formulation at 50°C and 40°C (±2°C for all temperatures).

Table 22

[0299] Stability Criteria The accelerated test must first meet the acceptance targets described in Table 21 below.

Table 23

[0300] Test Schedule Test the samples according to the test intervals described above.

[0301] Results The samples are predicted to pass as shown in Table 22 below.

Table 24

Claims

1. A composition for increasing the sulfonation ability of hair follicle cells and / or keratinocyte cells, inducing sulfotransferase in hair follicles, inducing the expression of sulfotransferase, increasing sulfotransferase activity, upregulating sulfotransferase, converting non-responders to minoxidil responders, and / or improving minoxidil response, wherein the composition comprises: (i) an agent configured to increase the sulfonation ability of hairy skin, hair follicles and / or keratinocyte cells in humans; (ii) an alkalizing agent; (iii) liposomes encapsulating at least a part of the alkalizing agent; (iv) an antioxidant configured to prevent oxidative degradation of the liposomes; and (v) a buffer system configured to increase the skin penetration of the liposomes and / or stabilize the liposome solution; and (vi) a solvent; comprising the liposomes contain phosphatidylcholine and / or lecithin; and optionally, the alkalizing agent and the buffer system are the same and / or contain the same components, a composition.

2. The composition according to claim 1, wherein the agent configured to increase the sulfonation ability of hairy skin, hair follicles and / or keratinocyte cells is an inorganic sulfur source such as cysteine, L-cysteine, hydrogen sulfide, elemental sulfur, sulfite, thiosulfate, polythionate, magnesium sulfate, sodium sulfate or sodium pyrosulfite; for example, sodium pyrosulfite.

3. The composition according to claim 1 or 2, wherein the alkalizing agent is a buffer system selected from pH regulators such as bicarbonate, acetate, citrate, Tris or HEPES; for example, a TRIS / TRIS HCl buffer solution with a pH of 8-9.

4. The composition according to any one of claims 1 to 3, wherein the buffer system is selected from carbonate such as sodium bicarbonate / sodium carbonate; acetate such as acetic acid / sodium acetate; citrate such as monosodium, disodium or trisodium citrate; Tris such as TRIS / TRIS HCl; or HEPES.

5. The composition according to any one of claims 1 to 4, wherein the buffer system contains TRIS / TRIS HCl with a pH of 8-9.

6. The composition according to any one of claims 1 to 5, wherein both the alkalizing agent and the buffer system contain TRIS, for example, TRIS / TRIS HCl.

7. The antioxidant is selected from ascorbic acid, monothioglycerol, potassium pyrosulfite, sodium bisulfite, sodium formaldehyde sulfoxylate, sodium sulfite, sodium thiosulfate, tocopherol, sodium pyrosulfite, butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), ascorbyl palmitate, propyl gallate, acai oil, α-lipoic acid, green tea extract, retinal, vitamin C, coenzyme Q10 (CoQ-10), isoflavone, polyphenol, curcumin, turmeric, pomegranate, rosemary extract, glutathione, selenium, zinc, chelating molecule, ethylenediaminetetraacetic acid (EDTA), disodium EDTA, tetrasodium EDTA, pentasodium pentetate, sodium metasilicate and sodium phosphate derivatives, etidronic acid and / or its derivatives, and / or galactaric acid; for example tocopherol, for example tocopheryl acetate [list other particularly preferred antioxidants], the composition according to any one of claims 1 to 6.

8. The composition according to any one of claims 1 to 7, further comprising a penetration enhancer; for example diethylene glycol monoethyl ether or a polyethylene glycol derivative of a mixture of mono-, di- and tri-glycerides of capric acid and caprylic acid containing on average 6 molecules of ethylene oxide.

9. The composition according to any one of claims 1 to 8, further comprising a chelating agent; for example tetrasodium EDTA.

10. The following: A preservative, for example an antibacterial / antifungal agent, for example EUXYL PE 9010; An aromatic compound; A surfactant, for example polysorbate 80; and Glycerol The composition according to any one of claims 1 to 9, further comprising one or more of the above.

11. The following: The agent configured to increase the sulfonation ability of hairy skin, hair follicles and / or keratinocyte cells is an inorganic sulfur source, for example sodium pyrosulfite; Each of the alkalizing agent and the buffer system contains TRIS / TRIS HCl; The antioxidant contains tocopherol; for example tocopheryl acetate; The solvent is water; and The liposome contains phosphatidylcholine, The composition according to claim 1.

12. The following: A chelating agent which is tetrasodium EDTA; An antibacterial / antifungal agent, such as EUXYL PE 9010; An aromatic compound; A surfactant, such as polysorbate 80; and Glycerol The composition according to claim 11, further comprising.

13. The following composition: 【Table 1】 The composition according to claim 1, having.

14. The composition according to any one of claims 1 to 13, wherein the composition is configured to be administered by applying the composition at a predetermined frequency and / or by administering the composition before applying topical minoxidil.

15. The composition according to any one of claims 1 to 14, wherein the composition is formulated as a cosmetic.

16. The composition according to any one of claims 1 to 15, wherein the composition is formulated as any one or a combination of a sustained-release vehicle, cream, solution, lotion, beauty liquid, ointment, spray, aerosol medium, capsule, shampoo, gel, foam, cosmetic, hair conditioner, hair care product, hair mask, deodorant, antiperspirant, moisturizer, or shaving cream or gel.

17. A kit for increasing the sulfonation ability of hair follicle cells and / or keratinocyte cells, inducing sulfotransferase in hair follicles, inducing the expression of sulfotransferase, increasing the activity of sulfotransferase, upregulating sulfotransferase, converting non-responders to minoxidil responders, and / or improving minoxidil response, the kit comprising a composition and a dispenser, implant or pill; The kit, wherein the composition comprises the composition according to claim 1.

18. The kit according to claim 17, wherein the composition is formulated as any one or a combination of a sustained-release vehicle, cream, solution, lotion, beauty liquid, ointment, spray, aerosol medium, capsule, shampoo, gel, foam, cosmetic, hair conditioner, hair care product, hair mask, deodorant, antiperspirant, moisturizer, or shaving cream or gel.

19. The kit according to claim 17 or 18, wherein the composition is the composition according to claim 11.

20. The kit according to any one of claims 17 to 19, wherein the composition further comprises minoxidil.

21. A method for producing a composition for increasing the sulfonation ability of hair follicle cells and / or keratinocyte cells, inducing sulfotransferase in hair follicles, inducing the expression of sulfotransferase, increasing sulfotransferase activity, upregulating sulfotransferase, converting non-responders to minoxidil responders, and / or improving minoxidil response, wherein the composition comprises: (i) an agent configured to increase the sulfonation ability of hairy skin, hair follicles and / or keratinocyte cells in humans; (ii) an alkalizing agent; (iii) liposomes encapsulating at least a part of the alkalizing agent; (iv) an antioxidant configured to prevent oxidative degradation of the liposomes; and (v) a buffer system configured to increase the skin penetration of the liposomes and / or stabilize the liposome solution; and (vi) a solvent; Optionally, a penetration enhancer; Optionally, a chelating agent; comprising, the liposomes comprising phosphatidylcholine and / or lecithin; and optionally, the alkalizing agent and the buffer system being the same or comprising the same components; the method comprising: a) encapsulating at least a part of each of an agent configured to increase sulfonation ability, an alkalizing agent, an antioxidant, a penetration enhancer (if present) and a chelating agent (if present) into liposomes to form a liposome solution; and b) adding a preservative, and optionally a fragrance and optionally a surfactant to the liposome solution; comprising, the liposomes comprising phosphatidylcholine and / or lecithin, method.

22. The method according to claim 21, wherein the product of the method is the composition according to claim 1.

23. The method according to claim 21, wherein the product of the method is the composition according to claim 11.

24. A method for stabilizing a composition for increasing the sulfonation ability of hair follicle cells and / or keratinocyte cells, inducing sulfotransferase in hair follicles, inducing the expression of sulfotransferase, increasing sulfotransferase activity, upregulating sulfotransferase, converting non-responders to minoxidil responders, and / or improving minoxidil response; The method includes the step of encapsulating the composition in a solution containing liposomes, nonionic liposomes, niosomes, novasomes I, erythromycin-Zn complex, microspheres, nanoparticles, solid lipid nanoparticles, nanoemulsions, micelles, nanogels, selenium nanoparticles, virosomes, dendrimers or carbon nanotubes; wherein the encapsulation increases the water solubility of the composition, decreases the water solubility of the composition, reduces loss by degradation, or promotes penetration through the stratum corneum, method.

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