Compositions and methods of oral supplementation to oral minoxidil for the treatment of alopecia

Abstract

Embodiments may relate to compositions and methods for treating hair loss, which may include treating alopecia. The compositions and methods relate to oral supplements to oral minoxidil, including an SLC22A9 inducer, a HIF-α inducer, and / or an acidifying agent. Acidifying the blood of patients suffering from alopecia can cause mild acidosis, which can upregulate SLC22A9 and / or downregulate AABC3. Induction of SLC22A9, induction of HIF-α, and / or acidifying the patient's blood can facilitate the entry of oral forms of minoxidil into hair follicles.

Description

[Technical Field]

[0001] Embodiments may relate to compositions and methods for the treatment of hair loss, which may include the treatment of alopecia. Specifically, the compositions and methods relate to oral supplements to oral minoxidil. [Background technology]

[0002] A drug that can be used to treat alopecia is minoxidil. In order for minoxidil to exert its hair growth properties, it must be activated by the SULT1A1 (minoxidil sulfotransferase) enzyme. The enzyme is expressed in both the scalp and the liver. Different people express different amounts of the enzyme or have genetic mutations that affect the activity of the enzyme. Therefore, the response to minoxidil treatment may vary from person to person and depends on the SULT1A1 enzyme.

[0003] Previous studies have demonstrated that alkalinizing the intracellular pH of keratinocytes induces the expression of the SULT1A1 enzyme in the scalp, subsequently improving, increasing, or enhancing the minoxidil response. Therefore, topical alkalinizing agents have been developed as minoxidil boosters. However, these topical minoxidil boosters have met with limited success because they are difficult to comply with twice-daily application, tend to alter hair color, and tend to leave sodium bicarbonate residue in the hair. Furthermore, minoxidil exerts its hair regenerating effects primarily through the dermal papilla and dermal sheath cells, which are difficult to treat with topical cosmetic products. The dermal papilla has a rich blood supply, which may be easier to regulate with orally administered compositions (e.g., drugs, ingredients, supplements, etc.). Therefore, an oral composition that increases the SULT1A1 enzyme in the dermal papilla, dermal sheath, or outer root sheath of the hair follicle, thereby subsequently increasing the response to minoxidil for the treatment of hair loss, would be advantageous.

[0004] Oral minoxidil sulfation occurs in the liver, but not in hair follicles.Therefore, oral minoxidil does not enter hair follicles.As described in this disclosure, the present inventors have discovered that the expression of SLC22A9 can promote oral minoxidil to enter hair follicles. Summary of the Invention

[0005] The present invention relates to compositions and methods for oral supplementation of oral minoxidil.As mentioned above, sulfation of oral minoxidil occurs in the liver but not in hair follicles, which leads to the inability of oral minoxidil to enter hair follicles.However, the expression of SLC22A9 can promote the entry of oral minoxidil into hair follicles.The expression of SLC22A9 can be achieved by inducing SLC22A9, HIF-1-A, and / or acidifying the patient's blood.

[0006] Exemplary embodiments relate to oral supplements to oral minoxidil, which may include an SLC22A9 inducer, a HIF-α inducer, and / or an acidifier.

[0007] In some embodiments, the acidifying agent may upregulate SLC22A9 and / or downregulate AABC3.

[0008] In some embodiments, the HIF-α inducer may include Juniperus cummunis extract, Green Tree extract, Glycyrrhiza glabra, o-phenanthroline, iodochlorohydroxyquinoline, and / or cobalt sulfate heptahydrate.

[0009] In some embodiments, the oral supplement may comprise an oral minoxidil treatment composition, wherein the oral minoxidil treatment composition comprises minoxidil or a pharmaceutically acceptable salt thereof.

[0010] In some embodiments, minoxidil or a pharmaceutically acceptable salt thereof may be present in the oral minoxidil treatment composition at a dosage ranging from 0.125 mg to 10 mg.

[0011] In some embodiments, the acidifying agent may include ammonium chloride, methanol, salicylate, biguanide, alcohol, polysaccharide, cyanide, and / or carbon monoxide.

[0012] An exemplary embodiment relates to a method for treating alopecia. The method may include administering oral minoxidil to a patient suffering from alopecia, and administering an oral supplement before, during, and / or after administration of the oral minoxidil, where the oral supplement comprises an SLC22A9 inducer, a HIF-α inducer, and / or an agent that acidifies the patient's blood, thereby treating the alopecia. Alternatively, the method may include administering an oral supplement containing oral minoxidil, where the oral supplement further comprises an SLC22A9 inducer, a HIF-α inducer, and / or an agent that acidifies the patient's blood.

[0013] In some embodiments, the acidifying agent may upregulate SLC22A9 and / or downregulate AABC3.

[0014] In some embodiments, the acidifying agent may cause mild acidosis in the patient.

[0015] In some embodiments, the HIF-α inducer may include Juniperus cummunis extract, Green Tree extract, Glycyrrhiza glabra, o-phenanthroline, iodochlorohydroxyquinoline, and / or cobalt sulfate heptahydrate.

[0016] In some embodiments, oral minoxidil can include minoxidil or a pharmaceutically acceptable salt thereof.

[0017] In some embodiments, minoxidil or a pharmaceutically acceptable salt thereof may be present in oral minoxidil at a dosage ranging from 0.125 mg to 10 mg.

[0018] In some embodiments, the acidifying agent may include ammonium chloride, methanol, salicylate, biguanide, alcohol, polysaccharide, cyanide, and / or carbon monoxide.

[0019] Exemplary embodiments relate to oral compositions for treating alopecia. The compositions may include an SLC22A9 inducer, a HIF-α inducer, and / or an acidifying agent.

[0020] In some embodiments, the acidifying agent may upregulate SLC22A9 and / or downregulate AABC3.

[0021] In some embodiments, the HIF-α inducer may include Juniperus cummunis extract, Green Tree extract, Glycyrrhiza glabra, o-phenanthroline, iodochlorohydroxyquinoline, and / or cobalt sulfate heptahydrate.

[0022] In some embodiments, the acidifying agent may include ammonium chloride, methanol, salicylate, biguanide, alcohol, polysaccharide, cyanide, and / or carbon monoxide.

[0023] Exemplary embodiments relate to a method of treating alopecia, the method comprising administering an oral composition to a patient suffering from alopecia, the oral composition comprising a SLC22A9 inducer, a HIF-α inducer, and / or an acidifying agent.

[0024] In some embodiments, the acidifying agent may upregulate SLC22A9 and / or downregulate AABC3.

[0025] In some embodiments, the HIF-α inducer comprises Juniperus cummunis extract, Green Tree extract, Glycyrrhiza glabra, o-phenanthroline, iodochlorohydroxyquinoline, and / or cobalt sulfate heptahydrate.

[0026] In some embodiments, the acidifying agent may include ammonium chloride, methanol, salicylate, biguanide, alcohol, polysaccharide, cyanide, and / or carbon monoxide.

[0027] As used herein, the term "prevent" or "prevention" and other derivatives of these terms, when used in relation to alopecia, such as androgenetic alopecia, can refer to the reduction of the likelihood of alopecia in an individual receiving a given treatment, compared with a similar individual at risk of alopecia but not receiving treatment.Therefore, the terms "prevent" and "prevention" can encompass a treatment that causes a given individual to experience alopecia to a lesser extent than would otherwise be expected.The effectiveness of preventing alopecia can be established, for example, by a controlled study in which a subject is administered a treatment (e.g., topically, orally, transdermally, etc.) and another subject is administered a placebo.Under these circumstances, if subjects treated with the treatment experience less hair loss over time than subjects receiving a placebo, for example, at least 5% less, at least 10% less, at least 15% less, at least 20% less, at least 25% less, at least 30% less, at least 35% less, at least 40% less, at least 45% less, at least 50% less, or more, the treatment can be considered effective in preventing alopecia.

[0028] As used herein, the term "subject" refers to a human or animal in need of therapeutic treatment for androgenetic alopecia or any other form of alopecia.

[0029] As used herein, the terms "treat," "treatment," or "treating" refer to therapeutic treatment, the purpose of which is to reverse, alleviate, improve, inhibit, slow, or stop the progression or severity of a disease or condition, such as androgenetic alopecia or other forms of alopecia. The term "treating" can include alleviating or alleviating at least one adverse effect or symptom of a disease or condition. Treatment can generally be considered "effective" if one or more symptoms are alleviated. Alternatively, treatment can be "effective" if the progression of the disease is slowed or stopped. That is, "treatment" can include not only the improvement of symptoms, but also the cessation of symptoms, or at least the slowing of the progression or worsening of symptoms compared to what would be expected in the absence of treatment. Beneficial or desired clinical results may include, but are not limited to, alleviation of one or more symptoms, reduction in the extent of disease, stabilization (e.g., no worsening) of disease, delay or slowing of disease progression, improvement or alleviation of disease state, remission (whether partial or total), and / or reduction in mortality.For example, treatment may be considered effective if the degree or amount of hair loss is reduced, or the progression of hair loss is slowed or stopped.The term "treatment" of a disease may also include providing relief from the symptoms or side effects of the disease (including palliative treatment).

[0030] The effectiveness of treatment for treating or preventing alopecia can be determined by monitoring the hair density in a given area of ​​the subject's body, for example, a given area of ​​scalp.For example, if hair loss rate is reduced by, for example, 10% or more after treatment, the treatment can be considered to be effective in preventing alopecia.Similarly, if hair density remains the same, the treatment can be considered to be effective in preventing alopecia.If hair density increases by, for example, 5% or more, for example, 10% or more after treatment, the treatment can also be considered to be effective in treating and / or preventing androgenetic alopecia.The effectiveness of treatment for treating or preventing androgenetic alopecia can be determined by monitoring overall photographs.For example, patients or specialists can use overall photographs before and after to evaluate treatment response.

[0031] As used herein, the term "alopecia" refers to all forms of hair loss in both male and female humans or animals, including but not limited to traction alopecia, androgenetic alopecia, male pattern baldness, female pattern baldness, alopecia areata, alopecia universalis, telogen effluvium, chemotherapy-induced alopecia, hair shedding, eyebrow hair loss, beard hair loss, thinning hair, etc. The term allows for the presence of factors that do not materially affect the basic and novel or functional property(ies) of that embodiment.

[0032] To utilize the compositions described herein, a subject can apply an effective amount of the composition to the scalp. The term "effective amount," as used herein, can be an amount effective to prevent or treat hair loss.

[0033] Further features, aspects, objects, advantages and possible applications of the present invention will become apparent from a study of the illustrative embodiments and examples described below in conjunction with the drawings and the appended claims. DETAILED DESCRIPTION OF THE INVENTION

[0034] The following is a description of exemplary embodiments presently contemplated for carrying out the present invention. This description is not to be taken in a limiting sense, but is made merely for the purpose of illustrating the general principles and features of the present invention. The scope of the present invention is not limited by this description.

[0035] Alopecia, especially androgenetic alopecia, is the progressive shrinkage of scalp hair follicles. It can be characterized by diffuse thinning of the scalp crown area while the frontal hairline remains intact. Alopecia is generally hereditary, but it can also depend on hormones that can affect its development. Oral and / or topical minoxidil is a US FDA-approved drug for the treatment of alopecia. Its use can moderately increase hair regrowth. The risk of adverse events from the use of such minoxidil is low. However, irritant dermatitis, allergic contact dermatitis, and hirsutism have been reported.

[0036] Although the embodiments disclosed herein may specifically discuss the treatment of forms of alopecia (e.g., androgenetic alopecia), it is understood that the disclosed compositions and methods may be applicable to the treatment of other forms of alopecia as well.

[0037] An embodiment may relate to a method for treating alopecia. The method may include administering oral minoxidil to a patient suffering from alopecia to treat the alopecia. The method may include administering an oral supplement before, during, and / or after administration of oral minoxidil. The oral supplement may include an SLC22A9 inducer, a HIF-1-A inducer, and / or an agent that acidifies the patient's blood.

[0038] An embodiment may relate to a composition for treating alopecia. For example, an embodiment may relate to a composition related to an oral supplement to oral minoxidil. The composition may be administered to induce solute carrier family 22 (e.g., SLC2A9), induce hypoxia-inducible factor 1-alpha (e.g., HIF-1-A), and / or acidify the blood of a patient suffering from alopecia (e.g., using ammonium chloride). Acidifying the patient's blood may upregulate SLC22A9 and / or downregulate AABC3. Upregulating SLC22A9 and / or downregulating AABC3 may allow or promote orally administered minoxidil to enter hair follicles.

[0039] The composition is an oral supplement to oral minoxidil. Thus, it is contemplated that the composition will be used in conjunction with oral minoxidil treatment. The minoxidil treatment can be a treatment that includes administering a composition containing minoxidil. The oral supplement can be administered before (e.g., before administering the minoxidil composition), during (e.g., while the minoxidil composition is being administered), and / or after (e.g., after administering the minoxidil composition) administration of oral minoxidil. This can include administering the oral supplement and minoxidil simultaneously, each at different times on the same day, etc. The oral supplement can be separate from the oral minoxidil composition (e.g., a separate oral supplement composition taken together with an oral form of minoxidil), or it can be part of the minoxidil composition (e.g., a component of an oral form of minoxidil), or minoxidil can be part of the oral supplement composition (e.g., the oral supplement composition can include minoxidil).

[0040] The minoxidil composition or the minoxidil component of the composition can be minoxidil or a pharmaceutically acceptable salt thereof. Minoxidil is a prodrug that is converted to its active form, minoxidil sulfate, by a sulfotransferase enzyme present in the outer root sheath (ORS) of hair follicles (Buhl AE, Waldon DJ, Baker CA, Johnson GA. Minoxidil sulfate is the active metabolite that stimulates hair follicles. J Invest Dermatol. 1990 November;95(5):553-7). It has been demonstrated that sulfotransferase activity in the ORS determines clinical response to minoxidil (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). Dosages of minoxidil ranging from about 0.125 mg to about 10 mg per day are contemplated, although other dosages may be used.

[0041] In an embodiment of the oral supplement composition used in conjunction with minoxidil, minoxidil can enter hair follicles. Once in the hair follicles, minoxidil induces (upregulates) the expression of sulfotransferase in hairy skin, hair follicles, and / or keratinocyte cells, such as scalp cells. This may include upregulating sulfonation ability. Thus, an embodiment of the oral supplement composition having minoxidil as a component of the oral supplement composition can induce the expression of sulfotransferase.

[0042] The oral supplement composition and / or the minoxidil composition can be administered at a predetermined frequency. This predetermined frequency can be once every 24 hours, twice every 24 hours, three times every 24 hours, four times every 24 hours, etc. The administration frequency of the oral supplement composition can be the same as or different from the frequency of minoxidil.

[0043] The form of the oral supplement composition may be in tablet form, pill form, capsule form, gel form, liquid form, spray form, etc. The form of the minoxidil composition may be in tablet form, pill form, capsule form, gel form, liquid form, spray form, etc. The form of the oral supplement composition may be the same as or different from the form of the minoxidil composition.

[0044] Any formulation of oral supplement composition and / or minoxidil composition may include a carrier. For example, any formulation may be encapsulated in a pharmaceutically acceptable carrier. Pharmaceutically acceptable carriers may encapsulate the composition in liposomes, sodium alginate, gum arabic, chitosan, cellulose, pectin, etc. In addition to being "pharmaceutically acceptable," each carrier may be "acceptable" in the sense of being compatible with other components of the formulation. A carrier may be used to temporarily encapsulate a composition until a condition that triggers its release is met. In some embodiments, the carrier may be formulated to controllably release the composition, for example, in a time-dependent manner.

[0045] An exemplary embodiment of the oral supplement composition can be formulated as an oral supplement for oral minoxidil. For example, the oral supplement can be administered in conjunction with oral minoxidil treatment, and for example, a patient suffering from alopecia can take the oral supplement composition(s) before, during, and / or after taking the oral minoxidil composition. The oral supplement can include a drug configured to express SLC22A9 so as to upregulate SLC22A9. Thus, the oral supplement can include a drug that induces SLC22A9 expression. Additionally or alternatively, the oral supplement can include a drug configured to express HIF-1-A so as to upregulate HIF-1-A. Thus, the oral supplement can include a drug that induces HIF-1-A expression. Examples of HIF-1-A inducers include Juniperus cummunis extract, Green Tree extract, Glycyrrhiza glabra, o-phenanthroline, iodochlorohydroxyquinoline, cobalt sulfate heptahydrate, etc. Oral supplements may include agents configured to acidify the patent's blood to upregulate SLC22A9 and / or downregulate AABC3. The blood acidifying agent is intended to acidify the blood to induce mild acidosis. An example of a blood acidifying agent may be ammonium chloride. For example, oral administration of 0.1 g / kg (1.9 mEq / kg) of ammonium chloride can induce metabolic acidosis in patients. Other acidosis agents may include methanol, salicylates, biguanides, alcohols, polysaccharides, cyanides, carbon monoxide, etc. The oral supplement may include an SLC22A9 inducer, an HIF-1-A inducer, and / or an acidifying agent. The oral supplement may include one or more SLC22A9 inducers, one or more HIF-1-A inducers, or one or more acidifying agents.

[0046] The oral supplement may include one or more compositions, including an oral minoxidil treatment composition. The oral minoxidil treatment composition may include minoxidil or a pharmaceutically acceptable salt thereof. Minoxidil or a pharmaceutically acceptable salt thereof may be present in the oral minoxidil treatment composition at a dosage ranging from 0.125 mg to 10 mg per day. Minoxidil may be included in a composition separate from the oral supplement, or may be part of the oral supplement.

[0047] As described herein, the oral supplement may include an SLC22A9 inducer, a HIF-1-A inducer, and / or an acidifier. The oral supplement may be a single composition containing one or more of an SLC22A9 inducer, a HIF-1-A inducer, or an acidifier. The oral supplement may be two or more compositions; for example, one composition may contain an SLC22A9 inducer or a HIF-1-A inducer, and another composition may contain an acidifier. The two compositions may be administered to a patient separately, but both may be administered in conjunction with minoxidil. It is understood that more or fewer compositions may be used, and other combinations of inducers / drugs in the compositions may be used.

[0048] As another example, an oral supplement composition can contain one or more SLC22A9 inducers, one or more HIF-1-A inducers, and / or one or more acidifying agents. For example, treatment can include administering Composition-1 and Composition-2, where Composition-1 has a first inducer or acidifying agent that is different from the inducer or acidifying agent used in Composition-2, or Composition-1 has a first concentration of an inducer or acidifying agent, and Composition-2 has the same inducer or acidifying agent but at a different concentration. Furthermore, one composition can be administered before administration of minoxidil, and the other can be administered after administration of minoxidil.

[0049] The number of compositions to be used, the number of inducing agents or acidifying agents to be used, the timing of their administration, etc. may be determined based on the desired effect and / or design criteria.

[0050] An exemplary formulation of an embodiment of the oral supplement composition includes: [Table 1]

[0051] A placebo-controlled study was conducted using an oral supplement of 268 mg of ammonium chloride to confirm increased SLC22A9 upregulation. Ten subjects received a placebo and ten subjects received ammonium chloride daily for five days. SLC22A9 expression from hair follicles was measured at baseline and on day five. SLC22A9 increased three-fold, with a statistically significant increase of p=0.01 in the active group versus the placebo group.

[0052]

[0013] Embodiments of the oral supplement composition may include one or more sulfotransferase enzymes. Any sulfotransferase enzyme may be human or non-human. Examples of sulfotransferase enzymes include carbohydrate sulfotransferases (e.g., CHST1, CHST2, CHST3, CHST4, CHST5, CHST6, CHST7, CHST8, CHST9, CHST10, CHST11, CHST12, CHST13, CHST14, etc.), galactose-3-O-sulfotransferases (e.g., GAL3ST1, GAL3ST2, GAL3ST3, GAL3ST4, etc.), heparan sulfate 2-O-sulfotransferases (e.g., HS2ST1), heparan sulfate 3-O-sulfotransferases (e.g., HS3ST1, HS3ST2, HS3ST3A1, HS3ST3B1, HS3ST4, HS3ST5, HS3ST6, etc.), heparan sulfate 6-O-sulfotransferases (e.g., HS2ST1), heparan sulfate 3-O-sulfotransferases (e.g., HS3ST1, HS3ST2, HS3ST3A1, HS3ST3B1, HS3ST4, HS3ST5, HS3ST6, etc.), and the like. The enzyme may be an O-sulfotransferase (e.g., HS6ST1, HS6ST2, HS6ST3, etc.), an N-deacetylase / N-sulfotransferase (e.g., NDST1, NDST2, NDST3, NDST4, etc.), a tyrosylprotein sulfotransferase (e.g., TPST1, TPST2, etc.), an uronyl-2-sulfotransferase, an estrone sulfotransferase, a chondroitin 4-sulfotransferase, SULT1A1, SULT1A2, SULT1A3, SULT1A4, SULT1B1, SULT1C2, SULT1C3, SULT1C4, SULT1D1P, SULT1E1, SULT2A1, SULT2B1, SULT4A1, SULT6B1, or the like.

[0053] The sulfotransferase enzyme can be a phenol sulfotransferase extract (eg, a phenol sulfotransferase extracted from a plant that produces sulfated salicinoids). Examples of plants that produce sulfated salicinoids include Populus trichocarpa, Populus x canescens, Salix sp., Arabidopsis thaliana, silver poplar (Populus alba), Simon poplar (Populus simonii), S. purpurea, P. tremuloides, I. polycarpa, P. nigra, Oryza sativa, Salicaceae family, poplar (Populus sp.), Idesia polycarpa - Japanese orange cherry, cherry), potato (Solanum tuberosum), cabbage (Brassica rapa), Populus trichocarpa (black cottonwood), Salix sp. (willow tree), cotton (Gossypium), Olea europaea L., Brassica napus, Apium graveolens, Brassica oleracea, Saccharina japonica, Solanum tuberosum, black cottonwood, and the like.

[0054] The sulfotransferase enzyme may be OeST1 (olive tree SULT1A1). OeST1 is a sulfotransferase plant supplement that can be extracted from olive trees. The human homolog of OeST1 is SULT1A1, which belongs to the cytosolic sulfotransferase family. Like OeST1, SULT1A1 catalyzes the transfer of a sulfonate group from PAPS to the hydroxyl group of various phenolic substrates, including flavonoids, catecholamines, and xenobiotics. OeST1 expression levels can vary depending on the tissue, developmental stage, and environmental conditions of the olive plant. However, studies have shown that OeST1 is most abundant in olive fruit and leaves. In olive fruit, OeST1 is expressed at high levels during the early stages of development and ripening, when flavonoids and other phenolic compounds are synthesized and accumulated. OeST1 expression in olive fruit is regulated by various factors, including light, temperature, and water availability, which can affect the synthesis and accumulation of flavonoids and other phenolics in the fruit. In olive leaves, OeST1 is also expressed at high levels, particularly in young and actively growing leaves. OeST1 expression in olive leaves is regulated by various factors, including light, temperature, and biotic and abiotic stresses, which can affect the biosynthesis and accumulation of flavonoids and other phenolics in leaves. Overall, OeST1 expression in olive fruits and leaves suggests that sulfated flavonoids and other phenolics may play an important role in olive plant physiology and adaptation and may contribute to the health benefits of olive fruits and leaves. Studies have measured the concentration of OeST1 (olive tree SULT1A1) in olive leaves. For example, a study published in the Journal of Agricultural and Food Chemistry in 2014 used quantitative real-time polymerase chain reaction (qPCR) analysis to measure the expression levels of various sulfotransferase genes, including OeST1, in olive leaves.This study found that OeST1 is expressed at relatively high levels in olive leaves compared to other sulfotransferase genes. Another study published in the same journal in 2018 used a radiolabeled assay to measure the activity of sulfotransferases, including OeST1, in olive leaf extracts. This study found that sulfotransferase activity in olive leaf extracts was primarily due to OeST1, and that its activity was higher in young leaves compared to older leaves. These studies suggest that OeST1 is present in significant amounts in olive leaves and is likely involved in the sulfation of various phenolic compounds in this plant tissue. However, it is important to note that the concentration of OeST1 or any other enzyme in olive leaves may vary depending on several factors, such as cultivar, growing conditions, and leaf age. Therefore, further research may be needed to determine the concentration of OeST1 in different olive leaf varieties and under different growing conditions.

[0055] Although some embodiments use the compositions of the present invention as an oral supplement to oral minoxidil, the compositions of the present invention can be used without minoxidil to treat alopecia.For example, embodiments may relate to oral compositions for treating alopecia, including an SLC22A9 inducer, an HIF-α inducer, and / or an acidifying agent.Therefore, by administering the compositions of the present invention that induce SLC22A9, induce HIF-α, and / or acidify the patient's blood, hair growth can be promoted, hair loss can be prevented, and / or the rate of hair loss can be reduced.In addition, the acidifying agent can upregulate SLC22A9 and / or downregulate AABC3.The acidifying agent can include ammonium chloride, methanol, salicylate, biguanide, alcohol, polysaccharide, cyanide, and / or carbon monoxide. HIF-α inducers may include Juniperus cummunis extract, Green Tree extract, Glycyrrhiza glabra, o-phenanthroline, iodochlorohydroxyquinoline, and / or cobalt sulfate heptahydrate.

[0056] It is understood that any plant that produces flavonoids or has minoxidil sulfotransferase enzyme, phenol sulfotransferase enzyme, and / or sulfotransferase enzyme can be used. Any method and composition can use the natural concentration of enzyme found in the plant or its extract. Furthermore, any enzyme can be derived from an animal.

[0057] It should be understood that the disclosure of a range of values ​​is a disclosure of all numerical values ​​within that range, including the endpoints. It should also be understood that while some components, features, and / or configurations may be described in connection with only one particular embodiment, these same components, features, and / or configurations may be applied to or used in many other embodiments and should be considered applicable to other embodiments unless otherwise specified or unless such components, features, and / or configurations are technically impossible to use in other embodiments. Thus, the components, features, and / or configurations of the various embodiments may be combined together in any manner, and such combinations are expressly contemplated and disclosed by this description.

[0058] In light of the above teachings of the present disclosure, it will be apparent to those skilled in the art that many modifications and variations of the described examples and embodiments are possible. The disclosed examples and embodiments are presented for illustrative purposes only. Other alternative embodiments may incorporate some or all of the features disclosed herein. Accordingly, it is intended to cover all such modifications and alternative embodiments that may fall within the true scope of the present invention, and the full breadth thereof should be accorded.

[0059] It is understood that modifications to the embodiments disclosed herein can be made to meet a particular set of design criteria. Thus, while certain exemplary embodiments of the compositions disclosed herein and methods of using and making same have been described and illustrated, it is to be clearly understood that the invention is not limited thereto and may be otherwise embodied and variously practiced within the scope of the following claims.

Claims

1. An oral supplement to oral minoxidil, SLC22A9 inducers, HIF-α inducers, and / or acidifiers Oral supplements, including:

2. the acidifying agent upregulates SLC22A9 and / or downregulates AABC3; The oral supplement of claim 1.

3. the HIF-α inducer comprises Juniperus cummunis extract, Green Tree extract, Glycyrrhiza glabra, o-phenanthroline, iodochlorohydroxyquinoline, and / or cobalt sulfate heptahydrate; The oral supplement of claim 1.

4. Oral minoxidil treatment composition comprising minoxidil or a pharmaceutically acceptable salt thereof 10. The oral supplement of claim 1, further comprising:

5. The minoxidil or pharmaceutically acceptable salt thereof is present in the oral minoxidil treatment composition in a dosage range of 0.125 mg to 10 mg. The oral supplement of claim 4.

6. the acidifying agent comprises ammonium chloride, methanol, salicylate, biguanide, alcohol, polysaccharide, cyanide, and / or carbon monoxide; The oral supplement of claim 1.

7. 1. A method of treating alopecia, comprising: administering oral minoxidil to a patient suffering from alopecia; and administering an oral supplement before, during, and / or after administration of oral minoxidil, wherein the oral supplement comprises an SLC22A9 inducer, an HIF-α inducer, and / or an agent that acidifies the patient's blood. Treating alopecia by or Treating alopecia by administering an oral supplement containing oral minoxidil, wherein the oral supplement further comprises an SLC22A9 inducer, an HIF-α inducer, and / or an agent that acidifies the patient's blood. A method comprising:

8. the acidifying agent upregulates SLC22A9 and / or downregulates AABC3; The method of claim 7.

9. the acidifying agent causes mild acidosis in the patient; The method of claim 7.

10. the HIF-α inducer comprises Juniperus cummunis extract, Green Tree extract, Glycyrrhiza glabra, o-phenanthroline, iodochlorohydroxyquinoline, and / or cobalt sulfate heptahydrate; The method of claim 7.

11. The oral minoxidil comprises minoxidil or a pharmaceutically acceptable salt thereof. The method of claim 7.

12. The minoxidil or pharmaceutically acceptable salt thereof is present in the oral minoxidil at a concentration ranging from 0.125 mg to 10 mg. The method of claim 11.

13. the acidifying agent comprises ammonium chloride, methanol, salicylate, biguanide, alcohol, polysaccharide, cyanide, and / or carbon monoxide; The method of claim 7.

14. 1. An oral composition for treating alopecia, comprising: SLC22A9 inducers, HIF-α inducers, and / or acidifiers An oral composition comprising:

15. the acidifying agent upregulates SLC22A9 and / or downregulates AABC3; The oral composition of claim 14.

16. the HIF-α inducer comprises Juniperus cummunis extract, Green Tree extract, Glycyrrhiza glabra, o-phenanthroline, iodochlorohydroxyquinoline, and / or cobalt sulfate heptahydrate; The oral composition of claim 14.

17. the acidifying agent comprises ammonium chloride, methanol, salicylate, biguanide, alcohol, polysaccharide, cyanide, and / or carbon monoxide; The oral composition of claim 14.

18. 1. A method of treating alopecia, comprising: Administering an oral composition to a patient suffering from alopecia, wherein the oral composition comprises an SLC22A9 inducer, a HIF-α inducer, and / or an acidifying agent. A method comprising:

19. the acidifying agent upregulates SLC22A9 and / or downregulates AABC3; 20. The method of claim 18.

20. the HIF-α inducer comprises Juniperus cummunis extract, Green Tree extract, Glycyrrhiza glabra, o-phenanthroline, iodochlorohydroxyquinoline, and / or cobalt sulfate heptahydrate; 20. The method of claim 18.

21. the acidifying agent comprises ammonium chloride, methanol, salicylate, biguanide, alcohol, polysaccharide, cyanide, and / or carbon monoxide; 20. The method of claim 18.

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