Methods for preventing and treating chemotherapy-induced alopecia

Abstract

Compositions and methods for treating alopecia, particularly alopecia induced by chemotherapy, using an acidifying agent or oxidant, a prooxidant compound, or an activator of P53. Compositions containing organic peroxides such as cumene hydroperoxide, tert-butyl hydroperoxide (t-BHP), hydrogen peroxide, benzoyl peroxide are preferred. The compositions can be applied subcutaneously, transdermally, or topically. Most preferably, the compositions are applied to the treatment site prior to a series of chemotherapy treatments to prevent or reduce hair loss at the treatment site.

Description

Technical Field

[0001] <Cross - Reference to Related Applications> This application claims the benefit of U.S. Provisional Application No. 63 / 357,783, filed on July 1, 2022, which is incorporated herein by reference.

[0002] <Field of the Invention> The present invention generally relates to a method of preventing or treating chemotherapy - induced alopecia by using hydrogen peroxide, organic peroxides, metal peroxides, polymeric peroxides, peroxy acids, or derivatives or analogs thereof, such as cumene hydroperoxide.

Background Art

[0003] <Description of Related Art> Hair is a unique feature that distinguishes mammals from other animals in the animal kingdom. Interestingly, although hair has no human life function, its psychological function is extremely important. Hair loss from the scalp is extremely demoralizing, and the same is true for excessive growth of body hair and facial hair.

[0004] Hair grows in three cycles: anagen, catagen, and telogen.

[0005] Anagen: Hair growth is active and is involved in determining the final length of the hair. (When not affected by the hair loss state) 80 - 90% of the hair follicles on a typical human scalp are in the anagen phase at any given time. When hair enters the anagen phase, it is the start of mitotic activity of epithelial cells. At the end of anagen, epithelial cell division decreases and stops, and the hair follicle enters an involuntary stage called catagen.

[0006] Catagen: This is the time when the lower part of the hair follicle shrinks due to apoptosis. The base of the hair follicle, together with its dermal papilla, begins to regress. The hair at this stage is called "club hair".

[0007] Telogen: The period from the completion of the regression of the hair follicle to the start of the next anagen phase is called the telogen phase. Club hair eventually falls out through an active process called exogen. The hair follicle may enter the anagen phase again before the club hair falls out. In that case, the old hair does not fall out until the hair follicle has progressed considerably into the next growth phase.

[0008] Anagen is the growth phase and lasts for 2 to 6 years. The catagen phase lasts for 1 to 2 weeks. At this stage, while the club hair moves upward towards the hair pore, the dermal papilla separates from the hair follicle. In the telogen phase, the dermal papilla completely separates from the hair follicle. This period lasts for 5 to 6 weeks. The dermal papilla moves upward and reaches the hair follicle again, and the hair matrix begins to form new hair, returning to the anagen phase. The hair follicle is most susceptible to the effects of chemotherapy during the anagen growth phase.

[0009] Alopecia is a condition in which hair partially or completely falls out from areas of the body where hair normally grows, particularly the head. Alopecia can be caused by exposure to high levels of environmental oxidants, high levels of ultraviolet light, high oxygen partial pressure, and oxidative chemicals contained in cosmetics and pharmaceuticals. Furthermore, oxidants generated during cell processes can cause damage to cell tissues. In fact, cultured keratinocytes are irreversibly damaged by high doses of oxidants or long-term treatment. Also, topical application of lipid peroxides has been shown to induce apoptosis of hair follicles in adult mice. Alopecia is a common and distressing side effect of many chemotherapeutic agents used in the treatment of cancer and other diseases. Currently, there are no effective preventive measures or FDA-approved treatment options for chemotherapy-induced alopecia (CIA). Therefore, alopecia remains one of the most distressing side effects of chemotherapy. In fact, one of the most psychologically difficult aspects of coping with cancer is the hair loss caused by chemotherapy and the associated social stigma. In one study, 35 out of 46 patients undergoing chemotherapy cited alopecia as a more important side effect than nausea. Furthermore, the psychosocial negative aspects of CIA can have a significant impact on the progression of the primary disease (e.g., cancer) and the patient's response to treatment of the disease.

[0010] In the field of CIA, progress has been made with the emergence of animal models. One of the most widely used is the neonatal rat model. For example, in 1992, through the use of the neonatal rat model, ImuVert, a biological response modifier derived from the bacterium Serratia marcescens, was demonstrated to have a protective effect against cytarabine-induced alopecia but not against cyclophosphamide-induced alopecia. Since Imuvert did not show a protective effect against cyclophosphamide (CTX)-induced alopecia, which is commonly used in clinical practice, or any combination thereof, the use of Imuvert to protect against CIA was not pursued. In subsequent animal experiments, a similar protective effect against cytarabine-induced alopecia was observed with recombinant interleukin 1β, and later with epidermal growth factor (EGF) and fibroblast growth factor. IL-1b and EGF were not used in clinical practice, similar to ImuVert, as they did not show a protective effect against CTX-induced alopecia.

[0011] As another example, in studies using human and neonatal rat models, the protective effect of the immunomodulator AS101 against CIA has been shown, and the translational validity of the neonatal rat model for the human counterpart has been demonstrated. However, when used under similar conditions, none of these formulations showed protection from alopecia induced by alkylating chemotherapy such as cyclophosphamide. Furthermore, in clinical practice, combination regimens are used that characterize chemotherapy with strong depilatory effects. Therefore, the neonatal rat model is suitable for studying various compounds and chemotherapy regimens to provide a means of screening for protective compounds. After extensive testing, it was demonstrated that pretreatment of the local area with 1,25-(OH)2D3, a vitamin D3 metabolite (also called "Calcitriol"), protected rats from the most commonly used depilatory chemotherapy. Recently, Calcitriol has been used in a proprietary topical formulation that has completed a Phase 1 clinical trial. In this Phase 1 trial, a dose escalation of Calcitriol was administered to 23 female patients undergoing chemotherapy with taxane-based anticancer agents, and Calcitriol at 5, 10, 20, 40, 60, 80 μg / mL was administered twice daily during the study period. In this clinical study, alopecia of <50% from baseline was observed in 8 patients at 7 weeks, and in 2 of these patients, alopecia of <50% was maintained even at 15 weeks. At the end of the study, since the maximum tolerated dose of the topical Calcitriol formulation was not reached, the study investigators concluded that topical Calcitriol therapy is a promising treatment and requires further investigation in a Phase 2 / 3 trial. Vitamin D3 compositions and methods for preventing chemotherapy-induced alopecia are described in detail in U.S. Patents Nos. 9,901,637 and 11,305,016, entitled "Vitamin D3 and Analogs Thereof for Treating Alopecia."

[0012] As a treatment for alopecia, other treatments than CIA are described in U.S. Patent No. 6,001,378. This '378 patent teaches using peroxidized lipids (e.g., almond oil, hazelnut oil, peanut oil, corn oil, grape seed oil, sesame oil, safflower oil, etc.) together with biologically active organosilicon compounds to treat alopecia, particularly male pattern baldness. In this '378 patent, the "peroxidized lipid" compounds used together with organosilicon compounds for alopecia treatment are not the peroxides described in connection with the invention of the present application, but are either the lipid oxidation reaction products of polyunsaturated vegetable oils and peroxides, or other oxidants for producing glyceryl triester oxides with a glyceride oxide content of 5 - 40%.

[0013] Other treatments for alopecia including CIA are disclosed in WO2022 / 035147. This '147 publication teaches orally administering salts of meta-arsenious acid to prevent hair loss and promote hair growth. U.S. Patent No. 5,877,209 discloses other treatments for preventing alopecia, but this is not related to CIA. This '209 patent discloses the use of ascorbic acid, butylhydroxytoluene, butylhydroxyanisole, or mixtures thereof to prevent alopecia. All of these prior art documents indicate that peroxides are not useful for the treatment or prevention of alopecia. In fact, the '147 publication suggests that peroxides can be a contributing factor to hair loss, and in the tests described in the '209 patent, cumene peroxide was used to induce alopecia in experimental rats, both indicating that peroxide compounds are not useful for the treatment or reduction of alopecia.

[0014] Publication WO2018 / 105941 teaches subcutaneous injection of pegylated keratin or a keratin - hyaluronic acid composite hydrogel together with a peroxide as a treatment for alopecia, and the peroxides specifically include carbamide peroxide, calcium peroxide, methyl hydroperoxide, ethyl hydroperoxide, propyl hydroperoxide, isopropyl hydroperoxide or hydrogen peroxide. In the '941 patent application, tests of keratin - hyaluronic acid - peroxide, PEG - keratin - peroxide, peroxide alone, and untreated control are shown for hair growth in a rat model. The combination of keratin - hyaluronic acid - peroxide and pegylated keratin - peroxide stimulates hair growth, but shows that for hair follicle formation, treatment with peroxide alone is worse than the untreated control. The '941 publication states that the invention can be used for the prevention of hair loss, but does not describe experiments demonstrating this or how the composition can be used for the prevention of alopecia due to chemotherapy. However, experiments using only peroxides further show that peroxides are not useful for the treatment or reduction of alopecia, particularly alopecia induced by chemotherapy (CIA).

[0015] In the technical field of compositions and methods for treating alopecia, particularly for use in treating alopecia induced by chemotherapy (CIA), there is a need for improvement in various chemotherapeutic agents and compositions and methods that can be used in treatments, including alkylating chemotherapeutic agents such as cyclophosphamide. It has not been previously known to use hydrogen peroxide, organic peroxides, derivatives or analogs, such as cumene hydroperoxide, for the treatment of alopecia. In fact, the '147 publication suggests that peroxides can be a contributing factor to alopecia, and in the tests described in the '209 patent, cumene peroxide was used to induce alopecia in test rats, both indicating that peroxide compounds are not useful for the treatment or prevention of alopecia. However, in a preferred embodiment of the present invention, by using hydrogen peroxide, organic peroxides, metal peroxides, polymeric peroxides, peroxyacids, or derivatives or analogs, such as cumene hydroperoxide, such improvements can be achieved even without including a synthetic keratin compound complex.

Summary of the Invention

[0016] <Summary of the Disclosure> The present invention relates to compositions and methods using oxidizing agents or oxidants for the treatment or prevention of alopecia, or compounds that generate said oxides when applied to the hair follicle or in the vicinity of the hair follicle for the treatment or prevention of alopecia. In one preferred embodiment of the present invention, a composition for treating, preventing, or reducing alopecia, particularly CIA, comprises (1) one or more oxidizing agents or oxidants; (2) a pro-oxidant compound that generates endogenous or in-situ peroxides, preferably one or more pro-oxidant compounds in which peroxides are generated at the application site of the treatment composition; (3) one or more activators of P53; or (4) a combination thereof, including one or more of them. In other preferred embodiments, the treatment composition further comprises a pharmaceutically acceptable vehicle or carrier for subcutaneous, transdermal, or topical application.

[0017] In one preferred embodiment, the one or more oxidizing agents or oxidants comprise one or more of hydrogen peroxide, metal peroxides, polymeric peroxides, organic peroxides, peroxy acids, or derivatives or analogs thereof. Most preferably, such peroxide compounds comprise one or more of t-BHP, cumene hydroperoxide, hydrogen peroxide, carbamide peroxide or urea peroxide, povidone-peroxide, silica xerogel hydrogen peroxide complex, calcium peroxide, zinc peroxide, barium peroxide, sodium peroxide, and benzoyl peroxide.

[0018] In other preferred embodiments, the treatment composition does not contain benzoyl peroxide. In other preferred embodiments, the treatment composition does not contain keratin, pegylated keratin, or keratin-hyaluronic acid, organic silicon, or combinations thereof. In other preferred embodiments, the treatment composition does not contain any lipid peroxides.

[0019] In other preferred embodiments, the one or more prooxidant compounds include any in-situ activators of human cell NADH oxidase and NOX gene activators. For example, the activation of such activators preferably occurs at the site of application of the treatment composition. In other preferred embodiments, the one or more prooxidant compounds include one or more of doxorubicin or other anthracyclines, cisplatin, cyclophosphamide, bleomycin, camptothecin, vinblastine, disulfiram, chelerythine, paracetamol, or imidazo[1,2-a]pyridine derivatives. In yet other preferred embodiments, the one or more prooxidant compounds include one or more inhibitors of the SOD gene, GPX gene, GSS gene, or NRF2 gene of human cells.

[0020] In other preferred embodiments, the one or more activators of P53 include MDM2-p53 modulators, and most preferably, RITA [2,5-bis(5-hydroxymethyl-2-thienyl)furan] or idasanutlin (RG-7388) or both.

[0021] In other preferred embodiments, the vehicle or carrier in the composition includes a topical gel, solution, cream, lotion, suspension, emulsion, or microemulsion, or a sterile physiologically buffered aqueous injection solution. In other preferred embodiments, the composition can be prepared for subcutaneous, transdermal, or topical delivery to a subject.

[0022] In other preferred embodiments, a method of treating or preventing alopecia, or reducing hair loss, comprises administering to a subject (1) one or more oxidizing agents or oxidants; (2) one or more pro-oxidant compounds that generate peroxide internally or in-situ; (3) one or more activators of P53; or (4) a combination thereof. In other preferred embodiments, the administering step comprises subcutaneously or transdermally administering a composition to the subject, or topically applying it locally to the subject or in the vicinity of the treatment site of the subject, and the step is carried out before the subject is administered one or more chemotherapeutic agents, which are cell cycle-specific substances, cell cycle-nonspecific substances, or a combination thereof, once or multiple times. In other preferred embodiments, the composition used in the above method is the composition according to the preferred embodiments of the present specification.

[0023] In other preferred embodiments, the method further comprises repeating the administering step at least once a day for a treatment period of at least three days before the subject receives one administration of one or more chemotherapeutic agents, and it is more preferred that this step is carried out before each administration of the chemotherapeutic agent if the subject receives multiple administrations over a certain period.

[0024] In other preferred embodiments, the administering step comprises topically applying about 0.5 g to 5 g of a composition comprising an activator and a vehicle locally to the scalp.

[0025] In another preferred embodiment, a method of treating or preventing alopecia including CIA, or a method of reducing hair loss, comprises applying a composition comprising hydrogen peroxide, a metal peroxide, a polymeric peroxide, or an organic peroxide or a derivative or analog thereof in a suitable pharmaceutical vehicle subcutaneously, transdermally, or topically to a treatment site (scalp or other site where hair loss is to be prevented). In another preferred embodiment, the method further comprises applying the composition at least once a day for at least three days. In yet another preferred embodiment, the composition is applied at least once a day for at least seven days before initiating a series of treatments with a chemotherapeutic agent or compound. This application may be repeated for subsequent series of treatments with the chemotherapeutic agent or compound. If the scalp or hair site requiring treatment is extensive, based on another preferred embodiment, the composition may be applied to the site by injection in multiple spaced-apart applications. When the composition is applied topically, the composition may be applied over the entire treatment site. In another preferred embodiment, the composition of the active agent and vehicle is applied at a dosage rate of about 1 to 20 mg per square centimeter of the treatment site. The composition used in the preferred method is most preferably according to a preferred embodiment of the present invention.

[0026] In preferred compositions and methods in another preferred embodiment, the amount of hair loss at the treatment site of a subject to which the composition is applied, particularly a subject to which a chemotherapeutic agent is administered one or more times and to which the composition is applied before the chemotherapeutic agent is administered during the treatment period, can be reduced by at least 25% on average compared to the amount of hair loss at a second site having a substantially the same size of the treatment site and the same body part of the treatment site of a subject to which the composition is not applied.

[0027] In other preferred embodiments, in preferred compositions and methods, when the chemotherapeutic agent comprises one or more of a cell cycle specific agent, a cell cycle non-specific agent, or combinations thereof, it is useful for the prevention or reduction of CIA. In other preferred embodiments, the preferred compositions and methods are useful for the prevention or reduction of CIA when the chemotherapeutic agent comprises one or more of Vp-16 (etoposide), taxanes, adriamycin, cyclophosphamide, cytosine arabinoside, or combinations thereof.

[0028] The compositions and methods according to preferred embodiments are useful for the treatment or prevention of alopecia, particularly CIA. Examples of compositions and methods that can be used in numerous chemotherapy treatments include cell cycle specific agents (e.g., cytosine arabinoside (ARA-C)) and non-cycle specific agents (e.g., cyclophosphamide), as well as taxanes alone or in combination. Further objects and advantages of the present invention will become apparent from the following description.

Brief Description of the Drawings

[0029] The compositions and methods of the present invention are further described and explained in connection with the following figures.

Figure 1A

Figure 1B

Modes for Carrying Out the Invention

[0030] <Detailed Description of Preferred Embodiments> In one preferred embodiment of the present invention, a treatment composition for treating, preventing, or reducing alopecia, particularly CIA, comprises: (1) one or more oxidizing agents or oxidants; (2) one or more prooxidant compounds that generate peroxides internally or in-situ; (3) one or more activators of P53; or (4) a combination thereof. In other preferred embodiments, the treatment composition further comprises a pharmaceutically acceptable vehicle or carrier for subcutaneous, transdermal, or topical administration. In other preferred embodiments, the vehicle of the composition comprises a topical gel, solution, cream, lotion, suspension, emulsion, or microemulsion, or a sterile physiologically buffered aqueous solution for injection.

[0031] One or more oxidizing agents or oxidants preferably comprise one or more of hydrogen peroxide, organic peroxides, metal peroxides, polymeric peroxides, hydroperoxides, peroxy acids, or derivatives or analogs thereof. More preferably, the treatment composition comprises a hydroperoxide, most preferably cumene hydroperoxide or tert-butyl hydroperoxide, although others can also be used. Other hydroperoxides that can be used include ethylbenzene hydroperoxide. In other preferred embodiments, the peroxide comprises one or more of benzoyl peroxide, valproate peroxide, acetyl peroxide, formyl hydroperoxide, propionic peroxy acid, butyric peroxy acid, urea peroxide, calcium peroxide, sodium peroxide, barium peroxide, zinc peroxide, povidone (PVP)-peroxide, and silica gel hydroperoxide or organic peroxide complex.

[0032] In one preferred embodiment, the treatment composition may or may not contain benzoyl peroxide. In one preferred embodiment, the treatment composition may or may not contain keratin or hyaluronic acid, or compounds of one or both of them, but preferably does not contain them. In other preferred embodiments, the treatment composition may or may not contain any peroxidized lipid or organosilicon compound, but preferably does not contain them.

[0033] In other preferred embodiments, a method for treating or preventing alopecia involving CIA comprises applying a composition comprising one or more oxidizing agents or oxidants, most preferably hydrogen peroxide or an organic peroxide, a polymeric peroxide, a peroxyl or hydroperoxide or derivatives or analogs thereof, subcutaneously, transdermally, or topically to the treatment site (scalp or other site where hair loss is to be prevented). In other preferred embodiments, the method further comprises applying the composition to the treatment site at least once a day for at least 3 days. In yet other preferred embodiments, the composition is applied at least once a day for at least 7 days prior to initiating a series of treatments with a chemotherapeutic agent or compound. This application may be repeated for a subsequent series of treatments with the chemotherapeutic agent or compound. If the scalp or hair site requiring treatment is larger, based on other preferred embodiments, the composition may be administered by multiple injections at intervals or topically applied to the site. When topically applied, the composition may be applied over the entire treatment site. In other preferred embodiments, the composition is applied at a dosage rate of about 1 to 20 mg per square centimeter of the treatment site. The composition used in the preferred method is most preferably according to a preferred embodiment of the present invention.

[0034] When treated according to preferred embodiments of the compositions and methods of the present invention, the hair loss rate at the treatment site in patients receiving chemotherapy is at least 25% lower, more preferably at least 50% lower, compared to patients receiving chemotherapy who are not treated according to the preferred embodiments or compared to sites where no treatment is performed.

Example

[0035] The method described in the following examples evaluates the preventive effect of cumene hydroperoxide on CIA. The following examples are for illustrative purposes only and are not intended to limit the scope of the disclosure.

[0036] Long Evans (LE) lactating rat pups were purchased from Envigo laboratories, Inc. The lactating LE rat pups were randomly assigned to a treatment group or a control group. The treatment group was subcutaneously (SC) injected with a treatment composition based on a preferred embodiment of the present invention behind the neck. The injected composition contained 100 μl of a solution of cumene hydroperoxide (concentration 80%; Sigma-Aldrich, St. Louis MO, USA) in a phosphate-buffered saline (PBS) vehicle. Cumene hydroperoxide was first diluted to a concentration of 20 μl / ml in PBS (the final concentration of injected cumene hydroperoxide was 1.8%). The injections were repeated once daily from day 5 to day 10 after birth. The control group was subcutaneously (SC) injected with only the PBS vehicle behind the neck once daily from day 5 to day 10 after birth.

[0037] From day 11 after birth, one of the following chemotherapeutic agents was intraperitoneally (i.p.) administered to a part of the treatment group and the control group: [Example I] For rats, VP-16 (Sigma-Aldrich, St. Louis MO, USA) at 1.5 mg / kg was administered continuously for 3 days; [Example II] Cytoxan (CTX) (Sigma-Aldrich, St. Louis MO, USA) at 35 mg / kg was administered only for 1 day; or [Example III] A combination of CTX and Adriamycin (ADM), where CTX at 5 mg / kg was administered for 1 day, and starting from the day after CTX administration, ADM at 2.5 mg / kg was administered continuously for 3 days. At these combined dosage concentrations, neither CTX nor ADM alone would cause hair loss.

[0038] In Example IV, from day 9 after birth, for a part of the treatment group and the control group, the chemotherapeutic agent, Cytozar-U (ARA-C) (Sigma-Aldrich, St. Louis MO, USA) at 50 mg / kg was intraperitoneally (i.p.) administered daily for 7 days. Alopecia was recorded 3 days after the last injection of ARA-C.

[0039] In each experimental example, a new group of neonatal rats was used. Alopecia was recorded 7 days after the last injection in each chemotherapy treatment example. Alopecia was recorded using the following scale: 0 = no alopecia, 1+ = 0 - 25% alopecia, 2+ = 25 - 50% alopecia, 3+ = 50 - 75% alopecia, 4+ = 75 - 100% alopecia.

[0040] Example I: Protection from alopecia induced by Vp - 16

[0041] Sixteen 5 - day - old rats were randomly divided into two groups of 8 rats each. One group of 8 rats received 100 μl of PBS by subcutaneous (SC) injection from day 5 to day 10 after birth, which served as the control. The other group of 8 rats in the experimental treatment group received a mixture of cumene hydroperoxide and PBS (described above) by SC injection from day 5 to day 10 after birth. From day 11, all rats were intraperitoneally administered 1.5 mg / kg of Vp - 16 for 3 consecutive days. Alopecia was recorded on the 7th day (20 days after birth) from the last injection of the chemotherapeutic agent. All rats in the control group had overall alopecia. On the other hand, in all rats in the experimental treatment group (administered cumene hydroperoxide), alopecia at the SC injection site was prevented (Table 1) (Figures 1A, 1B).

[0042] [Table 1]

[0043] The right sides of Figures 1A and 1B show the treated rats. As can be seen from the dark part, there is hair at the SC injection site of cumene hydroperoxide, indicating that the treatment was effective in preventing CIA near the treated site.

[0044] Example II: Protection from alopecia induced by CTX

[0045] Sixteen other rats at 5 days old were randomly divided into two groups of 8 rats each. One group of 8 rats was given 100 μl of PBS by subcutaneous injection from day 5 to day 10 after birth and served as the control in Example II. Similarly, another group of 8 rats was given a mixture of cumene hydroperoxide and PBS (described above) by subcutaneous injection from day 5 to day 10 after birth and served as the treatment group. On day 11, all rats were given CTX at 35 mg / kg intraperitoneally. Hair loss was recorded on the 7th day after the last injection of the chemotherapeutic agent. All rats in the control group were completely hairless. On the other hand, the SC injection sites of all animals in the experimental group (cumene hydroperoxide administration) were protected (Table 2).

[0046]

Table 2

[0047] Example III: Protection from CTX-ADM-induced alopecia

[0048] Sixteen other rats at 5 days old were randomly divided into two groups of 8 rats each. One group of 8 rats was given 100 μl of PBS by subcutaneous injection from day 5 to day 10 after birth and served as the control in Example III. Similarly, another group of 8 rats was given a mixture of cumene hydroperoxide and PBS (described above) by subcutaneous injection from day 5 to day 10 after birth and served as the treatment group. On day 11, all rats were given cyclophosphamide at 25 mg / kg intraperitoneally and doxorubicin at 2.5 mg / kg once a day for 3 days intraperitoneally. Hair loss was recorded on the 7th day after the last injection of the chemotherapeutic agent. All rats in the control group were completely hairless. On the other hand, the SC injection sites of all animals in the experimental treatment group (cumene hydroperoxide administration) were protected (Table 3).

[0049]

Table 3

[0050] Example IV: Protection from Ara-C-induced alopecia

[0051] Sixteen other 5-day-old rats were randomly divided into two groups of 8 rats each. One group of 8 rats was given 100 μl of PBS subcutaneously from day 5 to day 10 after birth as a control. The experimental treatment group of the other 8 rats was given a mixture of cumene hydroperoxide and PBS (described above) subcutaneously from day 5 to day 10 after birth. From day 9, all rats were given Ara-C 50 mg / kg intraperitoneally for 7 days. Alopecia was recorded on day 7 after the last injection of the chemotherapeutic agent. All rats in the control group were completely alopecic. On the other hand, the SC injection sites of all rats in the experimental treatment group (cumene hydroperoxide administration) were protected (Table 4).

[0052]

Table 4

[0053] The above study shows that the administration of reactive oxygen species (ROS), most preferably 100 μl of cumene hydroperoxide (80% concentrate) diluted to 20 μl / ml with PBS subcutaneously daily starting several days before depilatory chemotherapy, effectively prevents chemotherapy-induced alopecia. Although not shown above, in other experiments in which neonatal rats were given a dose of cumene hydroperoxide about 10 times or more the concentration that showed a protective effect from alopecia, alopecia was observed. Similarly, pretreatment with peroxide was essential to obtain a protective effect from CIA. For example, even when peroxide was used simultaneously with the chemotherapeutic agent, a protective effect from CIA was not obtained.

[0054] The experiment shows that 1) in the treatment composition according to the preferred embodiment, the non-toxic / non-apoptotic concentration of the oxidizing agent can protect hair follicles from alopecia when the administration of the oxidizing agent is carried out prior to chemotherapy and is administered locally by subcutaneous, transdermal, or topical administration.

[0055] When used in humans, multiple injections of the formulation for SC are not practical and may be painful, so topical application is preferred. However, injectable formulations can also be used. One preferred composition contains a peroxide concentration of 0.1 - 5% w / w based on the peroxide value equivalent to hydrogen peroxide for the SC injection formulation. Other preferred compositions contain a peroxide concentration of 0.5 - 15% w / w based on the peroxide value equivalent to hydrogen peroxide for topical application.

[0056] The above experiments have demonstrated how the use of exogenous peroxide compounds can prevent or reduce CIA. In other preferred embodiments, the treatment composition contains one or more prooxidant compounds, and by topically applying one or more prooxidant compounds, endogenous peroxide or in-situ peroxide, i.e., hydrogen peroxide, is generated within or around the hair follicle to prevent or reduce CIA. Topical application of prooxidant compounds can stimulate the biological cell response in humans to increase hydrogen peroxide, peroxide anion, or peroxyl radical in cells and tissues, and related reactive oxygen species. Generally, prooxidant compounds increase in-situ hydrogen peroxide by activating NADPH oxidase to generate hydrogen peroxide from oxygen or by inhibiting superoxide dismutase or other antioxidant enzymes. Prooxidants that can be used in the treatment composition according to other preferred embodiments for preventing or reducing CIA include one or more of doxorubicin or other anthracyclines, cisplatin, bleomycin, camptothecin, vincblastine, disulfiram, cyclophosphamide, khellin, paracetamol, and imidazo[1,2-a]pyridine derivatives. Most preferably, these prooxidants are applied topically. In one preferred embodiment, these prooxidants are applied without using any oxidants. In other preferred embodiments, prooxidants can also be applied in combination with oxidants such as peroxides.

[0057] The reaction of human cells to higher concentrations of hydrogen peroxide can activate the biological pathway of p53 and result in an apoptotic response of antioxidants or prooxidants. Since oxidative stress activates P53, it is considered that activators of P53 can also be used for the prevention of CIA. Inhibitors of MDM2 or MDMX maintain the activation of p53 towards apoptosis of cells. Without limiting the specific compounds that can be used, CIA can be prevented or reduced by locally applying modulators of the MDM2-p53 or MDMX-p53 pathway. Examples of MDM2-p53 pathway modulators that can be used in the compositions according to other preferred embodiments include RITA [2,5-bis(5-hydroxymethyl-2-thienyl)furan], nutlin, and idasanutlin (a cis-imidazoline analog). In a preferred embodiment, these DM2-p53 pathway modulators are applied without using any oxidant or prooxidant. In another preferred embodiment, the DM2-p53 pathway modulator may often be applied in combination with an oxidant such as peroxide and / or a prooxidant.

[0058] In still other preferred embodiments, a composition for treating and / or preventing alopecia, particularly alopecia caused by one or more chemotherapeutic agents, comprises the components and amounts in one or more of the items described below:

[0059] (A): A composition for treating or preventing alopecia, comprising (1) (a) one or more oxidizing agents or oxidants; (b) one or more prooxidant compounds that generate endogenous peroxide or in-situ peroxide; (c) one or more activators of P53; or (d) a combination thereof; and (2) optionally a carrier.

[0060] (B): The composition of item (A), wherein the one or more oxidizing agents include one or more of hydrogen peroxide, organic peroxide, polymeric peroxide, metal peroxide, peroxy acid, hydroperoxide, or derivatives or analogs thereof.

[0061] (C): The composition of any one of items (A) to (B), wherein the composition is configured to be applied subcutaneously, transdermally, or topically to the treatment site.

[0062] (D): The composition of any one of items (A) to (C), wherein the one or more oxidizing agents include one or more of cumene hydroperoxide, tert-butyl hydroperoxide (t-BHP), or benzoyl peroxide.

[0063] (E): The composition of any one of items (A) to (D), wherein alopecia is induced by one or more chemotherapeutic agents including one or more of cell cycle specific substances, non-cell cycle specific substances, or combinations thereof.

[0064] (F): The composition of any one of items (A) to (E), wherein the one or more prooxidant compounds include any in-situ activator of human cell NADH oxidase and NOX gene activator.

[0065] (G): The composition of any one of items (A) to (F), wherein the one or more prooxidant compounds include one or more of doxorubicin or other anthracyclines, cisplatin, bleomycin, camptothecin, vincblastine, disulfiram, khellin, cyclophosphamide, paracetamol, or imidazo[1,2-a]pyridine derivatives, and the composition is applied topically.

[0066] (H): A composition of any one of items (A) to (G), wherein the one or more pro-oxidant compounds comprise one or more inhibitors of the SOD gene, GPX gene, GSS gene, or NRF2 gene of human cells.

[0067] (I): A composition of any one of items (A) to (H), wherein the one or more activators of p53 comprise an MDM2-p53 modulator.

[0068] (J): A composition of item (I), wherein the MDM2-p53 modulator comprises RITA or idasanutlin or both.

[0069] (K): A composition of any one of items (A) to (J), wherein the alopecia is induced by one or more chemotherapeutic agents comprising one or more of a cell cycle-specific substance, a non-cell cycle-specific substance, or a combination thereof.

[0070] (L): A composition of any one of items (A) to (K), wherein the one or more chemotherapeutic agents comprise Vp-16, a taxane, doxorubicin, cyclophosphamide, cytosine arabinoside, or a combination thereof.

[0071] (M): A composition of any one of items (A) to (L), wherein the composition reduces the amount of hair loss at a first site to which the composition is applied by at least 25% compared to the amount of hair loss at a second site of the same size as the first site to which the composition is not applied.

[0072] (N): A composition of any one of items (A) to (M), wherein the one or more chemotherapeutic agents comprise Vp-16, a taxane, doxorubicin, cyclophosphamide, cytosine arabinoside, or a combination thereof.

[0073] (O): A composition of item (N), wherein the taxane comprises paclitaxel, docetaxel, cabazitaxel, or a combination thereof.

[0074] Still other preferred embodiments are methods of treating or preventing alopecia, particularly alopecia induced by one or more chemotherapeutic agents, and include steps, components, and amounts according to one or more of the following items.

[0075] (P): A method of treating or preventing alopecia, comprising supplying a composition to a subject in need of such treatment or prevention, the composition comprising: (1) one or more oxidizing agents or oxidants; (2) one or more prooxidant compounds that generate endogenous peroxides or in-situ peroxides; (3) one or more activators of P53; or (4) a combination thereof.

[0076] (Q): The method of item (P), wherein the supplying step comprises: (a) applying the composition subcutaneously, transdermally, or topically to or in the vicinity of the treatment site of the subject; (b) the supplying step is carried out before the subject receives one or more administrations of a chemotherapeutic agent; (c) the chemotherapeutic agent comprises one or more of a cell cycle-specific substance, a non-cell cycle-specific substance, or a combination thereof.

[0077] (R): The method of any one of items (P) to (Q), wherein the one or more oxidizing agents comprise one or more of hydrogen peroxide, organic peroxides, polymeric peroxides, metal peroxides, peroxyacids, hydroperoxides, or derivatives or analogs thereof.

[0078] (S): The method of any one of items (P) to (R), wherein the one or more oxidizing agents comprise cumene hydroperoxide or benzoyl peroxide.

[0079] (T): The method of any one of items (P) to (S), wherein the composition further comprises a carrier.

[0080] (U): The method of any one of items (P) to (T), wherein the composition is administered subcutaneously to or in the vicinity of the treatment site.

[0081] (V): A method of any one of items (P) to (U), the method comprising reducing the amount of hair removal at the treated site by at least 25% compared to the amount of hair removal at a second site of the same size as the treated site where the treatment is not performed.

[0082] (W): A method of any one of items (P) to (V), (a) the composition comprises one or more oxidizing agents, (b) the one or more oxidizing agents comprise a peroxide composition, and (c) the supplying step comprises topically applying about 0.5 to 10% by weight of the peroxide composition.

[0083] (X): A method of item (W), wherein the peroxide composition comprises one or more of hydrogen peroxide, organic peroxide, polymeric peroxide, metal peroxide, peroxy acid, hydroperoxide, or derivatives or analogs thereof.

[0084] (Y): A method of any one of items (W) to (X), wherein the peroxide composition comprises cumene hydroperoxide.

[0085] (Z): A method of any one of items (W) to (X), wherein the peroxide composition comprises benzoyl peroxide.

[0086] (AA): A method of any one of items (P) to (Z), wherein the one or more prooxidant compounds comprise any in-situ activator of human cell NADH oxidase and NOX gene activator.

[0087] (BB): A method of any one of items (P)-(AA), wherein the one or more prooxidant compounds comprise one or more of doxorubicin or other anthracyclines, cisplatin, bleomycin, camptothecin, vincblastine, disulfiram, khellin, paracetamol, or imidazo[1,2-a]pyridine derivatives, and the composition is topically applied.

[0088] (CC): A method according to any one of items (P)-(BB), wherein the one or more pro-oxidant compounds comprise one or more inhibitors of the SOD gene, GPX gene, GSS gene, or NRF2 gene of human cells.

[0089] (DD): A method according to any one of items (P)-(CC), wherein the one or more activators of p53 comprise an MDM2-p53 modulator.

[0090] (EE): A method according to item (DD), wherein the MDM2-p53 modulator comprises RITA or idasanutlin or both.

[0091] (FF): A method according to any one of items (P)-(EE), further comprising repeating the step of supplying the subject at least once a day during a treatment period including at least 7 days until the subject receives one or more administrations of a chemotherapeutic agent.

[0092] (GG): A method according to any one of items (P)-(FF), wherein the subject receives multiple administrations of a chemotherapeutic agent over a period of time, and the method further comprises repeating the step of supplying the subject at least once a day during a treatment period including at least 7 days until the subject receives each administration of the chemotherapeutic agent.

[0093] (HH): A method according to any one of items (P)-(GG), wherein the chemotherapeutic agent comprises Vp-16, taxane, adriamycin, cyclophosphamide, cytosine arabinoside, or a combination thereof.

[0094] (II): A method according to any one of items (P)-(HH), wherein the composition is according to any one of items (A)-(O).

[0095] As used herein, the terms "treat", "treating", "treatment", etc. refer to removing, reducing, or ameliorating a disease or disorder and / or symptoms associated therewith. It is not intended to preclude that treating a disease or condition does not require completely removing the disease, disorder, or symptoms associated therewith.

[0096] As used herein, the terms "treat", "treating", "treatment", etc. also include "preventive treatment", which refers to reducing the likelihood of a disease or disorder recurring or the likelihood of a previously controlled disease or disorder recurring in a subject who does not have the disease or disorder but has a risk or susceptibility of the disease or disorder recurring or reappearing. "Treatment" and its synonyms are intended to administer a therapeutically effective amount of the compositions of the present disclosure to a human in need of such treatment. Within the scope of the meaning of the present disclosure, "treatment" includes, in addition to preventing recurrence or preventing a phase, treating acute or chronic signs, symptoms, and / or dysfunctions. Treatment can be carried out symptomatically, for example, to suppress symptoms. Treatment may be affected in the short term, may be directionally oriented in the medium term, or may require long-term treatment, for example, as part of maintenance therapy. As used herein, the terms "prevent", "preventing", and "prevention" are recognized in the art and are widely understood to include the administration of a composition when used in connection with symptoms such as alopecia, reducing the frequency of symptoms of a medical disorder in a subject or delaying the onset of symptoms as compared to a subject not receiving the composition. Therefore, prevention of alopecia includes, for example, reducing the amount of hair loss, promoting hair retention, and promoting hair growth in treated hair follicles or in the vicinity thereof in a treated population as compared to an untreated control group, and the reduction and promotion are, for example, statistically and / or clinically significant amounts.

[0097] The compositions and methods disclosed herein may include compositions and methods for the treatment or prevention of alopecia. The compositions and methods disclosed herein may include compositions and methods for treating alopecia. The compositions and methods disclosed herein may include compositions and methods for preventing alopecia.

[0098] All numerical values, ratios, or percentages presented herein as ranges include the individual amounts, numerical values, or ratios within that range, and all combinations of subsets within that range, including subsets that overlap from one preferred range to a more preferred range. Unless specifically excluded, any preferred features and optional components for any embodiment of the compositions and / or steps of the methods described herein can be used in any other embodiment, even if not specifically described herein for that particular embodiment. Those skilled in the art will understand, upon reading this specification and the examples included herein, that modifications and variations to the compositions and their methods of use are possible within the scope of the present invention. Also, the scope of the invention disclosed herein is intended to be limited only by the broadest interpretation of the appended claims to which the inventor is legally entitled.

Claims

1. A composition for reducing the amount of hair loss caused by alopecia induced by a chemotherapy agent, The aforementioned composition contains an oxidizing agent, The oxidizing agent is a composition comprising one or more of hydrogen peroxide, benzoyl peroxide, tert-butyl hydroperoxide (t-BHP), and povidone-peroxide.

2. The composition according to claim 1, wherein the oxidizing agent comprises hydrogen peroxide.

3. The composition according to claim 1, wherein the oxidizing agent comprises benzoyl peroxide.

4. The composition according to claim 1, wherein the oxidizing agent comprises povidone-peroxide.

5. The composition according to claim 1, wherein the oxidizing agent is the sole active ingredient in the composition.

6. The composition according to claim 5, wherein the oxidizing agent comprises one or more of hydrogen peroxide, benzoyl peroxide, tert-butyl hydroperoxide (t-BHP), and povidone-peroxide.

7. The composition according to claim 5, wherein the oxide is hydrogen peroxide.

8. The composition according to claim 5, wherein the oxidizing agent is benzoyl peroxide.

9. The composition according to claim 5, wherein the oxidizing agent comprises povidone-peroxide.

10. The composition according to any one of claims 1 to 9, wherein the composition is configured to be applied subcutaneously, transdermally, or topically to a treatment site.

11. The composition according to any one of claims 1 to 9, wherein the chemotherapeutic agent comprises one or more of Vp-16, taxane, adriamycin, cytoxane, or cytosine arabinoside.

12. The composition according to claim 11, wherein the composition reduces the amount of hair loss in a first area to which the composition is applied by at least 25% compared to the amount of hair loss in a second area of ​​similar size to the first area but to which the composition is not applied.

13. The composition according to claim 11, wherein the taxane comprises paclitaxel, docetaxel, cavegitaxel, or a combination thereof.

14. The composition according to any one of claims 1 to 9, wherein the oxidizing agent is in an amount sufficient to result in a peroxide concentration of 0.1 to 15% w / w based on the peroxide value equivalent to hydrogen peroxide.

15. The composition according to claim 12, wherein the oxidizing agent is in an amount sufficient to result in a peroxide concentration of 0.1 to 15% w / w based on the peroxide value equivalent to hydrogen peroxide.

16. The composition according to any one of claims 1 to 9, wherein the oxidizing agent is in an amount sufficient to result in a peroxide concentration of 0.1 to 5% w / w based on the peroxide value equivalent to hydrogen peroxide, and the composition is configured to be administered by subcutaneous injection.

17. The composition according to any one of claims 1 to 9, wherein the composition comprises 0.5 to 10% by weight of an oxidizing agent and is configured as a topical application composition.

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