Composition for preventing, alleviating or treating peripheral neuropathy and use thereof

Abstract

The use of a TRPM8 activator for preparing a composition for preventing, alleviating or treating peripheral neuropathy in a subject in need thereof. A composition for preventing, alleviating or treating peripheral neuropathy, comprising an effective amount of the TRPM8 activator and a pharmaceutically or cosmetically acceptable carrier.

Description

Compositions for the prevention, relief or treatment of peripheral neuropathy and their uses This disclosure claims priority to US63 / 735,895, the entire text of which is incorporated herein by reference. Technical Field

[0001] This disclosure relates to compositions for the prevention, relief or treatment of neuropathy, and in particular to the prevention, relief or treatment of peripheral neuropathy. Background Technology

[0002] Peripheral neuropathy refers to damage to the peripheral nerves, affecting the sensory, motor, or autonomic nerve functions of the limbs, such as the hands and feet. This nerve damage is crucial to the limbs and extremities, leading to abnormal signal transmission and, in severe cases, impacting daily life. For example, patients often experience difficulty walking or balance problems due to numbness or loss of proprioception in their limbs. Furthermore, the abnormal pain caused by neuropathy (such as burning or tingling pain) often worsens at night, leading to severe sleep disorders such as difficulty falling asleep, frequent awakenings, or fragmented sleep structure, which in turn triggers a vicious cycle of daytime fatigue, anxiety, or depression.

[0003] However, current clinical treatment options for the aforementioned neuropathies are quite limited. Oral standard treatments such as antiepileptic drugs (e.g., gabapentin or pregabalin) or antidepressants (e.g., duloxetine) can partially relieve neuropathic pain, but they are often accompanied by systemic side effects such as drowsiness, dizziness, cognitive impairment, and edema, which seriously affect patient adherence to medication.

[0004] In conclusion, how to provide an efficient, simple, safe, and side-effect-free method to prevent, alleviate, or treat peripheral neuropathy is a problem that urgently needs to be solved in this field. Summary of the Invention

[0005] In view of the above problems, this disclosure provides the use of a Transient Receptor Potential Cation Channel Subfamily M Member 8 (TRPM8) activator for the preparation of compositions for the prevention, relief or treatment of peripheral neuropathy in subjects with such needs.

[0006] This disclosure also provides a composition for the prevention, relief or treatment of peripheral neuropathy, comprising: an effective amount of TRPM8 activator and a pharmaceutically or cosmetically acceptable carrier.

[0007] In at least one embodiment of this disclosure, the TRPM8 activator may be selected from at least one of the group consisting of 5-methyl-2-(prop-2-yl)cyclohexane-1-ol, 1,3,3-trimethyl-2-oxobicyclo[2.2.2]octane and 3-(2-hydroxyphenyl)-6-(3-nitrophenyl)-3,4-dihydropyrimidine-2(1H)-one. In some embodiments, the combination of 1,3,3-trimethyl-2-oxobicyclo[2.2.2]octane and 5-methyl-2-(prop-2-yl)cyclohexane-1-ol or the combination of 1,3,3-trimethyl-2-oxobicyclo[2.2.2]octane and 3-(2-hydroxyphenyl)-6-(3-nitrophenyl)-3,4-dihydropyrimidine-2(1H)-one can produce a synergistic effect. Compared with the individual application of the components, the combined application can achieve better efficacy at a lower concentration, thus avoiding skin irritation due to excessive concentration and reducing mass production costs.

[0008] In at least one embodiment disclosed herein, the TRPM8 activator can effectively prevent, alleviate or treat peripheral neuropathy caused by chemotherapy or diabetes, and can also improve sleep disorders and enhance sleep quality.

[0009] In at least one embodiment of this disclosure, the composition can be applied topically to the skin of a subject, for example, by formulation as a topical dosage form for application to the skin of a subject, or by application, impregnation, or integration into wearable items or medical dressings to facilitate prolonged contact and / or continuous release of the TRPM8 activator to the skin of the subject. Therefore, this disclosure avoids common systemic side effects (such as dizziness, edema, or cognitive impairment) compared to standard oral treatments, providing patients with a more effective, convenient, safe, and quality-of-life-benefit treatment option. Attached Figure Description

[0010] Figure 1 is a schematic diagram of the Von Frey test according to at least one embodiment of the present disclosure. Figure 2 is a flowchart of the treatment of chemotherapy-induced peripheral neuropathy (CIPN) with TRPM8 activator according to at least one embodiment of the present disclosure. ip: intraperitoneal injection. Figure 3 is a line graph of the Von Frey test results of the treatment of CIPN with TRPM8 activator according to at least one embodiment of the present disclosure. HE: 5-methyl-2-(prop-2-yl)cyclohexane-1-ol; EU: 1,3,3-trimethyl-2-oxobicyclo[2.2.2]octane; AG: 3-(2-hydroxyphenyl)-6-(3-nitrophenyl)-3,4-dihydropyrimidin-2(1H)-one. *: P<0.05 indicates a statistically significant difference compared to the solvent control group. Figure 4 is a flowchart of the treatment of diabetic peripheral neuropathy with TRPM8 activator according to at least one embodiment of the present disclosure. STZ: streptozotocin. ip: intraperitoneal injection. Figure 5 is a line graph of the Von Frey test results of the treatment of diabetic peripheral neuropathy with TRPM8 activator according to at least one embodiment of the present disclosure. HE: 5-methyl-2-(prop-2-yl)cyclohexane-1-ol; EU: 1,3,3-trimethyl-2-oxobicyclo[2.2.2]octane; AG: 3-(2-hydroxyphenyl)-6-(3-nitrophenyl)-3,4-dihydropyrimidin-2(1H)-one. *: P<0.05, indicating a statistically significant difference compared to the solvent control group. Figure 6 is a flowchart of the sleep analysis test with TRPM8 activator according to at least one embodiment of the present disclosure. ZT: time factor. HE: 5-Methyl-2-(prop-2-yl)cyclohexane-1-ol; EU: 1,3,3-trimethyl-2-oxobicyclo[2.2.2]octane. The left graph of Figure 7 is a histogram of the time required to fall asleep according to at least one embodiment of the present disclosure. The right graph of Figure 7 is a histogram of the results of the Quiet Sleep (QS) interruption analysis according to at least one embodiment of the present disclosure. HE: 5-Methyl-2-(prop-2-yl)cyclohexane-1-ol; EU: 1,3,3-trimethyl-2-oxobicyclo[2.2.2]octane. The left graph of Figure 8 is a line graph of the Theta wave activity changes during the QS periods (4 to 6 hours, 6 to 8 hours, 8 to 12 hours, 10 to 12 hours) according to at least one embodiment of the present disclosure. HE: 5-Methyl-2-(prop-2-yl)cyclohexane-1-ol; EU: 1,3,3-trimethyl-2-oxobicyclo[2.2.2]octane. The right-hand plot of Figure 8 is a histogram of Theta wave activity variations during the QS period (4 to 12 hours) according to at least one embodiment of this disclosure.HE: 5-Methyl-2-(prop-2-yl)cyclohexane-1-ol; EU: 1,3,3-trimethyl-2-oxobicyclo[2.2.2]octane. P<0.05 indicates a statistically significant difference between the solvent control group and the baseline value. *: P<0.05 indicates a statistically significant difference between the HE group and the HE+EU group and the solvent control group. #: P<0.05 indicates a statistically significant difference between the HE group and the solvent control group. The left graph of Figure 9 is a line graph showing the Delta wave activity changes during the QS period (4 to 6 hours, 6 to 8 hours, 8 to 12 hours, and 10 to 12 hours) according to at least one embodiment of the present disclosure. The right graph of Figure 9 is a histogram showing the Delta wave activity changes during the QS period (4 to 12 hours) according to at least one embodiment of the present disclosure. HE: 5-methyl-2-(prop-2-yl)cyclohexane-1-ol; EU: 1,3,3-trimethyl-2-oxobicyclo[2.2.2]octane. P<0.05 indicates a statistically significant difference between the solvent control group and the baseline value. *: P<0.05 indicates a statistically significant difference between the HE+EU group and the solvent control group. Detailed Implementation

[0011] The following embodiments are provided to illustrate this disclosure in detail. Those skilled in the art will readily understand the advantages and effects of this disclosure upon reading it, and it can be implemented or applied in other different embodiments. Therefore, the following embodiments for carrying out this disclosure can be modified and / or changed without departing from its various aspects and scope of application, and any element or method within the scope of this disclosure can be combined with any other element or method disclosed in any embodiment of this disclosure.

[0012] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure pertains. Otherwise, some terms used herein have the meanings set forth in the specification.

[0013] The terms "comprising," "including," "having," "containing," and any other variations thereof, as used herein, should be interpreted as non-exclusive open-ended conjunctions. For example, when describing a subject as "comprising" a requirement, it may additionally include other ingredients, compositions, steps, etc., unless otherwise stated, and should not exclude other requirements. The term "composed of" should be interpreted as an exclusive closed-ended conjunction. For example, when describing a subject as "composed of a requirement," it indicates the exclusion of other ingredients, compositions, steps, etc. The term "mainly composed of" should be interpreted as a semi-open-ended conjunction, falling between the above open-ended and closed-ended conjunctions. For example, when describing a subject as "mainly composed of a requirement," it does not exclude other ingredients, compositions, steps, etc., described in the specification but not substantially affecting this requirement.

[0014] Unless the context clearly indicates otherwise, the singular articles "a" and "the" may be used to refer to one or more (i.e., more than one) elements. The conjunctions "or" and "and / or" are used interchangeably unless otherwise clearly stated.

[0015] As used herein, the phrase "at least one" refers to one or more requirements and should be understood to mean at least one requirement selected from any one or more of the listed requirements, but not necessarily including at least one of each of the listed requirements, and does not exclude any combination of the listed requirements. This definition also allows for the presence of requirements other than those identified in the list of requirements referred to by the phrase "at least one," whether related to or unrelated to those identified requirements. Therefore, as a non-limiting example, "at least one of A and B" (equivalent to "at least one of A or B" or "at least one of A and / or B") in one embodiment may refer to at least one A, including more than one A as needed, with no B (and including elements other than B as needed); in another embodiment, it is at least one B, including more than one B as needed, with no A (and including elements other than A as needed); in yet another embodiment, it is at least one A, including more than one A as needed, and at least one B, including more than one B as needed (and including other elements as needed).

[0016] The numerical ranges used herein are inclusive and composable. Any value falling within these ranges can be considered a maximum or minimum value from which subranges can be derived. For example, the numerical range "0.01 wt% to 16 wt%" includes any subrange between the minimum value of 0.01 wt% and the maximum value of 16 wt%, such as subranges from 0.01 wt% to 0.1 wt%, 2 wt% to 8 wt%, and from 10 wt% to 16 wt%. Furthermore, multiple values ​​used herein can be selected as maximum and minimum values ​​as needed to derive numerical ranges. For example, numerical ranges from 2 wt% to 4 wt%, 2 wt% to 8 wt%, and 4 wt% to 8 wt% can be derived from values ​​of 2 wt%, 4 wt%, and 8 wt%.

[0017] While the numerical ranges and parameters described in this disclosure are approximate, the values ​​presented in specific examples are reported as precisely as possible. However, any value is inherently subject to variation, which may be caused by factors such as experimental error, typical errors in measurement or operating procedures during the preparation of compounds, compositions, concentrates, or formulations, the source of the starting materials or ingredients used, differences in manufacturing or purity, or similar considerations. Therefore, the term "about" as used herein generally means a variation within ±20%, ±10.0%, ±5.0%, ±1.0%, 0.5%, or ±0.1% of a given value or range. For example, 1% by weight concentration can range from 0.8% by weight to 1.2% by weight. Alternatively, the term "about" means within an acceptable standard error range of average values ​​as considered by someone of ordinary skill in the art. Except in operational / working instances, or unless expressly stated otherwise, all numerical ranges, quantities, values, and percentages disclosed herein (e.g., material quantity, duration, temperature, operating conditions, quantity ratios, and similar parameters) should be understood to be modified by the term "about" in all cases. Therefore, unless indicated to the contrary, the numerical parameters set forth in this disclosure and the appended claims are approximate values ​​that may vary as needed. Finally, each numerical parameter should be interpreted at least according to the number of significant figures reported and by applying common rounding techniques.

[0018] definition

[0019] In this article, the term "TRPM8" refers to Transient Receptor Potential Cation Channel Subfamily M Member 8, and the term "TRPM8 activator" refers to a substance that can activate TRPM8 receptors. TRPM8 is an ion channel distributed on sensory neurons, primarily responsible for sensing cold stimuli. For example, it is activated when the temperature is low or upon contact with a TRPM8 activator, producing a cooling sensation. TRPM8 activators can cause TRPM8 channels to open, allowing ions such as sodium, potassium, or calcium to enter the cell, producing a depolarization reaction, thereby transmitting a cooling sensation or a motor response to cold.

[0020] The term "treatment" as used herein includes the partial or complete elimination of a symptom, disease, or condition, or one or more symptoms associated with the symptom, disease, or condition, or the partial or complete elimination of the cause of the symptom, disease, or condition itself. The term "prevention" as used herein includes delaying and / or preventing the onset of a symptom, disease, or condition and / or its accompanying symptoms, preventing a subject from developing a symptom, disease, or condition, or reducing the risk of a subject developing a symptom, disease, or condition. The term "relief" as used herein includes the reduction of one or more symptoms of a symptom, disease, or condition (e.g., pain), but does not necessarily mean the eradication of the symptom, disease, or condition. These terms may also include the reduction of side effects associated with the active ingredient.

[0021] As used herein, the terms "subject" and "patient" are used interchangeably to refer to humans or other animals. In at least one embodiment of this disclosure, the subject may be a mammal, such as, but not limited to, humans, non-human primates (e.g., monkeys or apes), rodents (e.g., mice, rats, or guinea pigs), or livestock (e.g., rabbits, pigs, sheep, cattle, or horses). Furthermore, unless specifically indicated, the subject includes subjects of different sexes. In some preferred embodiments, the subject may be a human or a mouse.

[0022] As used herein, the term "application" means the delivery of an active ingredient (e.g., a TRPM8 activator) to a subject by a method or route, such that at least a portion of the active ingredient is located at a desired site to produce a desired effect. In at least one embodiment of this disclosure, the TRPM8 activator may be a topical or transdermal formulation applied to the skin of a subject, but this disclosure is not limited thereto.

[0023] As used herein, the term "effective amount" refers to an amount of an active ingredient or pharmaceutical composition sufficient to treat, prevent, or alleviate a condition, disease, or ailment in a subject who needs it. A specific effective amount can vary depending on factors such as, but not limited to, the specific condition, disease, or ailment being treated, the subject's physical condition (e.g., weight, age, or sex), the subject's species type, the duration of treatment, the nature of any concurrent treatments (if any), the specific formulation used, the type of carrier, the route of administration, and the possibility of co-administration with other treatments. An effective amount may be suitably divided into single, double, or multiple doses for administration over a specified time period.

[0024] As used herein, the terms "composition" or "formulation" refer to a mixture of excipients or other chemicals prepared according to a specific formulation and preparation procedure. Formulations constitute the final or intermediate form of a pharmaceutical, cosmetic, or complementary product, such as a solution, gel, or foam. A composition may contain a pharmaceutical product, if applicable. The terms "composition" and "formulation" are used interchangeably in this application.

[0025] As used herein, the term "pharmaceutical or cosmetically acceptable carrier" refers to pharmaceutically or cosmetically acceptable materials, compositions, or excipients, such as, but not limited to, liquid or solid fillers, binders, diluents, preservatives, biocompatible solvents, disintegrants, lubricants, suspending agents, flavoring agents, encapsulating materials, thickeners, acids, surfactants, complexing agents, wetting agents, or any combination thereof. In some embodiments, each component is "pharmaceutically or cosmetically acceptable" in the sense of compatibility with other ingredients in a cosmetic or pharmaceutical formulation and is suitable for contact with the tissues or organs of a subject (e.g., human or other animal) without excessive toxicity, irritation, allergic reactions, immunogenicity, or other problems or complications, with a proportionate and reasonable benefit / risk ratio. See Remington: The Science and Practice of Pharmaceuticals, 22nd ed.; Allen, ed.: Philadelphia, PA, 2012; Handbook of Pharmaceutical Excipients, 7th ed.; Rowe et al., ed.; Pharmaceutical Press and American Pharmaceutical Association: 2012; Handbook of Pharmaceutical Additives, 3rd ed.; Ash and Ash, ed.; Gower Publishing Company: 2007; Pre- and Formulation Drugs, 2nd ed.; Gibson, ed.; CRC Press LLC: Boca Raton, FL, 2009.

[0026] As used herein, the term "active ingredient" refers to a compound, disease, or condition that is administered to a subject, alone or in combination with one or more pharmaceutically or cosmetically acceptable carriers, to prevent, alleviate, or treat a symptom, disease, or condition.

[0027] One embodiment of this disclosure is the use of a TRPM8 activator for preparing a composition for the prevention, relief, or treatment of peripheral neuropathy in a subject with a need. Another embodiment of this disclosure is a composition for the prevention, relief, or treatment of peripheral neuropathy, comprising an effective amount of the TRPM8 activator and a pharmaceutically or cosmetically acceptable carrier. Yet another embodiment of this disclosure is a method for the prevention, relief, or treatment of peripheral neuropathy, comprising administering an effective amount of the TRPM8 activator to a subject with a need.

[0028] In at least one embodiment of this disclosure, the TRPM8 activator may include at least one selected from the group consisting of 5-methyl-2-(prop-2-yl)cyclohexane-1-ol, 1,3,3-trimethyl-2-oxobicyclo[2.2.2]octane and 3-(2-hydroxyphenyl)-6-(3-nitrophenyl)-3,4-dihydropyrimidine-2(1H)-one.

[0029] In at least one embodiment of this disclosure, the TRPM8 activator may comprise 1,3,3-trimethyl-2-oxobicyclo[2.2.2]octane. In some embodiments, the TRPM8 activator may comprise a combination of 1,3,3-trimethyl-2-oxobicyclo[2.2.2]octane and 5-methyl-2-(prop-2-yl)cyclohexane-1-ol or a combination of 1,3,3-trimethyl-2-oxobicyclo[2.2.2]octane and 3-(2-hydroxyphenyl)-6-(3-nitrophenyl)-3,4-dihydropyrimidin-2(1H)-one.

[0030] In at least one embodiment of this disclosure, the causes of peripheral neuropathy in the subject may include side effects of chemotherapy drugs, diabetes, long-term compression, vitamin deficiency, infection, autoimmune disease, drugs or poisoning, etc., but this disclosure is not limited to these.

[0031] In at least one embodiment of this disclosure, the subject may be a patient receiving chemotherapy. Chemotherapy-induced peripheral neuropathy (CIPN) is primarily caused by the neurotoxicity of some chemotherapy drugs, which can damage or interfere with sensory, motor, and autonomic nerve fibers. In some embodiments, such chemotherapy drugs may be platinum-based (e.g., cisplatin, oxaliplatin), taxanes (e.g., paclitaxel), vinca alkaloids (e.g., vincurstine), and / or bortezomib, etc. Administration of these chemotherapy drugs to the subject may lead to neuronal damage, microtubule structure changes, or mitochondrial dysfunction, thereby resulting in abnormal nerve conduction. In some embodiments, administration of these chemotherapy drugs to the subject induces nerve hypersensitivity, and the pain sensitivity persists. Treatment with a TRPM8 activator can rapidly improve nerve hypersensitivity and stably and continuously reduce pain sensitivity. In some embodiments, a combination of at least two of the group consisting of 5-methyl-2-(prop-2-yl)cyclohexane-1-ol, 1,3,3-trimethyl-2-oxobicyclo[2.2.2]octane and 3-(2-hydroxyphenyl)-6-(3-nitrophenyl)-3,4-dihydropyrimidine-2(1H)-one can produce a synergistic effect to achieve better therapeutic efficacy than the individual components. In some preferred embodiments, the combination of 1,3,3-trimethyl-2-oxobicyclo[2.2.2]octane with 5-methyl-2-(prop-2-yl)cyclohexane-1-ol or the combination of 1,3,3-trimethyl-2-oxobicyclo[2.2.2]octane with 3-(2-hydroxyphenyl)-6-(3-nitrophenyl)-3,4-dihydropyrimidine-2(1H)-one can produce a synergistic effect. Compared with the application of individual components, it can achieve better prevention, improvement and treatment of chemotherapy-induced nerve hypersensitivity and pain at lower concentrations, and can also avoid skin irritation due to excessive concentrations, and can also reduce mass production costs.

[0032] In at least one embodiment of this disclosure, the subject may be a diabetic patient. Diabetic peripheral neuropathy is primarily caused by long-term hyperglycemia damaging nerves and their supplying blood vessels, leading to impaired nerve conduction. Hyperglycemia induces various metabolic abnormalities, including the deposition of advanced glycation end products (AGEs), which damage nerve structures, accompanied by increased oxidative stress and chronic low-grade inflammation, further damaging nerve fibers and supporting cells. Furthermore, persistently poor glycemic control leads to microvascular complications, disrupting nerve nutrition and accelerating nerve degeneration. In some embodiments, neuropathic hypersensitivity and pain persist in diabetic subjects, and treatment with the TRPM8 activator rapidly improves neuropathic hypersensitivity and stably and sustainably reduces pain sensitivity. In some embodiments, a combination of at least two of the group consisting of 5-methyl-2-(prop-2-yl)cyclohexane-1-ol, 1,3,3-trimethyl-2-oxobicyclo[2.2.2]octane and 3-(2-hydroxyphenyl)-6-(3-nitrophenyl)-3,4-dihydropyrimidine-2(1H)-one can produce a synergistic effect to achieve better therapeutic efficacy than the individual components. In some preferred embodiments, the combination of 1,3,3-trimethyl-2-oxobicyclo[2.2.2]octane with 5-methyl-2-(prop-2-yl)cyclohexane-1-ol or the combination of 1,3,3-trimethyl-2-oxobicyclo[2.2.2]octane with 3-(2-hydroxyphenyl)-6-(3-nitrophenyl)-3,4-dihydropyrimidine-2(1H)-one can produce a synergistic effect, achieving better prevention, improvement and treatment of diabetic-induced nerve hypersensitivity and pain at lower concentrations compared to individual component application, while avoiding skin irritation due to excessive concentrations and reducing mass production costs.

[0033] In at least one embodiment of this disclosure, the TRPM8 activator can improve sleep disorders in subjects. In some embodiments, the TRPM8 activator can reduce the time required for subjects to fall asleep, sleep interruption events, and / or light sleep periods, and can also increase the subject's sleep depth, sleep stability, and / or sleep quality. In some embodiments, a combination of at least two of the group consisting of 5-methyl-2-(prop-2-yl)cyclohexane-1-ol, 1,3,3-trimethyl-2-oxobicyclo[2.2.2]octane, and 3-(2-hydroxyphenyl)-6-(3-nitrophenyl)-3,4-dihydropyrimidine-2(1H)-one can produce a synergistic effect to achieve better therapeutic effects than the individual components. In some preferred embodiments, the combination of 1,3,3-trimethyl-2-oxobicyclo[2.2.2]octane with 5-methyl-2-(prop-2-yl)cyclohexane-1-ol or the combination of 1,3,3-trimethyl-2-oxobicyclo[2.2.2]octane with 3-(2-hydroxyphenyl)-6-(3-nitrophenyl)-3,4-dihydropyrimidine-2(1H)-one produces a synergistic effect, increasing sleep depth and sleep stability more than when the individual components are administered. In some embodiments, the subject with sleep disorders may be a patient receiving chemotherapy or a diabetic patient, but this disclosure is not limited thereto.

[0034] In at least one embodiment of this disclosure, the composition may be applied topically to the skin of a subject. In some embodiments, the composition may be applied topically to the skin of the subject's hands and / or feet. Topical application avoids common systemic side effects (such as dizziness, edema, or cognitive impairment) compared to standard oral treatments, providing patients with a more effective, convenient, safe, and quality-of-life-benefit treatment option.

[0035] In at least one embodiment of the present disclosure, the dosage form of the composition may be selected from at least one of the group consisting of solutions, suspensions, emulsions, creams, ointments, gels, hydrogels, lotions, pastes, foams, sprays, aerosols, transdermal patches, mud scrubs and liniments.

[0036] In at least one embodiment of this disclosure, the composition may be coated, impregnated, or integrated into wearable articles or medical dressings to facilitate prolonged contact and / or continuous release of the TRPM8 activator to the skin of a subject. In some embodiments, the composition may be formulated as wearable articles or medical dressings covering the hands and / or feet for application to the skin of a subject's hands or feet. In some embodiments, the wearable articles covering the hands and / or feet have a layered structure for the subject's hands and / or feet to be worn therein to ensure continuous contact between the skin and the TRPM8 activator. For example, the wearable articles covering the hands and / or feet may be gloves, socks, hand masks, foot masks, socks, extensions of certain clothing, etc., but this disclosure is not limited thereto.

[0037] In at least one embodiment of this disclosure, the effective amount of the TRPM8 activator can be from about 0.01 wt% to 16 wt%, for example, but not limited to: 0.01 wt%, 0.02 wt%, 0.04 wt%, 0.06 wt%, 0.08 wt%, 0.1 wt%, 0.5 wt%, 1.0 wt%, 1.5 wt%, 2.0 wt%, 2.5 wt%, 3.0 wt%, 3.5 wt%, 4.0 wt%, 4.5 wt%. 5.5 wt%, 6.5 wt%, 7.5 wt%, 8.0 wt%, 8.5 wt%, 9.0 wt%, 9.5 wt%, 10.0 wt%, 10.5 wt%, 11.0 wt%, 11.5 wt%, 12.0 wt%, 12.5 wt%, 13.0 wt%, 13.5 wt%, 14.0 wt%, 14.5 wt%, 15.0 wt%, 15.5 wt%, 16.0 wt%.

[0038] In at least one embodiment of this disclosure, the effective amount of 1,3,3-trimethyl-2-oxobicyclo[2.2.2]octane may be from about 2 wt% to 16 wt%, for example, but not limited to: 2.0 wt%, 2.5 wt%, 3.0 wt%, 3.5 wt%, 4.0 wt%, 4.5 wt%, 5.5 wt%, 6.5 wt%, 7.5 wt%, 8.0 wt%, 8.5 wt%, 9.0 wt%, 9.5 wt%, 10.0 wt%, 10.5 wt%, 11.0 wt%, 11.5 wt%, 12.0 wt%, 12.5 wt%, 13.0 wt%, 13.5 wt%, 14.0 wt%, 14.5 wt%, 15.0 wt%, 15.5 wt%, and 16.0 wt%.

[0039] In at least one embodiment of this disclosure, the effective amount of 5-methyl-2-(prop-2-yl)cyclohexane-1-ol may be from about 2% to 8% by weight, for example, but not limited to: 2.0% by weight, 2.5% by weight, 3.0% by weight, 3.5% by weight, 4.0% by weight, 4.5% by weight, 5.5% by weight, 6.5% by weight, 7.5% by weight, and 8.0% by weight.

[0040] In at least one embodiment of this disclosure, the effective amount of 3-(2-hydroxyphenyl)-6-(3-nitrophenyl)-3,4-dihydropyrimidin-2(1H)-one may be from about 0.02% by weight to 0.1% by weight, for example, but not limited to: 0.02% by weight, 0.04% by weight, 0.06% by weight, 0.08% by weight or 0.1% by weight.

[0041] Example

[0042] Exemplary embodiments disclosed herein will be further described below, but should not be construed as limiting the scope of this disclosure.

[0043] For the sake of brevity, "HE" will be used to represent 5-methyl-2-(prop-2-yl)cyclohexane-1-ol; "EU" will be used to represent 1,3,3-trimethyl-2-oxobicyclo[2.2.2]octane; "AG" will be used to represent 3-(2-hydroxyphenyl)-6-(3-nitrophenyl)-3,4-dihydropyrimidine-2(1H)-one; "HE+EU" will be used to represent the combination of 5-methyl-2-(prop-2-yl)cyclohexane-1-ol and 1,3,3-trimethyl-2-oxobicyclo[2.2.2]octane; and "AG+EU" will be used to represent the combination of 3-(2-hydroxyphenyl)-6-(3-nitrophenyl)-3,4-dihydropyrimidine-2(1H)-one and 1,3,3-trimethyl-2-oxobicyclo[2.2.2]octane.

[0044] Experimental Example 1. TRPM8 activator improves sensory hypersensitivity in chemotherapy-induced peripheral neuropathy.

[0045] (1) Experimental design and establishment of an animal model of peripheral neuropathy induced by chemotherapy

[0046] Eight-week-old Sprague-Dawley (SD) rats were used as animals for chemotherapy-induced peripheral neuropathy. Before the experiment, a chemotherapy-induced peripheral neuropathy model was established using commonly used chemotherapy drugs. On the day of the test, the TRPM8 activator was administered, followed by the Von Frey test to observe the effect of the TRPM8 activator on the sensory abnormalities caused by peripheral neuropathy.

[0047] (2) Evaluation of the effect of TRPM8 activator on relieving paresthesia induced by chemotherapy drugs

[0048] The Von Frey test was used to evaluate the improvement of pain sensitivity induced by chemotherapy drugs in rats after administration of various TRPM8 activators. A pre-test was performed one day before administration of the commonly used chemotherapy drugs, and the Von Frey test was performed on rats at 0.5 hours, 1 hour, 2 hours, and 4 hours after administration of the TRPM8 activator. Peak pressure (grams) was recorded using an electronic monofilament tactile analgesia meter (Ugo, Basile). The tactile state of the animals was determined by the force applied through the electronic probe.

[0049] Rats were individually placed in custom-made plastic compartments on a metal grid (the grid was rectangular, with opposite corners 1.3 cm and 0.7 cm apart; the compartments were 8 cm wide × 17.5 cm long × 6.3 cm high) until no more exploratory behavior was observed (approximately 15 to 20 minutes). These compartments had three opaque white walls, with the front wall and ceiling made of transparent acrylic, and each compartment could accommodate eight rats side-by-side. A consistent probe was used to apply pressure vertically to the center of the hind paw until the paw was withdrawn, and the pressure value (in grams) was recorded as the tactile sensitivity threshold of the hind limb. This experimental procedure was repeated five times, with a few seconds of rest after each test. The paw withdrawal threshold of all animals was measured sequentially, with the left or right hind paw being measured randomly. The limbs were immersed in TRPM8 activator for 30 seconds. The pressure values ​​of peripheral neuropathy induced by chemotherapy were compared before and after administration of each TRPM8 activator to observe the improvement effect of each TRPM8 activator on peripheral neuropathy.

[0050] The experimental methods are shown in Figures 1 and 2, and the experimental materials are shown in Table 1 below:

[0051] [Table 1]

[0052] (3) Activating TRPM8 in the limbs improves chemotherapy-induced nerve hypersensitivity.

[0053] The effects of oxaliplatin on neurosensitivity were tested in a solvent control group and with various TRPM8 activators. Neurosensitivity was assessed by measuring the claw withdrawal threshold using the Von Frey test, and the results are shown in the left figure of Figure 3 and Table 2 below.

[0054] The effects of wickstin on neurosensitivity were tested in a solvent control group and with various TRPM8 activators. Neurosensitivity was assessed by measuring the claw withdrawal threshold using the Von Frey test, and the results are shown in the right figure of Figure 3 and Table 3 below.

[0055] [Table 2]

[0056] [Table 3]

[0057] Experimental Results: Chemotherapy drugs such as oxaliplatin and wickstin induced neuronal hypersensitivity, and the pain sensitivity persisted even after treatment with the solvent control group, indicating that the solvent did not improve the pain sensitivity induced by oxaliplatin and wickstin. In contrast, treatment with various TRPM8 activators significantly increased the claw withdrawal threshold (*p<0.05), indicating that TRPM8 activators can reduce pain sensitivity; the claw withdrawal threshold was significantly improved within 0.5 hours, indicating that TRPM8 activators can rapidly improve neuronal hypersensitivity; and the claw withdrawal threshold remained higher than the solvent control group for the following 4 hours, indicating that TRPM8 activators have a stable and sustained effect against neuropathic-induced pain sensitivity. In addition, the claw withdrawal threshold of the AG (0.02%) + EU (4%) group was significantly increased compared with the AG (0.02%) group and the EU (4%) group, indicating that the combination of EU and AG can produce a synergistic effect. Compared with the application of individual components, the combined application can achieve better efficacy at a lower concentration, avoid skin irritation due to excessive concentration, and also reduce mass production costs.

[0058] Experimental Example 2. TRPM8 activator improves sensory hypersensitivity in diabetic-induced peripheral neuropathy.

[0059] (1) Experimental design and establishment of an animal model of diabetic peripheral neuropathy

[0060] In at least one embodiment of this disclosure, 6-week-old SD rats were used as animals for inducing diabetic peripheral neuropathy. Before the experiment, the 6-week-old SD rats were fasted for 12 hours and then intraperitoneally injected with streptozotocin (STZ) at 60 mg / kg. Blood glucose levels were measured two weeks later. Animals with postprandial blood glucose levels less than 300 mg / dL were excluded from this experiment, as they were considered to have failed to induce diabetes. Animals with postprandial blood glucose levels greater than 300 mg / dL underwent a Von Frey test to measure sensory abnormalities in peripheral neuropathy.

[0061] (2) Evaluation of the effect of TRPM8 activator in relieving diabetic-induced sensory abnormalities

[0062] In at least one embodiment of this disclosure, the Von Frey test was used to assess the quantitative observation of the degree of sensory abnormalities induced by diabetes in rats after administration of each TRPM8 activator, in a manner similar to the method used to evaluate the improvement effect of TRPM8 activators on chemotherapy-induced sensory hypersensitivity.

[0063] In at least one embodiment of this disclosure, after confirming that STZ causes hyperglycemia in rats, a pre-test of monofilament tactile pain was performed, and the rats were subjected to the Von Frey test at 0.5 hours, 1 hour, 2 hours and 4 hours after administration of the TRPM8 activator, thereby comparing the degree of improvement of diabetes-induced sensory abnormalities by each TRPM8 activator.

[0064] The experimental methods are shown in Figures 1 and 4, and the experimental materials are shown in Table 4 below:

[0065] [Table 4]

[0066] (3) Activating TRPM8 in the limbs improves neuropathic hypersensitivity in diabetes.

[0067] The experimental results are recorded in Figure 5 and Table 5 below:

[0068] [Table 5]

[0069] Experimental Results: After 0.5 hours of treatment, the claw withdrawal thresholds in the HE (4%), EU (8%), and HE (2%) + EU (4%) TRPM8 activator treatment groups were significantly higher than those in the solvent control group (*: p<0.05), indicating that TRPM8 activators can reduce neuropathic hypersensitivity in diabetes. The claw withdrawal threshold was significantly improved within 0.5 hours, demonstrating that TRPM8 activators can rapidly improve neuropathic hypersensitivity in diabetes; furthermore, the claw withdrawal threshold remained higher than that in the solvent control group for the following 4 hours, indicating that TRPM8 activators have a stable and sustained effect against neuropathy-induced pain sensitivity. In addition, the claw withdrawal threshold in the HE (2%) + EU (4%) group was significantly increased compared to the HE (2%) and EU (4%) groups, indicating that the combination of EU and HE produces a synergistic effect. Compared to individual component application, combined application can achieve better efficacy at lower concentrations, avoid skin irritation due to excessively high concentrations, and reduce mass production costs.

[0070] Experimental Example 3. TRPM8 activator improves sleep

[0071] (1) Experimental Procedure

[0072] In at least one embodiment of this disclosure, as shown in Figure 6, after all rats underwent surgery to implant the wireless sleep measurement device, and following a 10-day recovery period, physiological signals from the 10-week-old rats were recorded during the 12-hour light-on period (Zeitgeber time, ZT 0-12 hours, representing the rat's primary sleep period) and the 8-hour light-off period (ZT 12-20 hours, representing the rat's primary activity period) as baseline values. Subsequently, 11-week-old rats were injected three times consecutively with oxaliplatin (6 mg / kg / time) (intraperitoneal injection, ip). Finally, 12-week-old rats were randomly divided into three groups as shown in Table 6 below. Two hours before the light period, the paws of each rat were immersed in the three groups for 15 seconds, and sleep physiological signals were recorded starting from the light period. However, this disclosure is not limited to this method.

[0073] [Table 6]

[0074] (2) Laboratory animals

[0075] In at least one embodiment of this disclosure, male Wistar-Kyoto rats, starting at 10 weeks of age, were used as experimental animals. The rats were housed in an environment with a 12:12 light-to-dark cycle, low noise, a room temperature maintained at 22±2°C, and humidity between 40% and 70%, allowing for the recording of physiological signals from freely moving rats without any interference. Ten days prior to the experimental recording, a wireless physiological sensor was implanted to record electroencephalogram (EEG), electromyogram (EMG), electrocardiogram (ECG), and triaxial acceleration signals. After the surgery, the wound was treated with the antibiotic chlortetracycline ointment to prevent infection. Once the animals were awake, they were placed in individual cages to recover and adapt to their environment.

[0076] (3) Self-made wireless sleep measurement system surgery

[0077] In at least one embodiment of this disclosure, rats were anesthetized with pentobarbital sodium (50 mg / kg) via intraperitoneal injection, then fixed using a stereotaxic apparatus. A 2 cm incision was made in the scalp from the parietal lobe, and connective tissue was removed from the skull to expose the anterior fontanelle and the lambda suture tip. Six stainless steel screws were symmetrically implanted into the dura mater of both hemispheres, located in the frontal lobe (2.0 mm anterior to the anterior fontanelle, 2.0 mm left and right), parietal lobe (2.0 mm posterior to the anterior fontanelle, 2.0 mm left and right), and occipital lobe (6.0 mm posterior to the anterior fontanelle, 2.0 mm left and right) of the cerebral cortex. Another reference electrode was implanted 2 mm posterior to the lambda suture tip. The wires of the micro-sockets were wound around the individual stainless steel screws to record cerebral cortical activity (EEG). Two micro-stainless steel wires were inserted into the neck muscles on both sides of the back to measure electromyography (EMG) signals. A pair of micro-stainless steel wires were also inserted subcutaneously in the back, one end placed between the neck and chest, and the other end placed on the waist to measure electrocardiogram (ECG) signals. Sodium barbiturate was administered as needed to maintain the depth of anesthesia during the procedure. After the wound was sutured, screws on the skull surface were fixed with dental powder. Subsequent recordings could begin after recovery. All physiological signals were transmitted wirelessly to a physiological signal amplification system for reception, recording, and subsequent analysis.

[0078] (4) Data collection and analysis

[0079] Signals were collected by a physiological telemetry system (KY4C, K&Y Lab, Taiwan, dimensions: 25mm × 21mm × 13mm, weight: 8.6g). The entire instrument includes sensors for electrophysiological signals, a radio transmitter, a radio receiver, display and storage software, and offline analysis programs. EEG, EMG, and ECG signals were amplified by 1,000, 1,000, and 500 times respectively at the sensing end on the miniature socket. Each signal was filtered, with filtering ranges of 0.16Hz to 48Hz, 34Hz to 103Hz, and 0.72Hz to 103Hz for EEG, EMG, and ECG respectively, and sampling rates of 125Hz, 250Hz, and 500Hz. The sampling rate for the triaxial acceleration signal was 62.5Hz. The digitized physiological signals were transmitted via 2.4GHz high-frequency digital radio waves to a business card-sized multi-channel physiological signal recorder (KY3, K&Y Lab). The radio transmitter is powered by a lithium polymer battery, which can record the animal's physiological signals for a full 24 hours and can be recharged and reused.

[0080] Awakeness / sleep determination was performed by calculating the mean spectral frequency (MPF) of the EEG and the power value of the EMG every 2 hours. Awake (AW) was defined as having an MPF ​​greater than the mean spectral power threshold (TMPF) and an EMG power greater than the EMG threshold (TEMG). Quiet sleep (QS) was defined as having an MPF ​​less than the TMPF and an EMG power less than the TMG. Paradoxical sleep (PS) was defined as having an MPF ​​greater than the TMPF but an EMG less than the TMG. The thresholds for TMG and TMPF were fine-tuned for each animal by trained animal researchers, and the original values ​​remained constant from the start to the end of the analysis. Histographic analysis of all MPF values ​​was performed by computer to obtain two group distributions: AW / PS and QS. The TMPF was then calculated using a reference value to distinguish between AW / PS and QS. EMG can also be used to obtain TEMG, which is then divided into two groups: AW and QS / PS. A normal sleep-wake cycle is defined as at least six consecutive epochs of the same state, meaning that at least six consecutive epochs are above or below the threshold. If different epoch changes occur in the middle, it is marked as an interruption. Interruptions during sleep are considered sleep disturbances.

[0081] (5) Evaluation of the effect of TRPM8 activator treatment on sleep parameters in a chemotherapy-induced peripheral neuropathy (CIPN) model.

[0082] As shown in the left panel of Figure 7, HE+EU treatment reduced the time required to fall asleep compared to the solvent control group. As shown in the right panel of Figure 7, the HE+EU treatment group had fewer sleep interruption events and better quiet sleep (QS) quality compared to the solvent control group.

[0083] In addition, changes in brainwave activity during the QS period were observed, including Theta waves and Delta waves. Theta waves indicate shallower sleep, while Delta waves are an indicator of deep sleep. Changes in Theta waves during the QS period are recorded in Figure 8 and Table 7 below, and changes in Delta waves during the QS period are recorded in Figure 9 and Table 8 below.

[0084] [Table 7]

[0085] [Table 8]

[0086] As shown in the left figure of Figure 8 and Table 7, the Theta wave power in the solvent control group was significantly higher than the baseline value during the overall period (ZT 4-12 hours). However, as shown in the right figure of Figure 8 and Table 7, the mean Theta wave power of the HE+EU group and the HE group was significantly lower (*p<0.05), indicating that HE+EU or HE treatment effectively reduced light sleep phase and maintained a more stable sleep pattern compared to the solvent control group.

[0087] As shown in Figure 9 and Table 8, HE+EU treatment maintained stronger Delta wave power throughout the recording period (ZT 4-12 hours), especially during ZT 6-8 (*p<0.05), indicating that HE+EU treatment increased sleep depth and enhanced sleep stability.

[0088] These findings collectively suggest that the synergistic effect of HE+EU not only promotes faster sleep onset but also fosters more stable sleep depth in the CIPN model.

[0089] The above descriptions are merely some embodiments of this disclosure. Those skilled in the art will readily understand that various modifications and alterations can be made to the embodiments without departing from the teachings of this disclosure. Therefore, all equivalent changes and modifications made within the scope of the claims of this disclosure should fall within the coverage of this disclosure.

Claims

1. Use of a TRPM8 activator for the preparation of a composition for the prevention, relief or treatment of peripheral neuropathy in a subject with such need.

2. The use as described in claim 1, wherein, The TRPM8 activator includes at least one selected from the group consisting of 5-methyl-2-(prop-2-yl)cyclohexane-1-ol, 1,3,3-trimethyl-2-oxobicyclo[2.2.2]octane and 3-(2-hydroxyphenyl)-6-(3-nitrophenyl)-3,4-dihydropyrimidine-2(1H)-one.

3. The use as described in claim 1, wherein, The TRPM8 activator includes 1,3,3-trimethyl-2-oxobicyclo[2.2.2]octane.

4. The use as described in claim 3, wherein, The TRPM8 activator also includes 5-methyl-2-(prop-2-yl)cyclohexane-1-ol.

5. The use as described in claim 3, wherein, The TRPM8 activator also includes 3-(2-hydroxyphenyl)-6-(3-nitrophenyl)-3,4-dihydropyrimidine-2(1H)-one.

6. The use as described in claim 1, wherein, The subject was a patient receiving chemotherapy.

7. The use as described in claim 1, wherein, The subject was a diabetic patient.

8. The use as described in claim 1, thereby improving the sleep disorder of the subject.

9. The use as described in claim 1, wherein, The composition was applied topically to the subject's skin.

10. The use as described in claim 9, wherein, The dosage form of the composition is selected from at least one of the group consisting of solutions, suspensions, emulsions, creams, ointments, gels, hydrogels, lotions, pastes, foams, sprays, aerosols, transdermal patches, mud dressings and liniments, or the composition is coated, impregnated or integrated into wearable articles or medical dressings.

11. A composition for preventing, alleviating, or treating peripheral neuropathy, comprising: Effective amounts of TRPM8 activator and pharmaceutically or cosmetically acceptable carriers.

12. The composition of claim 11, wherein, The TRPM8 activator comprises at least one selected from the group consisting of 5-methyl-2-(prop-2-yl)cyclohexane-1-ol, 1,3,3-trimethyl-2-oxobicyclo[2.2.2]octane and 3-(2-hydroxyphenyl)-6-(3-nitrophenyl)-3,4-dihydropyrimidine-2(1H)-one, and the effective amount is from 0.01% by weight to 16% by weight.

13. The composition of claim 11, wherein, The TRPM8 activator comprises 1,3,3-trimethyl-2-oxobicyclo[2.2.2]octane, and the effective amount of the 1,3,3-trimethyl-2-oxobicyclo[2.2.2]octane is from 2% to 16% by weight.

14. The composition of claim 13, wherein, The TRPM8 activator further comprises 5-methyl-2-(prop-2-yl)cyclohexane-1-ol, and the effective amount of the 5-methyl-2-(prop-2-yl)cyclohexane-1-ol is from 2% to 8% by weight.

15. The composition of claim 13, wherein, The TRPM8 activator further comprises 3-(2-hydroxyphenyl)-6-(3-nitrophenyl)-3,4-dihydropyrimidine-2(1H)-one, and the effective amount of the 3-(2-hydroxyphenyl)-6-(3-nitrophenyl)-3,4-dihydropyrimidine-2(1H)-one is from 0.02% by weight to 0.1% by weight.

Images