Compositions, systems and methods for reducing electrical induction and / or skin stimulation

Abstract

Compositions, systems, and methods for reducing electrical induction and / or skin irritation caused by application of an alternating electric field to the skin of a subject are disclosed. The compositions, systems, and methods involve administering to a subject at least one composition comprising at least one local anesthetic, and then applying an alternating electric field to the subject.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS / INCORPORATION BY REFERENCE STATEMENT

[0002] This application claims the benefit of U.S. Provisional Application No. 63 / 377,824, filed on September 30, 2022, under 35 U.S.C. § 119(e). The entire contents of the above patent application are expressly incorporated herein by reference. Background Art

[0003] Tumor Treatment Fields (TTFields) are low intensity (e.g., 1-3 V / cm) alternating electric fields in the mid-frequency range (such as, but not limited to, 100-500 kHz) that target solid tumors by disrupting mitosis. This non-invasive treatment is for solid tumors and is described in, for example, U.S. Patents Nos. 7,016,725; 7,089,054; 7,333,852; 7,565,205; 8,244,345; 8,715,203; 8,764,675; 10,188,851; and 10,441,776. TTFields are typically delivered via two pairs of transducer arrays that generate perpendicular fields within the tumor being treated; the transducer arrays making up each of these pairs are positioned on opposite sides of the body part being treated. More specifically, for In a TTField system, one pair of electrodes from the transducer array is located at the left and right sides (LR) of the tumor, and another pair of electrodes from the transducer array is located at the anterior and posterior sides (AP) of the tumor. TTField has been approved for the treatment of glioblastoma multiforme (GBM) and can be used, for example, to system (Novocure Limited, St. Helier, Jersey), which The system includes a transducer array placed on the patient's shaved head.

[0004] Alternating electric fields (such as, but not limited to, electric fields with frequencies between 50kHz and 1MHz) can also be used to treat medical conditions other than tumors. For example, as described in U.S. Pat. No. 10,967,167, an alternating electric field of 50-200kHz can increase the permeability of the blood-brain barrier (BBB), allowing, for example, chemotherapy drugs to enter the brain. And as described in U.S. Pat. No. 11,103,698, an alternating electric field of 50-500kHz can increase the permeability of cancer cell membranes, allowing large molecules to pass through cancer cell membranes.

[0005] Used in Each transducer array in the device that delivers TTFields consists of a set of ceramic disc electrodes that are coupled to the patient's skin (such as, but not limited to, the patient's shaved head when treating GBM) through a layer of conductive medical gel. The medical gel is designed to deform to match the contours of the body and provide good electrical contact between the array and the skin; thus, the gel interface bridges the skin and reduces interference. The patient wears the device continuously for 2-4 days, after which the device is removed for hygiene care and re-shaving (if necessary), and then a new set of arrays is put on.

[0006] When treating a subject with an alternating electric field, higher amplitudes are strongly associated with greater therapeutic effects. However, as the amplitude of the alternating electric field increases, and / or as the frequency of the alternating electric field decreases (e.g., to about 100 kHz), some subjects may experience electro-inductive effects when the alternating electric field changes direction, particularly at the beginning of treatment. Such electro-inductive effects may be, for example (but not limited to), sensations of vibration, paresthesias, and / or twitching or contraction of muscle fibers.

[0007] While not wishing to be bound by any theory, the induction is believed to arise from the interaction between the alternating electric field and nerve cells (i.e., neurons) located near or adjacent to the transducer array. For example, when the current density (e.g., the current through any given electrode divided by the area of ​​that electrode) exceeds a certain threshold (which may vary from person to person), induction begins to occur and becomes more pronounced as the current density increases further.

[0008] Electrical sensations may be a barrier to long-term ACEF therapy, as the presence of these sensations may discourage some subjects from continuing with ACEF therapy, especially at the beginning of treatment.

[0009] In addition, in Phase III clinical trials and post-marketing surveillance programs, the incidence of skin adverse events (dAEs) observed when using existing medical-grade hydrogels and TTFields generation systems was 16% and 22%, respectively; these dAEs include (but are not limited to) various types of skin irritation, allergic and irritant dermatitis, maceration, mechanical injury, ulcers, and skin infections. In particular, sweat on the skin may cause certain skin irritations. These adverse events are exacerbated by the requirement that the hydrogel be in continuous contact with the patient's skin for several days and that there is insufficient "breathing" time between the application of the TTField array to the skin. (Lacouture et al. (2014) Seminars in Oncology, 41: S1-S14).

[0010] Additionally, during wear, the hydrogel swells and degrades when it comes in contact with sweat, thereby increasing resistivity. Further, over a wear period of several days, losses in the hydrogel interface (such as, but not limited to, erosion of the hydrogel's adhesion and conductivity) reduce the standard current / field generated by the TTField system, thereby reducing the functionality and overall effectiveness of TTField therapy. DETAILED DESCRIPTION

[0011] Before explaining at least one embodiment of the inventive concept in detail through exemplary language and results, it should be understood that the application of the inventive concept is not limited to the details of the construction and arrangement of the components set forth in the following description. The concept of the present invention can be other embodiments or practiced or executed in various ways. Therefore, the language used herein is intended to give the widest possible scope and meaning; and these embodiments are intended to be exemplary rather than exhaustive. In addition, it should be understood that the wording and terminology used herein are for descriptive purposes and should not be considered restrictive.

[0012] Unless otherwise defined herein, scientific and technical terms used in conjunction with the inventive concepts disclosed herein shall have the meanings commonly understood by those of ordinary skill in the art. In addition, unless the context otherwise requires, singular terms shall include the plural, and plural terms shall include the singular. The aforementioned techniques and procedures are generally performed according to conventional methods well known in the art, as described in various general and more specific references cited and discussed throughout this specification. Terms and laboratory procedures and techniques associated with analytical chemistry, synthetic organic chemistry, medicine and pharmaceutical chemistry as described herein are well known and commonly used in the art. Standard techniques are used for chemical synthesis and chemical analysis.

[0013] All patents, published patent applications, and non-patent publications mentioned in the specification are indicative of the technical level of those skilled in the art to which the inventive concepts disclosed herein belong. All patents, published patent applications, and non-patent publications cited in any part of this application are expressly incorporated herein by reference in their entirety, as if each individual patent or publication was specifically and individually indicated to be incorporated herein by reference.

[0014] All compositions, components, systems, kits and / or methods disclosed herein can be prepared and performed according to the present invention without undue experimentation. Although the compositions, assemblies, systems, kits and methods of the inventive concept have been described according to specific embodiments, it will be apparent to those skilled in the art that the steps or sequence of steps of the compositions and / or methods and methods described herein may be changed without departing from the concept, spirit and scope of the inventive concept. All such similar substitutions and modifications apparent to those skilled in the art are considered to be within the spirit, scope and concept of the inventive concept as defined by the appended claims.

[0015] As used in accordance with the present invention, unless otherwise indicated, the following terms shall be understood to have the following meanings:

[0016] When used in conjunction with the term "comprising" in the claims and / or specification, the use of the term "a" may mean "one," but it is also consistent with the meaning of "one or more," "at least one," and "one or more than one." Thus, unless the context clearly indicates otherwise, the terms "a," "an," and "the" include plural referents. Thus, for example, reference to "a compound" may refer to one or more compounds, two or more compounds, three or more compounds, four or more compounds, or a greater number of compounds. The term "plurality" means "two or more."

[0017] The use of the term "at least one" should be understood to include one as well as any amount more than one, including but not limited to 2, 3, 4, 5, 10, 15, 20, 30, 40, 50, 100, etc. The term "at least one" can extend to 100 or 1000 or more, depending on the term to which it is attached; furthermore, quantities of 100 / 1000 should not be considered limiting, as higher limits may also produce satisfactory results. Furthermore, the use of the term "at least one of X, Y, and Z" will be understood to include X alone, Y alone, and Z alone, as well as any combination of X, Y, and Z. The use of ordinal terms (i.e., "first," "second," "third," "fourth," etc.) is used solely for the purpose of distinguishing two or more items and is not meant to imply, for example, any order or sequence or importance of one item relative to another or any order of addition.

[0018] The term "or" as used in the claims is intended to mean the inclusive "and / or" unless explicitly stated to refer to only alternatives or unless the alternatives are mutually exclusive. For example, the condition "A or B" may be satisfied by any of the following: A is true (or exists) and B is false (or does not exist); A is false (or does not exist) and B is true (or exists); or both A and B are true (or exist).

[0019] As used herein, any reference to "one embodiment," "an embodiment," "some embodiments," "an example," "for example," or "example" means that a particular element, feature, structure, or characteristic described in connection with the embodiment is included in at least one embodiment. For example, the appearances of the phrase "in some embodiments" or "an example" in different places in the specification are not necessarily all referring to the same embodiment. Furthermore, all references to one or more embodiments or examples should be construed as non-limiting to the claims.

[0020] In this application, the term "about" is used to indicate that a value includes the inherent error variation of the components / devices / equipment, the method used to determine the value, or the variation that exists in the subject matter. For example, but not as a limitation, when the term "about" is used, the specified value can vary within plus or minus 20 percent, or 15 percent, or 12 percent, or 11 percent, or 10 percent, or 9 percent, or 8 percent, or 7 percent, or 6 percent, or 5 percent, or 4 percent, or 3 percent, or 2 percent, or 1 percent of the specified value, as such variations are suitable for performing the disclosed methods and as understood by those of ordinary skill in the art.

[0021] As used in this specification and claims, the words "comprising" (and any forms of including, such as "comprise" and "comprises"), "having" (and any forms of having, such as "have" and "has"), "including" (and any forms of containing, such as "includes" and "include"), or "containing" (and any forms of containing, such as "contains" and "contain") are inclusive or open-ended, and do not exclude additional, unrecited elements or method steps.

[0022] As used herein. The term "or combinations thereof" refers to all permutations and combinations of the terms preceding the term. For example, "A, B, C, or combinations thereof" is intended to include at least one of A, B, C, AB, AC, BC, or ABC, and if order is important in a particular context, BA, CA, CB, CBA, BCA, ACB, BAC, or CAB. Continuing with this example, specifically included are combinations containing repetitions of one or more terms or terms, such as BB, AAA, AAB, BBC, AAABCCCC, CBBAAA, CABABB, etc. Those skilled in the art will appreciate that there is generally no limit to the number of terms or terms in any combination unless otherwise apparent from the context.

[0023] As used herein, the term "substantially" means that the subsequently described event or circumstance occurs completely, or that the subsequently described event or circumstance occurs to a large extent. For example, when related to a particular event or circumstance, the term "substantially" means that the subsequently described event or circumstance occurs at least 80% of the time, or at least 85% of the time, or at least 90% of the time, or at least 95% of the time. For example, the term "substantially adjacent" can mean that two items are 100% adjacent to each other, or that the two items are very close to each other but not 100% adjacent to each other, or that a portion of one of the two items is not 100% adjacent to the other item but is very close to the other item.

[0024] The term "pharmaceutically acceptable" refers to compounds and compositions that are suitable for administration to humans and / or animals without undue adverse side effects (such as (but not limited to) toxicity, irritation and / or allergic response), which are commensurate with a reasonable benefit / risk ratio.

[0025] As used herein, the term "patient" or "subject" includes both human and veterinary subjects. "Mammal" for therapeutic purposes refers to any animal classified as a mammal, including but not limited to humans, domestic and farm animals, non-human primates, and any other animal with mammary tissue.

[0026] The term "treatment" refers to therapeutic treatment as well as prophylactic or preventive measures. Those in need of treatment include, but are not limited to, individuals who already have a particular condition / disease / infection and individuals at risk of acquiring a particular condition / disease / infection (e.g., individuals in need of prophylactic / preventive measures). The term "treatment" refers to the administration of an agent / element / method to a patient for therapeutic and / or prophylactic / preventive purposes.

[0027] As used herein, the term "therapeutic composition" or "pharmaceutical composition" refers to an agent that can be administered in vivo to produce a therapeutic and / or prophylactic / preventive effect.

[0028] Administration of a therapeutically effective amount or a prophylactically effective amount is to provide a therapeutic benefit in the treatment, prevention and / or management of a disease, disorder and / or infection. The specific amount that is therapeutically effective can be readily determined by an ordinary physician and can vary according to factors known in the art, such as, but not limited to, the type of disorder / disease / infection, the patient's medical history and age, the stage of the disorder / disease / infection, and the combined administration of other drugs.

[0029] The term "effective amount" refers to the amount of a biologically active molecule or its conjugate or derivative, or the amount of a treatment regimen (i.e., an alternating electric field), which, when used in the manner of the inventive concept, is sufficient to show a detectable therapeutic effect without excessive adverse side effects (such as, but not limited to, toxicity, irritation, and allergic reactions), and a reasonable benefit / risk ratio is comparable. The therapeutic effect may include, for example, but not limited to, preventing, inhibiting, or reducing the occurrence of at least one condition. The effective amount of the subject will depend on the type of subject, the size and health of the subject, the nature and severity of the condition to be treated, the method of administration, the duration of treatment, the nature of the combined therapy (if any), the specific formulation used, etc. Therefore, it is impossible to predetermine an exact effective amount. However, the effective amount for a given situation can be determined by a person of ordinary skill in the art using routine experiments based on the information provided herein.

[0030] The term "administration" as used herein is understood to include all routes of administration known in the art, including but not limited to oral, topical, transdermal, parenteral, subcutaneous, intranasal, mucosal, intramuscular, intraperitoneal and intravenous routes, and includes local and systemic administration. In addition, the compositions of the present disclosure (and / or methods of administration thereof) can be designed to provide delayed release, controlled release or sustained release using formulation techniques well known in the art.

[0031] Turning now to the concepts of the present invention, methods of reducing, lowering the occurrence and / or improving electroinduction in a subject are disclosed, wherein the electroinduction is induced by applying an alternating electric field to the subject. Also disclosed herein are methods of reducing, lowering the occurrence and / or improving skin irritation in a subject, wherein the skin irritation is induced by applying an alternating electric field to the subject. In addition, compositions, kits, arrays and systems related to the method are disclosed herein. The compositions, kits, arrays, systems and methods utilize application of at least one active agent to a portion of the subject's skin within a target area to which an alternating electric field is applied, the active agent comprising at least one local anesthetic and / or at least one anti-hyperhidrosis agent. The at least one local anesthetic / anti-hyperhidrosis agent may be present in a separate composition that is applied to the skin, or may be combined in some manner with a portion of a system that generates or provides an alternating electric field. In addition, in some non-limiting embodiments, the at least one active agent is both a local anesthetic and an anti-hyperhidrosis agent.

[0032] Certain non-limiting embodiments of the present disclosure relate to a method for reducing electrical induction and / or skin irritation of a subject caused by applying an alternating electric field to the subject. The method comprises administering at least one composition to at least a portion of a target area of ​​the subject, wherein the at least one composition comprises at least one active agent selected from at least one local anesthetic, at least one anti-hyperhidrosis agent, and combinations thereof. In some non-limiting embodiments, the at least one active agent is both a local anesthetic and an anti-hyperhidrosis agent. The method further comprises applying an alternating electric field to the target area of ​​the subject. The alternating electric field may be applied simultaneously with the at least one composition, or applied sequentially in whole or in part.

[0033] According to the present disclosure, any local anesthetic known in the art or contemplated herein can be used, as long as the local anesthetic can reduce the electrical induction of the subject in the target area where the alternating electric field is applied. According to the present disclosure, non-limiting examples of local anesthetics that can be used include botulinum toxin, saxitoxin, tetrodotoxin, lidocaine, bupivacaine, ropivacaine, benzocaine, pramoxine, prilocaine, proparacaine, dibucaine, tetracaine, lignocaine, other sodium channel inhibitors, and any combination thereof.

[0034] In other specific (but non-limiting) embodiments, the at least one local anesthetic comprises one or more skin anesthetics, such as (but not limited to) lidocaine (such as present in skin anesthetic creams, gels, sprays, foams, liquids, ointments and / or injections, such as Pain relief spray (Advantice Health, LLC, CedarKnolls, NJ), Controlled-release transdermal gel (Gensco Pharma, LLC, Miami, FL) and hydrogel patch (Teikoku Pharma USA, San Jose, CA); bupivacaine, ropivacaine and / or lidocaine injection solution (or other dosage forms / formulations thereof); benzocaine (such as present in skin anesthetic creams, gels, sprays, foams, liquids, ointments and / or injections, such as (Bayer, Boca Raton, FL), (RB Health (US) LLC, Parsippany, NJ) and (Advantice Health, LLC, Cedar Knolls, NJ) products); pramoxine / pramocaine (such as found in skin anesthetic creams, gels, sprays, foams, liquids, ointments and / or injections, such as Sensitive (Crown Laboratories, Inc., Johnson City, TN), (Alaven Pharmaceutical LLC, Marietta, GA) and (product of Ferndale Laboratories, Inc., Ferndale, MI); dibucaine / cinchocaine (such as found in skin anesthetic creams, gels, sprays, foams, liquids, ointments, and / or injections, such as (Dr. Reddy's Laboratories Inc., Princeton, NJ) and Rectacaine products); tetracaine / amethocaine (such as found in skin anesthetic creams, gels, sprays, foams, liquids, ointments and / or injections, such as (Alliance Pharmaceutical Limited, Chippenham, UK), (Hospira, Inc., Lake Forest, IL), Viractin and (Blairex Laboratories, Inc., Columbus, IN) products); etc.; and any combination thereof (such as but not limited to lidocaine-bupivacaine, lidocaine-tetracaine, lidocaine-prilocaine, lidocaine-tetracaine, bupivacaine-saxitoxin, etc.)

[0035] According to the present disclosure, any anti-hyperhidrosis agent known in the art or contemplated herein can be used, so long as the anti-hyperhidrosis agent is capable of reducing perspiration from the subject's skin in the target area where the alternating electric field is applied. One non-limiting example of an anti-hyperhidrosis agent that can be used according to the present invention includes botulinum toxin.

[0036] The composition containing the active agent can be provided in any dosage form / formulation that allows the composition to be applied to the target area of ​​the subject and allows the active agent to penetrate into the subject's skin to reduce electrical induction and / or skin irritation. Non-limiting examples of dosage forms / formulations that can be used include creams, gels, foams, lotions, ointments, salves, oils, liquids, emulsions, sprays, aerosols, dispersions, solids (such as patches or bandages), adhesive bandages, etc., and any combination thereof.

[0037] In a specific (but non-limiting) embodiment, the at least one active agent may include a botulinum toxin type A complex (BoNT-A). BoNT-A is currently used to treat a variety of medical conditions, such as (but not limited to) dystonia, neuromuscular diseases, and pain. In addition, BoNT-A has been approved for the treatment of severe axillary hyperhidrosis. The effects of BoNT-A begin to appear 2 to 5 days after injection and last for 3 to 6 months. BoNT-A works by preventing the exocytosis of acetylcholine vesicles at the neuromuscular junction, thereby causing flaccid paralysis (Caron et al., (2015) PLoS ONE, 10(10): e0140439; Mark Hallett (2015) Toxicon, 107: 64–67). In addition, Li et al. (Med Eng Phys. (2017) 43:97–102) investigated the direct effects of BoNT-A injection on the intrinsic electrical properties of spastic muscles and found that, although resistance was significantly reduced in treated muscles, other impedance variables such as reactance, phase angle, or anisotropy of each parameter (i.e., resistance, reactance, and phase angle) did not change significantly after toxin injection.

[0038] In addition, the compositions of the present disclosure may contain at least one local anesthetic and at least one anti-hyperhidrosis agent simultaneously. Alternatively, the methods of the present disclosure may include the following steps: administering a first composition and a second composition, the first composition comprising at least one local anesthetic and the second composition comprising at least one anti-hyperhidrosis agent. When administered separately, the first composition may be administered simultaneously with the second composition or in whole or in part sequentially. In addition, the use of ordinal terms is for identification purposes only; it should be understood that the first composition may be administered before or after the second composition.

[0039] The at least one active agent can be present in the composition at any concentration that provides a therapeutically effective concentration of the active agent to reduce electrical induction and / or skin irritation when the composition is applied to the skin of a subject. For example, but not limited to, the concentration (by weight) of each active agent in the composition can be about 0.001%, about 0.005%, about 0.01%, about 0.02%, about 0.03%, about 0.04%, about 0.05%, about 0.06%, about 0.07%, about 0.08%, about 0.09%, about 0.1%, about 0.2%, about 0.3%, about 0.4%, about 0.5%, about 0.6%, about 0.7%, about 0.8%, about 0.9%, about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8% , about 9%, about 10%, about 11%, about 12%, about 13%, about 14%, about 15%, about 16%, about 17%, about 18%, about 19%, about 20%, about 21%, about 22%, about 23%, about 24%, about 25%, about 26%, about 27%, about 28%, about 29%, about 30%, etc., or it can be a range formed by any of the above values ​​(for example, a range of about 0.01% to about 20%, etc.), or it can be a range of two integers that fall between two of the above reference values ​​(for example, a range of about 0.025% to about 17.5%, etc.).

[0040] In a specific (but non-limiting) embodiment, the composition comprises a botulinum toxin in a concentration range of about 0.1% to about 10%. In a specific (but non-limiting) embodiment, the composition comprises lidocaine in a concentration range of about 0.1% to about 10% (and particularly, but not limitingly, in a range of about 1% to about 5%). In a specific (but non-limiting) embodiment, the composition comprises bupivacaine in a concentration range of about 0.1% to about 1%. In a specific (but non-limiting) embodiment, the composition comprises benzocaine in a concentration range of about 1% to about 25% (and particularly, but not limitingly, in a range of about 5% to about 20%). In a specific (but non-limiting) embodiment, the composition comprises tetracaine in a concentration range of about 0.1% to about 10% (and particularly, but not limitingly, in a range of about 0.5% to about 8%). In specific (but non-limiting) embodiments, the composition comprises lidocaine at a concentration ranging from about 1% to about 15% (and particularly, but non-limitingly, ranging from about 2% to about 10%). In specific (but non-limiting) embodiments, the composition comprises proparacaine at a concentration ranging from about 0.1% to about 2%.

[0041] However, the concentration of the active agent present in the composition can be measured by other mechanisms. For example, in certain non-limiting embodiments, the active agent can be present in the composition at a specific molar concentration. In accordance with the present disclosure, non-limiting examples of molar concentrations that can be used include about 0.0001M, about 0.0005M, about 0.001M, about 0.005M, about 0.01M, about 0.05M, about 0.1M, about 0.2M, about 0.3M, about 0.4M, about 0.5M, about 0.6M, about 0.7M, about 0.8M, about 0.9M, about 1M, about 2M, about 3M, about 4M, about 5M or more molar concentrations, as well as molar concentrations falling within a range formed by two of the above values ​​(e.g., a range of about 0.0001M to about 1M, a range of about 0.001M to about 0.1M, etc.), or a concentration within a range of two values, each of which is between the above two values ​​(e.g., a range of about 0.007M to about 0.86M, etc.).

[0042] In another alternative, the active agent may be present in a composition so as to deliver a specific number of units in each dose. In accordance with the present disclosure, non-limiting examples of unit doses that can be used include about 0.1, about 0.2, about 0.3, about 0.4, about 0.5, about 0.6, about 0.7, about 0.8, about 0.9, about 1, about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, about 10, about 15, about 20, about 25, about 30, about 35, about 40, about 45, about 50, about 55, about 60, about 65, about 70, about 75, about 80, about 85, about 90, about 95, about 100, about 125, about 150, about 175, or about 200 units or more, as well as unit dose ranges formed by two of the above values ​​(e.g., a range of about 0.5 units to about 100 units, etc.), or a unit dose range formed by two values, each value falling between the above two values ​​(e.g., a range of about 0.25 units to about 180 units, etc.).

[0043] Depending on the effective duration of the active agent, the composition can be formulated for repeated administration to the patient. The dose can be repeated as needed, for example (but not limited to): about once per hour, about once every two hours, about once every three hours, about once every four hours, about once every five hours, about once every six hours, about once every seven hours, about once every eight hours, about once every nine hours, about once every 10 hours, about once every 11 hours, about once every 12 hours, about once a day, about once every two days, about once every three days, about once every four days, about once every five days, about once every six days, about once a week, about once every two weeks, about once every three weeks, etc., and the range formed by the above two values.

[0044] In certain non-limiting embodiments, the compositions of the present disclosure can be designed to provide modified release (such as, but not limited to, extended release, controlled release, and / or sustained release) of one or more active agents using formulation techniques known in the art. Non-limiting examples of formulation techniques include coatings, polymer conjugations, delivery systems (such as, but not limited to, liposomes, lipid-based particles, microspheres, microparticles, nanoparticles, polymer conjugates, SABER (sucrose acetate isobutyrate) systems, collagen implants, DepoFoam, and combinations thereof) and the like, and combinations thereof. Various formulation methods for providing modified release of active agents are well known in the art and therefore need not be further described.

[0045] The use of modified release formulations allows one or more active agents to be released from the composition over a longer period of time, such as, but not limited to, at least about 8 hours, at least about 12 hours, at least about 18 hours, at least about 1 day, at least about 2 days, at least about 3 days, at least about 4 days, at least about 5 days, at least about 6 days, at least about 7 days (i.e., at least about 1 week), at least about 8 days, at least about 9 days, at least about 10 days, at least about 11 days, at least about 12 days, at least about 13 days, at least about 14 days (i.e., at least about 2 weeks), ), at least about 15 days, at least about 16 days, at least about 17 days, at least about 18 days, at least about 19 days, at least about 20 days, at least about 21 days (i.e., at least about 3 weeks), at least about 22 days, at least about 23 days, at least about 24 days, at least about 25 days, at least about 26 days, at least about 27 days, at least about 28 days, at least about 29 days, at least about 30 days, at least about one month, etc., and ranges formed by any of the above values ​​(i.e., a range from about one day to about two weeks, a range from about two weeks to about three weeks, etc.).

[0046] Specific non-limiting examples of modified release formulations of local anesthetics that can be used in accordance with the present disclosure include liposomal formulations of saxitoxin (saxitoxin plus dexamethasone liposomes, which have been shown to provide up to 7.5 days of nerve block (Epstein-Barash et al., (2009) PNAS, 106(17):7125-7130)); polymer-tetrodotoxin conjugates (which have been shown to produce nerve block durations ranging from several hours to three days (Elofsson et al., (2019) Nature Commun, 10:2566)); tetrodotoxin microspheres (Kohane et al., (2003) Pain, 104:415-421); liposomal formulations of bupivacaine ( ( bupivacaine liposomal injectable suspension in , which is FDA-approved to provide up to 48-72 hours of analgesia); SABER-bupivacaine (SABER is being developed as a biodegradable injectable reservoir system with the potential to deliver the drug over a period of days to months); Bupivacaine-collagen matrix / implant ( implant (Innocoll Pharmaceuticals Limited, Princeton, NJ), which has been shown to provide 24-72 hours of analgesia); etc.; and any combination thereof.

[0047] The compositions of the present disclosure can be administered by any route of administration that allows local anesthesia of at least a portion of the skin of the target area of ​​the subject. Selected routes of administration include, but are not limited to, topical, transdermal, intravenous, intramuscular, intradermal, intraperitoneal, subcutaneous, spinal or other parenteral routes of administration, such as by injection or infusion.

[0048] In certain specific (but non-limiting) embodiments, microneedles are used when administering the at least one composition, wherein the composition containing the active agent is coated on the microneedles prior to administration to the subject. For example, but not limited to, microneedles are currently used in the art to deliver botulinum toxin to treat various cosmetic problems.

[0049] At least one active agent may be treated and administered in any formulation known in the art or contemplated herein that reduces the electrical induction and / or skin irritation caused by the application of an alternating electric field to a subject. For example, but not limited to, the composition containing at least one active agent may be administered in the form of a pharmaceutical composition comprising at least one active agent and at least one pharmaceutically acceptable carrier. According to the present disclosure, non-limiting examples of suitable pharmaceutically acceptable carriers that can be used include water; saline; dextrose solution; fructose or mannitol; calcium carbonate; cellulose; ethanol; oils of animal, plant or synthetic origin; carbohydrates such as glucose, sucrose or dextran; antioxidants such as ascorbic acid or glutathione; chelating agents; low molecular weight proteins; detergents; liposome carriers; buffer solutions such as sodium chloride, saline, phosphate-buffered saline and / or other substances that are physiologically acceptable and / or safe to use; diluents; excipients such as polyethylene glycol (PEG); or any combination thereof. Suitable pharmaceutically acceptable carriers for pharmaceutical preparations are described, for example, in Remington: The Science and Practice of Pharmacy, 23rd Edition (2020).

[0050] In addition, the composition containing at least one active agent may contain other agents that enable the composition to be administered by a specific route of administration. For example, but not limited to, the composition may be formulated for administration by topical, transdermal and / or subcutaneous routes, or by any other route described or contemplated herein. Depending on the route of administration, in addition to the active agent (i.e., local anesthetic and / or anti-hyperhidrosis agent), the composition may also contain one or more additional components. Examples of additional second compounds that may be present include, but are not limited to, fillers, salts, buffers, preservatives, stabilizers, solubilizers, wetting agents, emulsifiers, dispersants, and other materials well known in the art.

[0051] In addition, in certain specific (but non-limiting) embodiments, the composition containing at least one local anesthetic and / or at least one anti-hyperhidrosis agent may further contain other active agents, which are usually combined with anesthetic / anti-hyperhidrosis agents in existing preparations. For example (but not limited to this), some local anesthetic creams include hydrocortisone to reduce redness, itching and swelling. In addition, some local anesthetic creams include epinephrine, norepinephrine or phenylephrine to improve the depth and duration of anesthesia at the target site.

[0052] In certain non-limiting embodiments, the composition comprising at least one active agent can be applied prior to applying the electrodes, but can also be applied substantially simultaneously with applying the electrodes and / or applied after applying the electrodes.

[0053] In addition, the composition containing at least one local anesthetic and / or at least one anti-hyperhidrosis agent can be applied before the application of the alternating electric field, but can also be applied substantially simultaneously with the application of the alternating electric field. For example (but not limited to), the composition can be administered within a time period of at least about 1 minute, about 5 minutes, about 10 minutes, about 15 minutes, about 30 minutes, about 45 minutes, about 1 hour, about 1.5 hours, about 2 hours, about 3 hours, about 4 hours, about 5 hours, about 6 hours, about 7 hours, about 8 hours, about 9 hours, about 10 hours, about 12 hours, about 15 hours, about 18 hours, about 21 hours, about 24 hours, about 27 hours, about 30 hours, about 33 hours, about 36 hours, about 39 hours, about 40 hours, about 41 hours, about 42 hours, about 43 hours, about 44 hours, about 45 hours, about 46 hours, about 47 hours, about 48 hours, about 49 hours, about 50 hours, about 51 hours, about 52 hours, about 53 hours, about 54 hours, about 55 hours, about 56 hours, about 57 hours, about 58 hours, about 59 hours, about 60 hours, about 61 hours, about 62 hours, about 63 hours, about 64 hours, about 65 hours, about 66 hours, about 67 hours, about 68 hours, about 69 hours, about 70 hours, about 71 hours, about 72 hours, about 73 hours, about 74 hours, about 75 hours, about 76 hours, about 77 hours, about 78 hours, about 79 hours, about 80 hours, about 81 hours, about 82 hours, about 83 hours, about 84 hours, about 85 hours, about 86 About 42 hours, about 45 hours, about 48 hours, about 51 hours, about 54 hours, about 57 hours, about 60 hours, about 63 hours, about 66 hours, about 69 hours, about 72 hours, about 75 hours, about 78 hours, about 81 hours, about 84 hours, about 87 hours, about 90 hours, about 93 hours, about 96 hours, etc., and it can also be a range formed by any of the above values ​​(i.e., a range from about 1 minute to about 24 hours, etc.), or it can be a range combining two integers that fall between two of the above reference values ​​(i.e., a range from about 14 minutes to about 94 hours, etc.).

[0054] Furthermore, when two or more compositions are administered, each composition may be administered independently prior to application of the alternating electric field and / or may be administered substantially simultaneously with application of the alternating electric field.

[0055] The alternating electric field applied according to the methods of the present disclosure can be used for any therapeutic purpose disclosed or contemplated herein. In one non-limiting embodiment, the alternating electric field is applied to treat any type of cancer cell / cancer / tumor that responds to TTField therapy. According to the present disclosure, non-limiting examples of treatable cancer cells / cancers / tumors include hepatocellular carcinoma, glioblastoma, pleural mesothelioma, differentiated thyroid cancer, advanced renal cell carcinoma, ovarian cancer, breast cancer, pancreatic cancer, lung cancer (such as but not limited to non-small cell lung cancer), etc., and any combination thereof. In another non-limiting embodiment, the alternating electric field is applied to increase the permeability of tight junction structures between endothelial cells, such as in the blood-brain barrier or the intestine.

[0056] According to the methods of the present disclosure, any type of conductive or non-conductive electrodes and / or transducer arrays that can be used to generate an alternating electric field, whether known in the art or contemplated herein, can be used to generate the alternating electric field. In accordance with the present disclosure, non-limiting examples of electrodes and transducer arrays that can be used to generate alternating electric fields include those that function as part of a TTField system, such as, but not limited to, the electrodes and transducer arrays described in the following patent applications: U.S. Patent Nos. 7,016,725, 7,089,054, 7,333,852, 7,565,205, 8,244,345, 8,715,203, 8,764,675, 10,188,851, and 10,441,776; and U.S. Patent Application Nos. US2018 / 0160933, US2019 / 0117956, US2019 / 0307781; and US 2019 / 0308016.

[0057] According to the present disclosure, the alternating electric field can be generated at any frequency. For example (but not limited to), the alternating electric field can have a frequency of about 50kHz, about 75kHz, about 100kHz, about 125kHz, about 150kHz, about 175kHz, about 200kHz, about 225kHz, about 250kHz, about 275kHz, about 300kHz, about 325kHz, about 350kHz, about 375kHz, about 400kHz, about 425kHz, about 450kHz, about 475kHz, about 500kHz, about 550kHz, about 600kHz, about 650kHz, about 700kHz, about 750kHz, about 800kHz, about 850kHz, about 900kHz, about 900kHz, about 10 ... The frequencies of 950kHz, about 1MHz, about 2MHz, about 3MHz, about 4MHz, about 5MHz, about 6MHz, about 7MHz, about 8MHz, about 9MHz, about 10MHz, etc. may also have a range formed by any of the above values ​​(for example, a range of about 50kHz to about 10MHz, a range of about 50kHz to about 1MHz, a range of about 100kHz to about 500kHz, a range of about 150kHz to about 300kHz, etc.), and may also have a range that is a combination of two integers that fall between two of the above reference values ​​(for example, a range of about 122kHz to about 313kHz, a range of about 78kHz to about 298kHz, etc.).

[0058] In some specific (but non-limiting) embodiments, the alternating electric field may be applied at two or more different frequencies. When there are two or more frequencies, each frequency is selected from any of the above values, or a range formed by any of the above values, or a range combining two integers falling between two of the above reference values.

[0059] The alternating electric field may have any field strength in the subject / cell as long as the alternating electric field is able to function according to the present disclosure. For example, but not limited to, the field strength of the alternating electric field can be at least about 1 V / cm, about 1.5 V / cm, about 2 V / cm, about 2.5 V / cm, about 3 V / cm, about 3.5 V / cm, about 4 V / cm, about 4.5 V / cm, about 5 V / cm, about 5.5 V / cm, about 6 V / cm, about 6.5 V / cm, about 7 V / cm, about 7.5 V / cm, about 8 V / cm, about 9 V / cm, about 9.5 V / cm, about 10 V / cm, about 10.5 V / cm, about 11 V / cm, about 11.5 V / cm, about 12 V / cm, about 12.5 V / cm, about 13 V / cm, about 13.5 V / cm, about 14 V / cm, about 14.5 V / cm, about 15 V / cm, about 16 V / cm, about 17 V / cm, about 18 V / cm, about 19 V / cm, about 20 V / cm, about 21 V / cm, about 22 V / cm, about 23 V / cm, about 24 V / cm, about 25 V / cm, about 26 V / cm, about 27 V / cm, about 28 V / cm, about 29 V / cm, about 30 V / cm, about 31 V / cm, about 32 V / cm, about 33 V / cm, about 34 V / cm, about 35 V / cm, about 36 V / cm, about 37 V / cm, about 38 V / cm, about 39 V / cm, about 40 V / cm, about 41 V / cm The range of the present invention can be any of the above values, for example, about 1V / cm to about 20V / cm, about 1V / cm to about 10V / cm, about 1V / cm to about 4V / cm, or a combination of two integers falling between two of the above reference values ​​(for example, a range of about 1.1V / cm to about 18.6V / cm, a range of about 1.2V / cm to about 9.8V / cm, a range of about 1.3V / cm to about 4.7V / cm, or a combination of two integers falling between two of the above reference values.

[0060] The alternating electric field can be applied for a sufficient time to achieve a therapeutic purpose, such as, but not limited to, reducing the survival rate of cancer cells and / or reducing tumor volume (and / or preventing tumor volume from increasing). For example, but not limited to, the alternating electric field can be applied for at least about 1 hour, about 2 hours, about 3 hours, about 4 hours, about 5 hours, about 6 hours, about 7 hours, about 8 hours, about 9 hours, about 10 hours, about 11 hours, about 12 hours, about 15 hours, about 18 hours, about 21 hours, about 24 hours, about 27 hours, about 30 hours, about 33 hours, about 36 hours, about 39 hours, about 42 hours, about 45 hours, about 48 hours, about 51 hours, about 54 hours, about 55 hours, about 56 hours, about 57 hours, about 58 hours, about 59 hours, about 60 hours, about 61 hours, about 62 hours, about 63 hours, about 64 hours, about 65 hours, about 66 hours, about 67 hours, about 68 hours, about 69 hours, about 70 hours, about 71 hours, about 72 hours, about 73 hours, about 74 hours, about 75 hours, about 76 hours, about 77 hours, about 78 hours, about 79 hours, about 80 hours, about 81 hours, about 82 hours, about 83 hours, about 84 hours, about 85 hours, about 86 hours, about 87 hours, about 88 hours, about 89 hours, about 90 hours, about 91 hours, about 92 hours, about 93 hours, about 94 hours, about 95 hours, about 96 hours, about 97 hours, about 98 hours, about 99 hours, about 100 hours, about 101 hours, about 102 hours, about 1 About 57 hours, about 60 hours, about 63 hours, about 66 hours, about 69 hours, about 72 hours, about 75 hours, about 78 hours, about 81 hours, about 84 hours, about 87 hours, about 90 hours, about 93 hours, about 96 hours, etc. It can also be a range formed by any of the above values ​​(for example, a range from about 24 hours to about 72 hours), or a range combining two integers that fall between two of the above reference values ​​(for example, a range from about 14 hours to about 68 hours, etc.).

[0061] In a specific (but non-limiting) embodiment, the alternating electric field is applied for a period of at least about 24 hours.

[0062] In certain specific (but non-limiting) embodiments, the method includes one or more additional steps. For example (but not limited to), the method may further include repeating any step one or more times. Each step may be repeated as many times as desired. When the alternating electric field is repeatedly applied, the transducer array may be placed in a slightly different position on the subject than its original position; repositioning the array in this manner may further aid in treating the disease / disorder / tumor / cancer.

[0063] In addition, any step of administering the composition containing the active agent can be repeated at different times and at different intervals to follow any known and / or generally accepted dosage regimen for local anesthetics / anti-hyperhidrosis agents. For example (but not limited to), the composition can be administered once or multiple times per day (or once or multiple times over multiple days) over a long period of time (such as but not limited to at least about one week, about two weeks, about three weeks, about four weeks, about one month, about five weeks, about six weeks, about seven weeks, about eight weeks, about two months, etc.). In addition, when the alternating electric field is repeatedly applied and the transducer array is replaced during the repeated step, the composition containing the active agent can be repeatedly administered each time the transducer array is replaced. In addition, during the repeated step, if the position of the transducer array on the subject is slightly different from its initial position, the composition containing the active agent can be administered in multiple steps to different parts of the transducer array that are subsequently attached.

[0064] For example, in a specific (but non-limiting) embodiment, the method is further defined as comprising the steps of: (1) administering at least one composition to at least a portion of a first target area of ​​a subject, wherein the at least one composition comprises at least one local anesthetic and / or at least one anti-hyperhidrosis agent; (2a) applying a first alternating electric field generating system transducer array to the first target area of ​​the subject; (2) applying an alternating electric field to the first target area of ​​the subject using the first transducer array; (3) removing the first transducer array from the subject; (4) administering at least one composition to a second target area of ​​the subject, wherein the composition comprises at least one local anesthetic and / or at least one anti-hyperhidrosis agent; (5) applying a second alternating electric field generating system transducer array to the second target area of ​​the subject; and (6) applying an alternating electric field to the second target area of ​​the subject using the second transducer array. In a specific (but non-limiting) embodiment, the first and second target areas are the same. In another specific (but non-limiting) embodiment, the first and second target areas are different.

[0065] After treatment is initiated, induction is typically observed within a relatively short period of time, such as within the first two months, or the first six weeks, or the first month, or the first four weeks, or the first three weeks, or the first two weeks, or the first week, etc. during the initial treatment period. After the initial period of time, the patient typically gradually adapts to the treatment and has a greater tolerance to any induction that occurs, so that compliance issues are reduced as the duration of alternating electric field treatment increases. Therefore, the methods of the present disclosure include the use of a composition containing a local anesthetic / anti-hyperhidrosis agent for an extended period of time, as well as the use of a composition containing a local anesthetic / anti-hyperhidrosis agent for a limited period of time (such as, but not limited to, about two months, about eight weeks, about seven weeks, about six weeks, about five weeks, about one month, about four weeks, about three weeks, about two weeks, about one week, or less), even though alternating electric field treatment may be used for a longer period of time. In addition, anesthesia and / or reduction in perspiration provided by a composition containing an active agent can be achieved by administering multiple doses of the composition over a period of time, or by administering a controlled release / slow release formulation of a single dose of the composition.

[0066] In a specific (but non-limiting) embodiment, the composition comprising at least one local anesthetic and / or at least one anti-hyperhidrosis agent can be effective in relieving electrical induction / skin irritation for an extended period of about 2 to about 4 days (or longer), which is about equal to or longer than the time the transducer array is applied to the patient's skin. Thus, in this non-limiting embodiment, the composition comprising at least one active agent can be reapplied each time the transducer array is replaced.

[0067] As described above, the composition containing at least one local anesthetic and / or at least one anti-hyperhidrosis agent can be administered to the subject in the form of a topical / transdermal / injectable formulation, respectively. Alternatively, the composition can be added to, included in, or otherwise associated with one or more components of an alternating electric field generating system (such as, but not limited to, a hydrogel, an adhesive for fixing electrodes, a space arranged between electrodes, etc.). In this manner, the composition containing at least one local anesthetic and / or at least one anti-hyperhidrosis agent can be directly applied between the subject's skin and the electrodes, or the composition can be included in the material surrounding the electrodes, etc. When the composition containing the active agent is associated with a component of an alternating electric field generating system, steps (1) and (2) of the method are performed substantially simultaneously.

[0068] Certain non-limiting embodiments of the present disclosure include components of an alternating electric field generating system having any active agent-containing composition associated therewith. For example, but not limited to, the present disclosure includes a polymeric conductive hydrogel for application to a patient's skin and placement between the patient's skin and at least one transducer array that generates an alternating electric field having a frequency in the range of about 50 kHz to about 10 MHz; in addition, the polymeric conductive hydrogel also includes at least one local anesthetic and / or at least one anti-hyperhidrosis agent disposed therein or attached thereto, wherein the agent includes any anesthetic / anti-hyperhidrosis agent described or contemplated herein, and any formulation described or contemplated herein.

[0069] The polymerized conductive hydrogel can be in any form that allows the assembly to function according to the present disclosure. In certain specific (but non-limiting) embodiments, the hydrogel is sterile. In addition, in certain non-limiting embodiments, the hydrogel does not significantly degrade when exposed to sterilization conditions including gamma radiation or ethylene oxide gas. In certain specific (but non-limiting) embodiments, the polymerized hydrogel is semi-solid.

[0070] The polymerized hydrogel can be formed by any hydrophilic polymer that allows the hydrogel to work according to the present disclosure. For example, but not limited to, the hydrogel can be a polyacrylic acid gel, a polyvidone gel or a cellulose gel. In addition, the hydrogel can include: chitosan, alginate, agarose, methylcellulose, hyaluronic acid, collagen, laminin, matrigel, fibronectin, vitronectin, polylysine, proteoglycan, fibrin glue, at least one of the gels made by engineering and / or natural tissues processed by decellularization and any combination thereof. In addition, the gel can include polyglycolic acid (PGA), polylactic acid (PLA), polycaprolactone (PCL), polyvinyl alcohol (PVA), polyethylene glycol (PEG), methyl methacrylate, poly (methyl methacrylate) (PMMA), poly (2-hydroxyethyl methacrylate) (PolyHEMA), poly (glycerol sebacate), polyurethane, poly (isopropyl acrylamide), poly (N-isopropyl acrylamide) at least one or any combination thereof.

[0071] The polymerized hydrogel can have any pH value that does not damage the patient's skin or cause chemical irritation to the skin when in contact with the gel for a long time. For example (but not limited to), the pH value of the gel can be about 6, about 6.5, about 7, about 7.5, about 8, and ranges formed by any of the above values ​​(i.e., a range of about 6 to about 8, a range of about 6.5 to about 7.5, etc.).

[0072] The polymerized hydrogel can have any thickness that allows the gel to function according to the present disclosure. According to the present disclosure, non-limiting examples of thicknesses that can be used include about 1 mil, about 5 mil, about 10 mil, about 15 mil, about 20 mil, about 25 mil, about 30 mil, about 35 mil, about 40 mil, about 45 mil, about 50 mil, about 55 mil, about 60 mil, about 65 mil, about 70 mil, about 75 mil, about 80 mil, about 85 mil, about 90 mil, about 95 mil, about 100 mil or more, and can also be a range of any two of the above reference values ​​combined (i.e., a range of about 10 mil to about 50 mil, etc.), and can also be a range of two integers that fall between the two above reference values ​​(i.e., a range of about 12 mil to about 48 mil, etc.).

[0073] The polymerized hydrogel can have any skin adhesion rate that allows the gel to function according to the present disclosure. For example, but not limited to, the skin adhesion rate of the gel can be at least about 100 g / inch, at least about 110 g / inch, at least about 120 g / inch, at least about 130 g / inch, at least about 140 g / inch, at least about 150 g / inch, at least about 160 g / inch, at least about 170 g / inch, at least about 180 g / inch, at least about 190 g / inch, at least about 200 g / inch, at least about 210 g / inch, at least about 220 g / inch, at least about 230 g / inch, inch, at least about 240 g / inch, at least about 250 g / inch, at least about 260 g / inch, at least about 270 g / inch, at least about 280 g / inch, at least about 290 g / inch, at least about 300 g / inch or more, can also be a range of any of the above values ​​(a range of about 120 g / inch to about 300 g / inch, etc.), can also be a range of two integers that fall between two of the above reference values ​​(i.e., a range of about 115 g / inch to about 295 g / inch, etc.).

[0074] Another component of the alternating electric field generating system is a transducer array, which can be associated with the composition containing the local anesthetic / anti-hyperhidrosis agent. Therefore, certain non-limiting embodiments of the present disclosure are directed to an alternating electric field generating system transducer array, the array comprising at least two insulated electrodes, wherein the frequency range of the alternating electric field generated by each electrode is about 50kHz to about 10MHz (e.g., about 50kHz to about 1MHz, about 50kHz to about 500kHz, or about 100kHz to about 300kHz). The transducer array also includes at least one composition associated therewith, wherein the at least one composition includes at least one of any local anesthetic / anti-hyperhidrosis agent disclosed or contemplated herein, and at least one of any formulation disclosed or contemplated herein.

[0075] In certain non-limiting embodiments, the composition containing the active agent is disposed on or between at least two electrodes. Alternatively, the composition containing the active agent can be disposed in at least one adhesive for adhering the transducer array to the patient's skin. In another non-limiting alternative, the system further comprises at least one bandage for securing the transducer array to the patient's skin, and the at least one composition containing the active agent is contained in at least a portion of the at least one bandage and / or disposed on at least a portion of the lower surface of the at least one bandage.

[0076] In certain specific (but non-limiting) embodiments, each electrode can be an insulating electrode comprising at least one non-conductive layer, at least one conductive layer and a high-capacitance layer, wherein the high-capacitance layer has a top surface and a bottom surface; in addition, at least one opening can be set between the top surface and the bottom surface of the high-capacitance layer.

[0077] Certain non-limiting embodiments of the present disclosure relate to kits that include any components of an alternating electric field generating system (such as, but not limited to, one or more transducer arrays and / or one or more hydrogel compositions, as disclosed in the following patent applications: U.S. Pat. Nos. 7,016,725, 7,089,054, 7,333,852, 7,565,205, 8,244,345, 8,715,203, 8,764,675, 10,188,851, and 10,441,776; and U.S. Patent Application Nos. US2018 / 0160933, US 2019 / 0117956, US2019 / 0307781; and US2019 / 0308016) in combination with any composition disclosed or contemplated herein containing at least one local anesthetic and / or at least one anti-hyperhidrosis agent, and any formulation disclosed or contemplated herein. The kit may optionally further include one or more of any optional compositions disclosed or contemplated herein. The kit may optionally further include one or more devices (or one or more components of a device) for use in one or more additional treatment steps.

[0078] In certain specific (but non-limiting) embodiments, the kit may further include one or more elements or devices for administering the composition containing at least one local anesthetic and / or at least one anti-hyperhidrosis agent to a subject. For example (but not limited to), when the composition containing a local anesthetic / anti-hyperhidrosis agent is delivered by microneedles, the kit may also include at least one component having a plurality of microneedles. The composition containing at least one local anesthetic and / or at least one anti-hyperhidrosis agent may be present in the kit, the kit being separate from the component (or other delivery element / device); or, at least a portion of the microneedle (or other delivery element / device) may be coated with the composition containing a local anesthetic / anti-hyperhidrosis agent. In a specific (but non-limiting) embodiment, the at least one composition containing at least one local anesthetic and / or at least one anti-hyperhidrosis agent is associated with a distal portion of at least one of the plurality of microneedles.

[0079] In a specific (but non-limiting) embodiment, the kit may also include instructions for practicing any of the methods disclosed or contemplated herein. For example (but not limited to), the kit may include instructions for applying the composition comprising at least one local anesthetic and / or at least one anti-hyperhidrosis agent to the patient's skin, instructions for applying one or more components of the alternating electric field to the patient's skin, instructions for applying the alternating electric field to the patient, optionally, instructions for when and how to reapply the composition comprising at least an active agent and / or one or more components of the alternating electric field to the patient's skin, and / or instructions for when to activate and deactivate the alternating electric field.

[0080] In addition to the components described in detail above, the kit may also contain other components / reagents for implementing any specific method described or contemplated herein. For example (but not limited to), the kit may further include: (i) components for preparing the skin before disposing the hydrogel composition and / or the transducer array thereon (i.e., razors, cleaning compositions or wipes / towels, etc.); (ii) components for removing the gel / transducer array; (iii) components for cleaning the skin after removing the gel / transducer array; and / or (iv) other components for use with the system (i.e., conductive materials, non-conductive materials, moisturizing gels or creams, bandages, etc.). The properties of these additional components / reagents will depend on the specific treatment modality, and their identification is well within the skill of those of ordinary skill in the art; therefore, no further description thereof is required. In addition, the components / reagents present in the kit may each be in a separate container / compartment, or the various components / reagents may be combined in one or more containers / compartments, depending on the sterility, cross-reactivity, and stability of the components / reagents.

[0081] The kit can be arranged in any package that allows the components present therein to function according to the present disclosure. In certain non-limiting embodiments, the kit also includes a sealed package in which the components are arranged. In certain specific (but non-limiting) embodiments, the sealed package is substantially airtight and / or substantially lighttight.

[0082] In addition, the kit may also include a set of written instructions explaining how to use one or more components of the kit. Kits of this nature can be used in any method described or contemplated herein.

[0083] In certain non-limiting embodiments, the kit has a shelf life of at least about 6 months, such as, but not limited to, at least about 9 months, or at least about 12 months.

[0084] Certain non-limiting embodiments of the present disclosure relate to systems including any components of the alternating electric field generating system (such as, but not limited to, one or more transducer arrays and / or one or more hydrogel compositions, as disclosed in the following patent applications: U.S. Pat. Nos. 7,016,725, 7,089,054, 7,333,852, 7,565,205, 8,244,345, 8,715,203, 8,764,345, ,675, 10,188,851 and 10,441,776; and U.S. Patent Application Nos. US2018 / 0160933, US2019 / 0117956, US2019 / 0307781; and US2019 / 0308016) with at least one of any composition disclosed or contemplated herein comprising a local anesthetic and / or an anti-hyperhidrosis agent, and any formulation disclosed or contemplated herein. The system may optionally further include one or more of any optional compositions disclosed or contemplated herein.

[0085] Certain non-limiting embodiments of the present disclosure are directed to an assembly comprising a plurality of microneedles, wherein at least a portion of the plurality of microneedles has at least one composition associated therewith, wherein the at least one composition comprises at least one of any local anesthetic / anti-hyperhidrosis agents disclosed or contemplated herein, and at least one of any formulations disclosed or contemplated herein. In a specific (but non-limiting) embodiment, at least a portion of the microneedles is coated with the composition comprising a local anesthetic / anti-hyperhidrosis agent. In a specific (but non-limiting) embodiment, the at least one composition comprising at least one local anesthetic and / or at least one anti-hyperhidrosis agent is associated with a distal portion of at least one of the plurality of microneedles. Non-limiting illustrative embodiments of the inventive concepts

[0086] Illustrative Example 1: A method of reducing electroinduction and / or skin irritation of a subject caused by applying an alternating electric field to the subject, the method comprising the steps of: (1) administering at least one composition to at least a portion of a target area of ​​the subject, wherein the at least one composition comprises at least one active agent selected from at least one local anesthetic, at least one anti-hyperhidrosis agent, and combinations thereof; and (2) applying the alternating electric field to the target area of ​​the subject.

[0087] Illustrative Example 2: A method of reducing electrical induction in a subject caused by applying an alternating electric field to the subject, the method comprising the steps of: (1) administering at least one composition to at least a portion of a target area of ​​the subject, wherein the at least one composition comprises at least one local anesthetic; and (2) applying the alternating electric field to the target area of ​​the subject.

[0088] Illustrative Example 3: A method of reducing skin irritation in a subject caused by applying an alternating electric field to the subject, the method comprising the steps of: (1) administering at least one composition to at least a portion of a target area of ​​the subject, wherein the at least one composition comprises at least one anti-hyperhidrosis agent; and (2) applying the alternating electric field to the target area of ​​the subject.

[0089] Illustrative Embodiment 4: The method of Illustrative Embodiment 1 or 2, wherein the at least one local anesthetic comprises at least one substance selected from the group consisting of botulinum toxin, saxitoxin, tetrodotoxin, lidocaine, bupivacaine, ropivacaine, benzocaine, pramoxine, prilocaine, proparacaine, dibucaine, tetracaine, lignocaine, and combinations thereof.

[0090] Illustrative Embodiment 5: According to the method of any one of Illustrative Embodiments 1, 3 or 4, the at least one anti-hyperhidrosis agent comprises at least one botulinum toxin.

[0091] Illustrative Embodiment 6: The method according to Illustrative Embodiment 4 or 5, wherein the botulinum toxin is a botulinum toxin type A complex.

[0092] Illustrative Embodiment 7: The method according to any one of Illustrative Embodiments 1-6, wherein the at least one composition is administered in a form selected from a cream, a gel, a foam, a lotion, an ointment, an salve, an oil, a liquid, an emulsion, an aerosol, a dispersion, a solid (a patch or a bandage), an adhesive bandage, and combinations thereof.

[0093] Illustrative Embodiment 8: The method according to any one of Illustrative Embodiments 1-7, wherein the at least one composition is formulated for controlled release or extended release.

[0094] Illustrative Embodiment 9: The method according to Illustrative Embodiment 8, wherein the at least one anesthetic agent and / or the at least one anti-hyperhidrosis agent is effective for at least about two weeks.

[0095] Illustrative Embodiment 10: The method according to Illustrative Embodiment 8 or 9, wherein the at least one composition comprises at least one delivery system for delivering the at least one anesthetic agent and / or at least one anti-hyperhidrosis agent.

[0096] Illustrative Example 11: The method according to Illustrative Example 10, wherein the delivery system is selected from the group consisting of liposomes, lipid-based particles, microspheres, microparticles, nanoparticles, polymer conjugates, SABER (sucrose acetate isobutyrate) system, collagen implants, and combinations thereof.

[0097] Illustrative Embodiment 12: The method according to any one of Illustrative Embodiments 1-11, wherein the at least one composition is administered by injection.

[0098] Illustrative Embodiment 13: The method according to any one of Illustrative Embodiments 1-12, wherein the at least one composition is administered to the subject topically or transdermally.

[0099] Illustrative Embodiment 14: The method according to any one of Illustrative Embodiments 1-13, wherein microneedles are used when administering the at least one composition.

[0100] Illustrative Example 15: The method according to any one of Illustrative Examples 1-14, wherein at least one of the following conditions is met: the alternating electric field is applied at a frequency in the range of about 50 kHz to about 10 MHz or in the range of about 50 kHz to about 1 MHz; the alternating electric field has a field strength of at least about 1 V / cm in at least a portion of the cancer cells; and / or the alternating electric field is applied for at least about 24 hours.

[0101] Illustrative Embodiment 16: The method according to any one of Illustrative Embodiments 1-15, wherein steps (1) and (2) are repeated one or more times.

[0102] Illustrative embodiment 17: The method according to illustrative embodiment 16, wherein step (1) is repeated one or more times within a period of at least two weeks from the start of applying the alternating electric field.

[0103] Illustrative embodiment 18: The method according to illustrative embodiment 16 or 17, wherein the method is further defined as comprising the steps of: administering at least one composition to at least a portion of a target area of ​​a subject, wherein the at least one composition comprises at least one local anesthetic and / or at least one anti-hyperhidrosis agent; (2a) applying a first alternating electric field generating system transducer array to the target area of ​​the subject; (2) applying an alternating electric field to the target area of ​​the subject using the first transducer array; (3) removing the first transducer array from the subject; (4) administering at least one composition to the subject, wherein the at least one composition comprises at least one local anesthetic; (5) applying a second alternating electric field generating system transducer array to the subject; and (6) applying an alternating electric field to the target area of ​​the subject using the second transducer array.

[0104] Illustrative Example 19: The method according to Illustrative Example 18, wherein in steps (4) and (5), the at least one composition is administered to and the second transducer array is applied to a target area that is different from the target area of ​​steps (1), (2a) and (2).

[0105] Illustrative Embodiment 20: The method according to Illustrative Embodiment 18, wherein in steps (4) and (5), the at least one composition is administered to and the second transducer array is applied to the target area of ​​steps (1), (2a) and (2).

[0106] Illustrative Embodiment 21: A hydrogel comprising: a polymeric conductive hydrogel for application to a patient's skin and placement between the patient's skin and at least one transducer array that generates an alternating electric field having a frequency in the range of about 50 kHz to about 10 MHz, wherein the polymeric conductive hydrogel comprises at least one composition disposed therein or attached thereto, wherein the composition comprises at least one active agent selected from at least one local anesthetic, at least one anti-hyperhidrosis agent, and combinations thereof.

[0107] Illustrative Embodiment 22: A hydrogel comprising: a polymeric conductive hydrogel for application to a patient's skin and placement between the patient's skin and at least one transducer array that generates an alternating electric field having a frequency in the range of about 50 kHz to about 10 MHz, wherein the polymeric conductive hydrogel includes at least one composition disposed therein or attached thereto, wherein the composition includes at least one local anesthetic.

[0108] Illustrative Embodiment 23: A hydrogel comprising: a polymeric conductive hydrogel for application to a patient's skin and placement between the patient's skin and at least one transducer array that generates an alternating electric field having a frequency in the range of about 50 kHz to about 10 MHz, wherein the polymeric conductive hydrogel includes at least one composition disposed therein or attached thereto, wherein the composition includes at least one anti-hyperhidrosis agent.

[0109] Illustrative embodiment 24: The hydrogel according to any one of illustrative embodiments 21-23, wherein at least one of the following conditions is met: the hydrogel is sterile; the hydrogel is a polyacrylic acid gel, a povidone gel or a cellulose gel; the hydrogel comprises at least one additional substance, the at least one additional substance is selected from the group consisting of chitosan, alginate, agarose, methylcellulose, hyaluronic acid, collagen, laminin, matrix glue, fibronectin, vitronectin, polylysine, proteoglycan, fibrin glue, gels made from engineered and / or natural tissues treated by decellularization, and combinations thereof; the hydrogel comprises at least one polymer, the at least one polymer is selected from the group consisting of poly The invention relates to a hydrogel comprising the following: glycolic acid (PGA), polylactic acid (PLA), polycaprolactone (PCL), polyvinyl alcohol (PVA), polyethylene glycol (PEG), methyl methacrylate, poly(methyl methacrylate) (PMMA), poly(2-hydroxyethyl methacrylate) (PolyHEMA), poly(glycerol sebacate), polyurethane, poly(isopropylacrylamide), poly(N-isopropylacrylamide), and combinations thereof; the hydrogel has a pH range of about 6.5 to about 7.5; the hydrogel has a skin adhesion of at least about 120 g / inch; the hydrogel has a thickness in the range of about 10 mil to about 50 mil; and / or the hydrogel has a shelf life of at least about 6 months.

[0110] Illustrative Embodiment 25: The hydrogel of any one of Illustrative Embodiments 21, 22 or 24, wherein the at least one local anesthetic comprises at least one substance selected from the group consisting of botulinum toxin, saxitoxin, tetrodotoxin, lidocaine, bupivacaine, ropivacaine, benzocaine, pramoxine, prilocaine, proparacaine, dibucaine, tetracaine, lignocaine, and combinations thereof.

[0111] Illustrative Embodiment 26: The hydrogel according to any one of Illustrative Embodiments 21 or 23-25, wherein the at least one anti-hyperhidrosis agent comprises at least one botulinum toxin.

[0112] Illustrative Embodiment 27: The hydrogel of Illustrative Embodiment 25 or 26, wherein the botulinum toxin is a botulinum toxin type A complex.

[0113] Illustrative Embodiment 28: The hydrogel according to any one of Illustrative Embodiments 21-27, wherein the at least one composition is formulated for controlled or extended release.

[0114] Illustrative Embodiment 29: The hydrogel of Illustrative Embodiment 28, wherein the at least one composition comprises at least one delivery system for delivering the at least one anesthetic agent.

[0115] Illustrative Embodiment 30: The hydrogel according to Illustrative Embodiment 29, wherein the delivery system is selected from the group consisting of liposomes, lipid-based particles, microspheres, microparticles, nanoparticles, polymer conjugates, SABER (sucrose acetate isobutyrate) system, collagen implants, and combinations thereof.

[0116] Illustrative embodiment 31: An alternating electric field generating system transducer array, comprising: at least two insulated electrodes, wherein each electrode generates an alternating electric field having a frequency in the range of about 50 kHz to about 10 MHz; and at least one composition arranged between the at least two electrodes, wherein the at least one composition includes at least one active agent, the at least one active agent selected from the group consisting of at least one local anesthetic, at least one anti-hyperhidrosis agent, and combinations thereof.

[0117] Illustrative Embodiment 32: An alternating electric field generating system transducer array comprising: at least two insulated electrodes, wherein each electrode generates an alternating electric field having a frequency in the range of about 50 kHz to about 10 MHz; and at least one composition disposed between the at least two electrodes, wherein the at least one composition includes at least one local anesthetic.

[0118] Illustrative Embodiment 33: An alternating electric field generating system transducer array comprising: at least two insulated electrodes, wherein each electrode generates an alternating electric field having a frequency in the range of about 50 kHz to about 10 MHz; and at least one composition disposed between the at least two electrodes, wherein the at least one composition comprises at least one anti-hyperhidrosis agent.

[0119] Illustrative embodiment 34: A transducer array according to any one of illustrative embodiments 31-33, wherein each electrode comprises at least one non-conductive layer, at least one conductive layer and a high capacitance layer, the high capacitance layer having a top surface and a bottom surface, wherein at least one opening is provided between the top surface and the bottom surface of the high capacitance layer.

[0120] Illustrative Embodiment 35: The transducer array according to any one of Illustrative Embodiments 31-34, wherein the at least one composition comprises at least one adhesive for adhering the transducer array to the patient's skin.

[0121] Illustrative embodiment 36: A transducer array according to any one of illustrative embodiments 31-32 or 34-35, wherein the at least one local anesthetic comprises at least one substance selected from the group consisting of botulinum toxin, saxitoxin, tetrodotoxin, lidocaine, bupivacaine, ropivacaine, benzocaine, pramoxine, prilocaine, proparacaine, dibucaine, tetracaine, lignocaine, and combinations thereof.

[0122] Illustrative Embodiment 37: The transducer array according to any one of Illustrative Embodiments 31 or 33-35, wherein the at least one anti-hyperhidrosis agent comprises at least one botulinum toxin.

[0123] Illustrative Embodiment 38: The transducer array of Illustrative Embodiment 36 or 37, wherein the botulinum toxin is a botulinum toxin type A complex.

[0124] Illustrative Embodiment 39: The transducer array according to any one of Illustrative Embodiments 31-38, wherein the at least one composition is formulated for controlled release or extended release.

[0125] Illustrative Embodiment 40: The transducer array of Illustrative Embodiment 39, wherein the at least one composition comprises at least one delivery system for delivering the at least one anesthetic agent.

[0126] Illustrative Embodiment 41: The transducer array according to Illustrative Embodiment 40, wherein the delivery system is selected from the group consisting of liposomes, lipid-based particles, microspheres, microparticles, nanoparticles, polymer conjugates, SABER (sucrose acetate isobutyrate) system, collagen implants, and combinations thereof.

[0127] Illustrative embodiment 42: According to any one of illustrative embodiments 31-41, the transducer array further comprises at least one bandage for fixing the transducer array on the skin of the patient, and wherein the at least one composition is contained in at least a portion of the at least one bandage and / or is arranged on at least a portion of the lower surface of the at least one bandage.

[0128] Illustrative embodiment 43: A kit comprising: an alternating electric field generating system transducer array, the alternating electric field generating system transducer array comprising at least two insulated electrodes, each electrode comprising at least one non-conductive layer, at least one conductive layer and a high capacitance layer, the high capacitance layer having a top surface and a bottom surface, wherein at least one opening is provided between the top surface and the bottom surface of the high capacitance layer, further wherein each electrode generates an alternating electric field having a frequency in the range of about 50 kHz to about 10 MHz; and at least one composition, wherein the at least one composition comprises at least one active agent selected from the group consisting of at least one local anesthetic, at least one anti-hyperhidrosis agent, and combinations thereof.

[0129] Illustrative embodiment 44: A kit comprising: an alternating electric field generating system transducer array, the alternating electric field generating system transducer array comprising at least two insulated electrodes, each electrode comprising at least one non-conductive layer, at least one conductive layer and a high capacitance layer, the high capacitance layer having a top surface and a bottom surface, wherein at least one opening is provided between the top surface and the bottom surface of the high capacitance layer, further wherein each electrode generates an alternating electric field having a frequency in the range of about 50 kHz to about 10 MHz; and at least one composition, wherein the at least one composition comprises at least one local anesthetic.

[0130] Illustrative embodiment 45: A kit comprising: an alternating electric field generating system transducer array, the alternating electric field generating system transducer array comprising at least two insulated electrodes, each electrode comprising at least one non-conductive layer, at least one conductive layer and a high capacitance layer, the high capacitance layer having a top surface and a bottom surface, wherein at least one opening is provided between the top surface and the bottom surface of the high capacitance layer, further wherein each electrode generates an alternating electric field having a frequency in the range of about 50 kHz to about 10 MHz; and at least one composition, wherein the at least one composition comprises at least one anti-hyperhidrosis agent.

[0131] Illustrative Embodiment 46: The kit of claim 43 or 44, wherein the at least one local anesthetic comprises at least one substance selected from the group consisting of botulinum toxin, saxitoxin, tetrodotoxin, lidocaine, bupivacaine, ropivacaine, benzocaine, pramoxine, prilocaine, proparacaine, dibucaine, tetracaine, lignocaine, and combinations thereof.

[0132] Illustrative Embodiment 47: The kit according to any one of Illustrative Embodiments 43 or 45-46, wherein the at least one anti-hyperhidrosis agent comprises at least one botulinum toxin.

[0133] Illustrative Embodiment 48: The kit of claim 46 or 47, wherein the botulinum toxin is a botulinum toxin type A complex.

[0134] Illustrative Embodiment 49: The kit according to any one of Illustrative Embodiments 43-48, wherein the at least one composition is formulated for controlled release or extended release.

[0135] Illustrative Embodiment 50: The kit according to Illustrative Embodiment 49, wherein the at least one composition comprises at least one delivery system for delivering the at least one anesthetic agent.

[0136] Illustrative Embodiment 51: The kit according to Illustrative Embodiment 50, wherein the delivery system is selected from the group consisting of liposomes, lipid-based particles, microspheres, microparticles, nanoparticles, polymer conjugates, SABER (sucrose acetate isobutyrate) system, and combinations thereof.

[0137] Illustrative Embodiment 52: The kit according to any one of Illustrative Embodiments 43-51, further comprising at least one component having a plurality of microneedles.

[0138] Illustrative Embodiment 53: The kit according to Illustrative Embodiment 52, wherein the at least one composition comprising at least one local anesthetic and / or at least one anti-hyperhidrosis agent is associated with the distal portion of at least one of the plurality of microneedles.

[0139] Illustrative Example 54: A composition comprising at least one local anesthetic for use in a method for reducing electrical induction in a subject caused by applying an alternating electric field to the subject, the method comprising: (1) administering the at least one composition to at least a portion of a target area of ​​the subject; and (2) applying the alternating electric field to the target area of ​​the subject.

[0140] Illustrative Embodiment 55: The composition of Illustrative Embodiment 54, wherein the at least one local anesthetic comprises at least one substance selected from the group consisting of botulinum toxin, saxitoxin, tetrodotoxin, lidocaine, bupivacaine, ropivacaine, benzocaine, pramoxine, prilocaine, proparacaine, dibucaine, tetracaine, lignocaine, and combinations thereof.

[0141] Illustrative Embodiment 56: The composition of Illustrative Embodiment 55, wherein the at least one local anesthetic comprises at least one botulinum toxin.

[0142] Illustrative Embodiment 57: The composition of Illustrative Embodiment 56, wherein the at least one botulinum toxin comprises a botulinum toxin type A complex.

[0143] Illustrative Example 58: A composition comprising at least one anti-hyperhidrosis agent for use in a method of reducing skin irritation in a subject caused by applying an alternating electric field to the subject, the method comprising: (1) administering the at least one composition to at least a portion of a target area of ​​the subject; and (2) applying the alternating electric field to the target area of ​​the subject.

[0144] Illustrative Embodiment 59: The composition of Illustrative Embodiment 58, wherein the at least one anti-hyperhidrosis agent comprises at least one botulinum toxin.

[0145] Illustrative Embodiment 60: The composition of Illustrative Embodiment 59, wherein the at least one botulinum toxin comprises a botulinum toxin type A complex.

[0146] Illustrative Example 61: A composition comprising at least one botulinum toxin for use in a method of reducing electroinduction and / or skin irritation in a subject caused by applying an alternating electric field to the subject, the method comprising: (1) administering at least one composition to at least a portion of a target area of ​​the subject; and (2) applying the alternating electric field to the target area of ​​the subject.

[0147] Illustrative Embodiment 62: The composition of Illustrative Embodiment 61, wherein the at least one botulinum toxin comprises a botulinum toxin type A complex.

[0148] Illustrative Embodiment 63: The composition according to any one of Illustrative Embodiments 54-62, wherein the at least one composition is administered in a form selected from the group consisting of a cream, a gel, a foam, a lotion, an ointment, a salve, an oil, a liquid, an emulsion, an aerosol, a dispersion, a solid (patch or bandage), an adhesive bandage, and combinations thereof.

[0149] Illustrative Embodiment 64: The composition according to any one of Illustrative Embodiments 54-63, wherein the at least one composition is formulated for controlled release or extended release.

[0150] Illustrative Embodiment 65: The composition of Illustrative Embodiment 64, wherein the at least one anesthetic agent and / or the at least one anti-hyperhidrosis agent is effective for at least about two weeks.

[0151] Illustrative Embodiment 66: The composition according to Illustrative Embodiment 64 or 65, wherein the at least one composition comprises at least one delivery system for delivering the at least one anesthetic agent and / or at least one anti-hyperhidrosis agent.

[0152] Illustrative Embodiment 67: The composition according to Illustrative Embodiment 66, wherein the delivery system is selected from the group consisting of liposomes, lipid-based particles, microspheres, microparticles, nanoparticles, polymer conjugates, SABER (sucrose acetate isobutyrate) system, collagen implants, and combinations thereof.

[0153] Illustrative Embodiment 68: The composition according to any one of Illustrative Embodiments 54-67, wherein the at least one composition is administered by injection.

[0154] Illustrative Embodiment 69: The composition according to any one of Illustrative Embodiments 54-68, wherein the at least one composition is administered to the subject topically or transdermally.

[0155] Illustrative Embodiment 70: The composition according to any one of Illustrative Embodiments 54-69, wherein microneedles are used when administering the at least one composition.

[0156] Illustrative Example 71: A composition according to any one of illustrative examples 54-70, wherein at least one of the following conditions is met: the alternating electric field is applied at a frequency in the range of about 50 kHz to about 10 MHz or in the range of about 50 kHz to about 1 MHz; the alternating electric field has a field strength of at least about 1 V / cm in at least a portion of the cancer cells; and / or the alternating electric field is applied for a period of at least about 24 hours.

[0157] Illustrative Embodiment 72: The composition of any one of Illustrative Embodiments 54-71, wherein the method steps are repeated one or more times.

[0158] Illustrative Embodiment 73: The composition of Illustrative Embodiment 72, wherein the composition is applied repeatedly one or more times over a period of at least two weeks from the start of applying the alternating electric field.

[0159] Although the above disclosure describes the concept of the present invention in conjunction with the specific experiments, results and language described, it is obvious that many substitutions, modifications and variations are obvious to those skilled in the art. Therefore, it is intended to include all such substitutions, modifications and variations that fall within the spirit and broad scope of the present invention.

Claims

1. A method for reducing electrical induction and / or skin irritation of a subject caused by applying an alternating electric field to the subject, the method comprising the steps of: (1) administering at least one composition to at least a portion of a target area of ​​the subject, wherein the at least one composition comprises at least one active agent selected from at least one local anesthetic, at least one anti-hyperhidrosis agent, and combinations thereof; and (2) Applying an alternating electric field to the target area of ​​the subject.

2. The method according to claim 1, wherein: The at least one local anesthetic comprises at least one substance selected from the group consisting of Botulinum toxin, saxitoxin, tetrodotoxin, lidocaine, bupivacaine, ropivacaine, benzocaine, pramoxine, prilocaine, proparacaine, dibucaine, tetracaine, lignocaine, and combinations thereof; and / or The at least one anti-hyperhidrosis agent includes at least one botulinum toxin, and combinations thereof.

3. The method of claim 2, wherein the botulinum toxin is a botulinum toxin type A complex.

4. The method according to any one of claims 1-3, wherein the at least one composition is administered in a form selected from the group consisting of a cream, a gel, a foam, a lotion, an ointment, a salve, an oil, a liquid, an emulsion, an aerosol, a dispersion, a solid (a patch or a bandage), an adhesive bandage, and a combination thereof.

5. The method of any one of claims 1-4, wherein the at least one composition is formulated for controlled or extended release and comprises at least one delivery system for delivering the at least one active agent, wherein the delivery system is selected from the group consisting of liposomes, lipid-based particles, microspheres, microparticles, nanoparticles, polymer conjugates, the SABER (sucrose acetate isobutyrate) system, collagen implants, and combinations thereof.

6. The method according to any one of claims 1-5, wherein the at least one composition is administered by injection.

7. The method according to any one of claims 1-6, wherein the at least one composition is administered to the subject topically or transdermally.

8. The method according to any one of claims 1 to 7, wherein microneedles are used when administering the at least one composition.

9. The method according to any one of claims 1 to 8, wherein at least one of the following conditions is met: applying the alternating electric field at a frequency in the range of about 50 kHz to about 10 MHz; The alternating electric field has a field strength of at least about 1 V / cm in at least a portion of the cancer cells; and / or The alternating electric field is applied for a period of at least about 24 hours.

10. The method according to any one of claims 1 to 9, wherein steps (1) and (2) are repeated one or more times.

11. A hydrogel comprising: A polymeric conductive hydrogel for application to a patient's skin and placement between the patient's skin and at least one transducer array that generates an alternating electric field having a frequency in the range of about 50 kHz to about 10 MHz; wherein the polymeric conductive hydrogel comprises at least one composition disposed therein or attached thereto, wherein the at least one composition comprises at least one active agent selected from at least one local anesthetic, at least one anti-hyperhidrosis agent, and combinations thereof.

12. The hydrogel according to claim 11, wherein at least one of the following conditions is met: The hydrogel is sterile; The hydrogel is polyacrylic acid gel, povidone gel or cellulose gel; The hydrogel comprises at least one additional substance selected from the group consisting of chitosan, alginate, agarose, methylcellulose, hyaluronic acid, collagen, laminin, matrigel, fibronectin, vitronectin, polylysine, proteoglycan, fibrin glue, gels made from engineered and / or natural tissues processed by decellularization, and combinations thereof; The hydrogel comprises at least one polymer selected from the group consisting of polyglycolic acid (PGA), polylactic acid (PLA), polycaprolactone (PCL), polyvinyl alcohol (PVA), polyethylene glycol (PEG), methyl methacrylate, poly(methyl methacrylate) (PMMA), poly(2-hydroxyethyl methacrylate) (PolyHEMA), poly(glycerol sebacate), polyurethane, poly(isopropylacrylamide), poly(N-isopropylacrylamide), and combinations thereof; The pH of the hydrogel is in the range of about 6.5 to about 7.5; The hydrogel has a skin adhesion of at least about 120 g / inch; The hydrogel has a thickness ranging from about 10 mils to about 50 mils; and / or The hydrogel has a shelf life of at least about 6 months.

13. The hydrogel according to claim 11 or 12, wherein: The at least one local anesthetic comprises at least one substance selected from the group consisting of Botulinum toxin, saxitoxin, tetrodotoxin, lidocaine, bupivacaine, ropivacaine, benzocaine, pramoxine, prilocaine, proparacaine, dibucaine, tetracaine, lignocaine, and combinations thereof; and / or The at least one anti-hyperhidrosis agent includes at least one botulinum toxin, and combinations thereof.

14. The hydrogel of any one of claims 11-13, wherein the at least one composition is formulated for controlled or extended release and comprises at least one delivery system for delivering the at least one active agent, wherein the delivery system is selected from the group consisting of liposomes, lipid-based particles, microspheres, microparticles, nanoparticles, polymer conjugates, the SABER (sucrose acetate isobutyrate) system, collagen implants, and combinations thereof.

15. A transducer array of an alternating electric field generating system, comprising: at least two insulated electrodes, wherein each electrode generates an alternating electric field having a frequency in the range of about 50 kHz to about 10 MHz; and At least one composition disposed between the at least two electrodes, wherein the at least one composition comprises at least one active agent selected from at least one local anesthetic, at least one anti-hyperhidrosis agent, and combinations thereof.

16. The transducer array of claim 15, wherein: The at least one local anesthetic comprises at least one substance selected from the group consisting of Botulinum toxin, saxitoxin, tetrodotoxin, lidocaine, bupivacaine, ropivacaine, benzocaine, pramoxine, prilocaine, proparacaine, dibucaine, tetracaine, lignocaine, and combinations thereof; and / or The at least one anti-hyperhidrosis agent includes at least one botulinum toxin, and combinations thereof.

17. The transducer array of claim 15 or 16, wherein the at least one composition is formulated for controlled or extended release and comprises at least one delivery system for delivering the at least one anesthetic agent, wherein the delivery system is selected from the group consisting of liposomes, lipid-based particles, microspheres, microparticles, nanoparticles, polymer conjugates, SABER (sucrose acetate isobutyrate) systems, collagen implants, and combinations thereof.

18. A method of reducing the electrical induction of a subject caused by applying an alternating electric field to the subject, the method comprising the steps of: (1) administering at least one composition to at least a portion of a target area of ​​the subject, wherein the at least one composition comprises at least one local anesthetic; and (2) Applying an alternating electric field to the target area of ​​the subject.

19. The method of claim 18, wherein the at least one local anesthetic comprises at least one substance selected from the group consisting of Botulinum toxin, saxitoxin, tetrodotoxin, lidocaine, bupivacaine, ropivacaine, benzocaine, pramoxine, prilocaine, proparacaine, dibucaine, tetracaine, lignocaine, and combinations thereof.

20. The method of claim 19, wherein the botulinum toxin is a botulinum toxin type A complex.

21. The method of any one of claims 18-20, wherein the at least one composition is administered in a form selected from the group consisting of a cream, a gel, a foam, a lotion, an ointment, a salve, an oil, a liquid, an emulsion, an aerosol, a dispersion, a solid (patch or bandage), an adhesive bandage, and combinations thereof.

22. The method of any one of claims 18-21, wherein the at least one composition is formulated for controlled or extended release and comprises at least one delivery system for delivering the at least one active agent, wherein the delivery system is selected from the group consisting of liposomes, lipid-based particles, microspheres, microparticles, nanoparticles, polymer conjugates, SABER (sucrose acetate isobutyrate) systems, collagen implants, and combinations thereof.

23. The method according to any one of claims 18-22, wherein the at least one composition is administered by injection.

24. The method of any one of claims 18-23, wherein the at least one composition is administered to the subject topically or transdermally.

25. The method of any one of claims 18-24, wherein microneedles are used when administering the at least one composition.

26. The method according to any one of claims 18 to 25, wherein at least one of the following conditions is met: applying the alternating electric field at a frequency in the range of about 50 kHz to about 10 MHz; The alternating electric field has a field strength of at least about 1 V / cm in at least a portion of the cancer cells; and / or The alternating electric field is applied for a period of at least about 24 hours.

27. The method according to any one of claims 18 to 26, wherein steps (1) and (2) are repeated one or more times.

28. A hydrogel comprising: A polymeric conductive hydrogel for application to a patient's skin and placement between the patient's skin and at least one transducer array that generates an alternating electric field having a frequency in the range of about 50 kHz to about 10 MHz; wherein the polymeric conductive hydrogel includes at least one composition disposed therein or attached thereto, wherein the at least one composition includes at least one local anesthetic.

29. The hydrogel according to claim 28, wherein at least one of the following conditions is met: The hydrogel is sterile; The hydrogel is polyacrylic acid gel, povidone gel or cellulose gel; The hydrogel comprises at least one additional substance selected from the group consisting of chitosan, alginate, agarose, methylcellulose, hyaluronic acid, collagen, laminin, matrigel, fibronectin, vitronectin, polylysine, proteoglycan, fibrin glue, gels made from engineered and / or natural tissues processed by decellularization, and combinations thereof; The hydrogel comprises at least one polymer selected from the group consisting of polyglycolic acid (PGA), polylactic acid (PLA), polycaprolactone (PCL), polyvinyl alcohol (PVA), polyethylene glycol (PEG), methyl methacrylate, poly(methyl methacrylate) (PMMA), poly(2-hydroxyethyl methacrylate) (PolyHEMA), poly(glycerol sebacate), polyurethane, poly(isopropylacrylamide), poly(N-isopropylacrylamide), and combinations thereof; The pH of the hydrogel is in the range of about 6.5 to about 7.5; The hydrogel has a skin adhesion of at least about 120 g / inch; The hydrogel has a thickness ranging from about 10 mils to about 50 mils; and / or The hydrogel has a shelf life of at least about 6 months.

30. The hydrogel of claim 28 or 29, wherein the at least one local anesthetic comprises at least one substance selected from the group consisting of Botulinum toxin, saxitoxin, tetrodotoxin, lidocaine, bupivacaine, ropivacaine, benzocaine, pramoxine, prilocaine, proparacaine, dibucaine, tetracaine, lignocaine, and combinations thereof.

31. The hydrogel of any one of claims 28-30, wherein the at least one composition is formulated for controlled or extended release and comprises at least one delivery system for delivering the at least one active agent, wherein the delivery system is selected from the group consisting of liposomes, lipid-based particles, microspheres, microparticles, nanoparticles, polymer conjugates, the SABER (sucrose acetate isobutyrate) system, collagen implants, and combinations thereof.

32. A transducer array of an alternating electric field generating system, comprising: at least two insulated electrodes, wherein each electrode generates an alternating electric field having a frequency in the range of about 50 kHz to about 10 MHz; and At least one composition is disposed between the at least two electrodes, wherein the at least one composition comprises at least one local anesthetic.

33. The transducer array of claim 32, wherein the at least one local anesthetic comprises at least one substance selected from the group consisting of Botulinum toxin, saxitoxin, tetrodotoxin, lidocaine, bupivacaine, ropivacaine, benzocaine, pramoxine, prilocaine, proparacaine, dibucaine, tetracaine, lignocaine, and combinations thereof.

34. The transducer array of claim 32 or 33, wherein the at least one composition is formulated for controlled or extended release and comprises at least one delivery system for delivering the at least one anesthetic, wherein the delivery system is selected from the group consisting of liposomes, lipid-based particles, microspheres, microparticles, nanoparticles, polymer conjugates, SABER (sucrose acetate isobutyrate) systems, collagen implants, and combinations thereof.

35. A method of reducing electrical induction and / or skin irritation in a subject caused by applying an alternating electric field to the subject, the method comprising the steps of: (1) administering at least one composition to at least a portion of a target area of ​​the subject, wherein the at least one composition comprises at least one anti-hyperhidrosis agent; and (2) Applying an alternating electric field to the target area of ​​the subject.

36. The method of claim 35, wherein the at least one anti-hyperhidrosis agent comprises at least one botulinum toxin, and combinations thereof.

37. The method of claim 36, wherein the botulinum toxin is a botulinum toxin type A complex.

38. The method of any one of claims 35-37, wherein the at least one composition is administered in a form selected from the group consisting of a cream, a gel, a foam, a lotion, an ointment, a salve, an oil, a liquid, an emulsion, an aerosol, a dispersion, a solid (patch or bandage), an adhesive bandage, and combinations thereof.

39. The method of any one of claims 35-38, wherein the at least one composition is formulated for controlled or extended release and comprises at least one delivery system for delivering the at least one active agent, wherein the delivery system is selected from the group consisting of liposomes, lipid-based particles, microspheres, microparticles, nanoparticles, polymer conjugates, SABER (sucrose acetate isobutyrate) systems, collagen implants, and combinations thereof.

40. The method according to any one of claims 35-39, wherein the at least one composition is administered by injection.

41. The method of any one of claims 35-40, wherein the at least one composition is administered to the subject topically or transdermally.

42. The method of any one of claims 35-41, wherein microneedles are used when administering the at least one composition.

43. The method according to any one of claims 35-42, wherein at least one of the following conditions is met: applying the alternating electric field at a frequency in the range of about 50 kHz to about 10 MHz; The alternating electric field has a field strength of at least about 1 V / cm in at least a portion of the cancer cells; and / or The alternating electric field is applied for a period of at least about 24 hours.

44. The method according to any one of claims 35-44, wherein steps (1) and (2) are repeated one or more times.

45. A hydrogel comprising: A polymeric conductive hydrogel for application to a patient's skin and placement between the patient's skin and at least one transducer array that generates an alternating electric field having a frequency in the range of about 50 kHz to about 10 MHz; wherein the polymeric conductive hydrogel comprises at least one composition disposed therein or attached thereto, wherein the at least one composition comprises at least one anti-hyperhidrosis agent.

46. ​​The hydrogel according to claim 45, wherein at least one of the following conditions is met: The hydrogel is sterile; The hydrogel is polyacrylic acid gel, povidone gel or cellulose gel; The hydrogel comprises at least one additional substance selected from the group consisting of chitosan, alginate, agarose, methylcellulose, hyaluronic acid, collagen, laminin, matrigel, fibronectin, vitronectin, polylysine, proteoglycan, fibrin glue, gels made from engineered and / or natural tissues processed by decellularization, and combinations thereof; The hydrogel comprises at least one polymer selected from the group consisting of polyglycolic acid (PGA), polylactic acid (PLA), polycaprolactone (PCL), polyvinyl alcohol (PVA), polyethylene glycol (PEG), methyl methacrylate, poly(methyl methacrylate) (PMMA), poly(2-hydroxyethyl methacrylate) (PolyHEMA), poly(glycerol sebacate), polyurethane, poly(isopropylacrylamide), poly(N-isopropylacrylamide), and combinations thereof; The pH of the hydrogel is in the range of about 6.5 to about 7.5; The hydrogel has a skin adhesion of at least about 120 g / inch; The hydrogel has a thickness ranging from about 10 mils to about 50 mils; and / or The hydrogel has a shelf life of at least about 6 months.

47. The hydrogel of claim 45 or 46, wherein the at least one anti-hyperhidrosis agent comprises at least one botulinum toxin.

48. The hydrogel of any one of claims 45-47, wherein the at least one composition is formulated for controlled or extended release and comprises at least one delivery system for delivering the at least one active agent, wherein the delivery system is selected from the group consisting of liposomes, lipid-based particles, microspheres, microparticles, nanoparticles, polymer conjugates, the SABER (sucrose acetate isobutyrate) system, collagen implants, and combinations thereof.

49. A transducer array of an alternating electric field generating system, comprising: at least two insulated electrodes, wherein each electrode generates an alternating electric field having a frequency in the range of about 50 kHz to about 10 MHz; and At least one composition is disposed between the at least two electrodes, wherein the at least one composition comprises at least one anti-hyperhidrosis agent.

50. The transducer array of claim 49, wherein the at least one anti-hyperhidrosis agent comprises at least one botulinum toxin.

51. The transducer array of claim 49 or 50, wherein the at least one composition is formulated for controlled or extended release and comprises at least one delivery system for delivering at least one anesthetic, wherein the delivery system is selected from the group consisting of liposomes, lipid-based particles, microspheres, microparticles, nanoparticles, polymer conjugates, SABER (sucrose acetate isobutyrate) systems, collagen implants, and combinations thereof.