Compositions, systems, and methods for reducing electrical sensations and / or skin irritation

Abstract

Disclosed are compositions, systems, and methods for reducing electrical sensations and / or skin irritation in response to application of an alternating current electric field to the skin of a subject. The compositions, systems, and methods involve administering to the subject at least one composition comprising at least one local anesthetic agent, followed by application of an alternating current electric field to the subject.

Description

[Technical Field]

[0001] This application claims the benefit under 35 USC § 119(e) of U.S. Provisional Application No. 63 / 377,824, filed September 30, 2022. The entire contents of the above-referenced patent application(s) are expressly incorporated herein by reference. [Background technology]

[0002] Tumor treating fields (TT fields) are low-intensity (e.g., 1-3 V / cm) alternating electric fields in the mid-frequency range (e.g., 100-500 kHz) that target solid tumors by inhibiting mitosis. This non-invasive treatment is targeted to solid tumors and is described, for example, in 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. TT fields are typically delivered via two pairs of transducer arrays that generate perpendicular magnetic fields within the tumor to be treated; the electrode arrays that make up each pair are positioned on opposite sides of the body part to be treated. Specifically, in the OPTUNE® system, one pair of electrodes is placed on the left and right (LR) sides of the tumor, and another pair is placed on the anterior-posterior (AP) sides of the tumor. TT fields are approved for the treatment of glioblastoma multiforme (GBM) and can be delivered, for example, via the OPTUNE® system (Novocure Limited, St. Helier, Jersey), which includes a transducer array placed on the patient's shaved head.

[0003] Alternating current electric fields (e.g., frequencies between 50 kHz and 1 MHz) can also be used to treat conditions other than tumors. For example, as described in U.S. Patent No. 10,967,167, an alternating current electric field between 50 and 200 kHz can increase the permeability of the blood-brain barrier (BBB), thereby allowing, for example, chemotherapy drugs to reach the brain. Also, as described in U.S. Patent No. 11,103,698, an alternating current electric field between 50 and 500 kHz can increase the permeability of cancer cell membranes, allowing larger molecules to pass through them.

[0004] In the OPTUNE® device, each transducer array used to deliver the TT field consists of a series of ceramic disc electrodes coupled to the patient's skin (e.g., a patient's shaved head for the treatment of GBM) via a layer of conductive medical gel. The purpose of the medical gel is to conform to the contours of the body and provide good electrical contact between the array and the skin, so the gel interface bridges the skin and reduces interference. The device is intended to be worn continuously by the patient for 2–4 days for hygiene purposes and re-shaving (if necessary), after which a new set of arrays can be reattached. Summary of the Invention [Problem to be solved by the invention]

[0005] When treating a subject with an AC electric field, the greater the amplitude, the greater the therapeutic effect. However, as the amplitude of the AC electric field increases and / or the frequency of the AC electric field decreases (e.g., to around 100 kHz), some subjects may experience an electrosensory effect, particularly when the AC field switches direction at the beginning of treatment. This electrosensation may be, for example (but not limited to), a vibratory sensation, paresthesia, and / or a sensation of muscle fiber twitching or contraction.

[0006] Without wishing to be bound by any theory, it is believed that electric sensations arise from the interaction of alternating electric fields with nerve cells (neurons) placed near or adjacent to the transducer array. For example, when the current density (e.g., the current through a particular electrode divided by the area of ​​that electrode) exceeds a threshold (which may vary from person to person), electric sensations begin to occur, and may become more noticeable as the current density increases further.

[0007] Electrical sensations may be a barrier to long-term AC electric field treatment, and the presence of these sensations may deter some subjects from continuing treatment with AC electric fields, especially at the beginning of treatment.

[0008] Additionally, the use of existing medical-grade hydrogels with TT field-generating systems has resulted in dermatological adverse events (dAEs) observed at a 16% and 22% incidence in Phase III clinical trials and post-marketing surveillance programs, 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, certain skin inflammations can be triggered by skin sweat. These adverse events are exacerbated by the need to keep the hydrogel in continuous contact with the patient's skin for several days at a time, without long "breathing" periods between TT field array applications (Lacouture et al. (2014) Seminars in Oncology, 41:S1-S14).

[0009] Furthermore, contact of the hydrogel with sweat during wear can cause the hydrogel to swell and degrade, increasing resistance. Furthermore, loss of the hydrogel interface over a wear period of approximately several days (such as, but not limited to, due to erosion of the hydrogel's adhesive and conductive properties) can reduce the standard current / electric field generated by the TT field system, reducing the functionality and overall effectiveness of the TT field treatment. DETAILED DESCRIPTION OF THE INVENTION

[0010] Before describing at least one embodiment of the inventive concept(s) in detail using illustrative language and results, it should be understood that application of the inventive concept(s) is not limited to the details of construction and the arrangement of components set forth in the following description. The inventive concept(s) is capable of other embodiments or of being practiced or carried out in various ways. Accordingly, the language used herein is intended to be accorded the broadest possible scope and meaning, and the embodiments are intended to be illustrative and not exhaustive. It should also be understood that the phraseology and terminology used herein is for the purpose of description and should not be regarded as limiting.

[0011] Unless otherwise defined herein, scientific and technical terms used in connection with the presently disclosed inventive concept(s) shall have the meanings commonly understood by those of ordinary skill in the art. Furthermore, unless otherwise required by context, singular terms shall include the plural and plural terms shall include the singular. The foregoing techniques and procedures are generally carried out according to conventional methods well known in the art and as described in various general and more specific references cited and described throughout the specification. The nomenclature used in connection with, and the laboratory procedures and techniques of, analytical chemistry, synthetic organic chemistry, medicinal chemistry, and pharmaceutical chemistry described herein are those well known and commonly used in the art. Standard techniques are used for chemical syntheses and chemical analyses.

[0012] All patents, published patent applications, and non-patent publications mentioned in this specification are indicative of the level of skill of those skilled in the art to which the presently disclosed inventive concept(s) pertain. All patents, published patent applications, and non-patent publications referenced in any part of this application are expressly incorporated by reference herein in their entirety to the same extent as if each individual patent or publication was specifically and individually indicated to be incorporated by reference.

[0013] All of the compositions, assemblies, systems, kits, and / or methods disclosed herein can be made and executed without undue experimentation in light of the present disclosure. While the compositions, assemblies, systems, kits, and methods of the inventive concept(s) have been described with reference to specific embodiments, it will be apparent to those skilled in the art that variations can be applied to the compositions and / or methods, and to the steps or sequence of steps of the methods described herein without departing from the concept(s), spirit, and scope of the invention. All such similar substitutes and modifications apparent to those skilled in the art are deemed to be within the spirit, scope, and concept(s) of the inventive concept(s) as defined by the appended claims.

[0014] As used in accordance with the present disclosure, the following terms, unless otherwise indicated, shall be understood to have the following meanings:

[0015] The use of the terms "a" or "an" in the claims and / or specification when used in conjunction with the term "comprising" may mean "one," but is also consistent with the meaning of "one or more," "at least one," or "one or more." Thus, the terms "a," "an," and "the" encompass the plural meaning unless the context clearly indicates otherwise. Thus, for example, the phrase "a compound" can refer to one or more compounds, two or more compounds, three or more compounds, four or more compounds, or an even greater number of compounds. The term "plurality" refers to two or more.

[0016] Use of the term "at least one" is understood to encompass quantities greater than one, including but not limited to 1, as well as 2, 3, 4, 5, 10, 15, 20, 30, 40, 50, 100, etc. The term "at least one" may extend to 100 or 1000 or more, depending on the term to which it is attached, and quantities of 100 / 1000 are not considered limiting, and higher limits may also be satisfactory. Additionally, use of the term "at least one of X, Y, Z" is understood to encompass X alone, Y alone, Z alone, and any combination of X, Y, and Z, and the use of ordinal terms (e.g., "first," "second," "third," "fourth," etc.) is intended only to distinguish between two or more items and does not imply any order of superiority or importance of one item over another, or any additional order.

[0017] The use of the word "or" in the claims is used to mean an inclusive "and / or" unless explicitly stated to refer only to alternatives or unless the alternatives are mutually exclusive. For example, a condition "A or B" can be satisfied by any of the following: A being true (or existing) and B being false (or not existing), A being false (or existing) and B being true (or existing), and both A and B being true (or existing).

[0018] As used herein, references to "one embodiment," "embodiment," "some embodiments," "one example," "for example," or "one example" mean that a particular element, feature, structure, or characteristic described in connection with an embodiment is included in at least one embodiment. For example, the appearances of the phrases "in some embodiments" or "in one example" in various places in the specification do not necessarily all refer to the same embodiment. Moreover, all references to one or more embodiments or examples should not be construed as limiting the claims.

[0019] Throughout this application, the term "about" is used to indicate that a value encompasses the inherent variation of error for a composition / apparatus / device, the method used to determine the value, or the variation that exists between study subjects. For example, and without limitation, when the term "about" is used, the specified value may vary from the specified value by plus or minus 20 percent, 15 percent, 12 percent, 11 percent, 10 percent, 9 percent, 8 percent, 7 percent, 6 percent, 5 percent, 4 percent, 3 percent, 2 percent, or 1 percent, as appropriate for performing the disclosed methods and as understood by one of ordinary skill in the art.

[0020] As used in this specification and claim(s), the words "comprising" (and all forms of "including", such as "comprise" and "comprises"), "having" (and all forms of "having", such as "have" and "has"), "including" (and all forms of "including", such as "includes" and "include") or "containing" (and all forms of "containing", such as "contains" and "contain") are inclusive or open-ended and do not exclude additional, unrecited elements or method steps.

[0021] As used herein, the term "or combinations thereof" refers to all permutations and combinations of the items listed before 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, also includes BA, CA, CB, CBA, BCA, ACB, BAC, or CAB. Continuing with this example, combinations containing repeats of one or more items or terms are expressly included, such as BB, AAA, AAB, BBC, AAABCCCC, CBBAAA, CABABB, etc. One of ordinary skill in the art will understand that there is typically no limit to the number of items or terms that may be combined unless otherwise apparent from the context.

[0022] As used herein, the term "substantially" means that a described event or circumstance occurs entirely, or that a described event or circumstance occurs to a significant extent or degree. For example, when associated with a particular event or circumstance, the term "substantially" means that the subsequently described event or circumstance occurs at least 80% of the time, at least 85% of the time, 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, that two items are very close to each other but not 100% adjacent, or that a portion of one of two items is not 100% adjacent to the other item but is very close to the other item.

[0023] The term "pharmaceutically acceptable" refers to compounds and compositions that are suitable for administration to humans and / or animals without undue side effects, such as toxicity, irritation, and / or allergic response, commensurate with a reasonable benefit / risk ratio.

[0024] As used herein, the term "patient" or "subject" includes human and veterinary subjects. For purposes of treatment, "mammal" refers to any animal classified as a mammal, including, but not limited to, humans, domestic animals, farm animals, non-human primates, and other animals with mammary tissue.

[0025] The term "treatment" refers to both therapeutic and prophylactic measures. Those in need of treatment include, but are not limited to, those who already have a particular condition / disease / infection, as well as those who are at risk of contracting a particular condition / disease / infection (such as those who require prophylactic measures). The term "treating" refers to the administration of an agent / substance / method to a patient for therapeutic and / or prophylactic purposes.

[0026] 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 effect.

[0027] Administration of a therapeutically or prophylactically effective amount is intended to provide a therapeutic benefit in the treatment, prevention, and / or management of a disease, condition, and / or infection. The specific therapeutically effective amount can be readily determined by a practitioner of ordinary skill and may vary depending on factors known in the art, including, but not limited to, the type of condition / disease / infection, the patient's medical history and age, the stage of the condition / disease / infection, and the use of other drugs.

[0028] The term "effective amount," when used in accordance with the concept(s) of the present invention, refers to an amount of a biologically active molecule or its conjugate or derivative, or an amount of a treatment protocol (i.e., an alternating electric field), sufficient to exert a detectable therapeutic effect without undue side effects (such as, but not limited to, toxicity, irritation, allergic reaction, etc.) commensurate with a reasonable benefit / risk ratio. Therapeutic effects may include, for example, but are not limited to, preventing, inhibiting, or alleviating the occurrence of at least one condition. The effective amount for a subject will vary depending on the type of subject, the subject's size and health, the nature and severity of the symptoms being treated, the method of administration, the duration of treatment, the nature of concomitant therapy (if any), the particular formulation used, and the like. Thus, an exact effective amount cannot be specified in advance. However, an effective amount for a particular situation can be determined by one of ordinary skill in the art using routine experimentation based on the information provided herein.

[0029] As used herein, the terms "administration" and "administering" are understood to encompass 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 to encompass both local and systemic application. In addition, the compositions of the present disclosure (and / or methods of administration thereof) may be designed to provide delayed-, controlled-, or sustained-release using formulation techniques well known in the art.

[0030] Turning now to the concept(s) of the present invention, methods are disclosed for alleviating, reducing the occurrence of, and / or mitigating electrical sensations in a subject, where the electrical sensation is caused by application of an alternating current electric field to the subject. Also disclosed herein are methods for alleviating, reducing the occurrence of, and / or ameliorating skin irritation caused by application of an alternating current electric field to a subject. Also disclosed herein are compositions, kits, arrays, and systems related to the methods. The compositions, kits, arrays, systems, and methods utilize application of at least one active agent, including at least one topical anesthetic and / or at least one anti-hyperhidrosis agent, to a portion of the subject's skin to which the alternating current electric field is applied. The at least one topical anesthetic(s) / anti-hyperhidrosis agent may be present in a separate composition applied to the skin or may be associated in some way with the portion of the system that generates or provides the alternating current electric field. Additionally, in some non-limiting embodiments, the at least one active agent is both a topical anesthetic and an anti-hyperhidrosis agent.

[0031] Certain non-limiting embodiments of the present disclosure relate to a method for reducing electrical sensations and / or skin irritation in a subject caused by application of an alternating current electric field to the subject. The method includes administering at least one composition to at least a portion of a target area of ​​the subject, the at least one composition including at least one active agent selected from at least one topical anesthetic, at least one anti-hyperhidrosis agent, and combinations thereof. In some non-limiting embodiments, the at least one active agent is both a topical anesthetic and an anti-hyperhidrosis agent. The method also includes applying an alternating current electric field to the target area of ​​the subject. The alternating current electric field can be applied substantially simultaneously with the administration of the at least one composition or sequentially, in whole or in part, with the administration of the at least one composition.

[0032] Any local anesthetic known in the art or otherwise contemplated herein may be utilized in accordance with the present disclosure, so long as the local anesthetic is capable of reducing electrical sensations in the target area of ​​the subject to which the alternating current electric field is applied. Non-limiting examples of local anesthetics that may be utilized in accordance with the present disclosure may include botulinum toxin, saxitoxin, tetrodotoxin, lidocaine, bupivacaine, ropivacaine, benzocaine, pramoxine, prilocaine, proparacaine, dibucaine, tetracaine, lignocaine, other sodium channel inhibitors, and the like, and any combination thereof.

[0033] In other specific (but non-limiting) embodiments, the at least one local anesthetic agent comprises one or more skin anesthetic agents, including, but not limited to, lidocaine (e.g., skin anesthetic cream, gel, spray, foam, liquid, ointment, and / or injectable, e.g., DERMOPLAST® pain relief spray (Advantice Health, LLC, Cedar Knolls, NJ), LidoRx® sustained-release transdermal gel (Gensco Pharma, LLC, Miami, FL), and LIDODERM® hydrogel patch (Teikoku Pharma USA, San Jose, CA); bupivacaine, ropivacaine, and / or lignocaine injection (or other forms / formulations thereof); benzocaine (e.g., skin anesthetic cream, gel, spray, foam, liquid, ointment, and / or injectable, e.g., SOLARCAINE® (Bayer, Boca Raton, FL), LANACANE® (RB Health (US) LLC, Parsippany, NJ), DERMOPLAST® (Advantice Health, LLC, Cedar Knolls, NJ) products); pramoxine / pramocaine (e.g., skin numbing cream, gel, spray, foam, liquid, ointment, and / or SARNA® Sensitive (Crown Laboratories, Inc., Johnson City, TN), PROCTOFOAM® (Alaven Pharmaceutical LLC, Marietta, GA), and PRAX® (Ferndale Laboratories, Inc., Ferndale, MI) products); dibucaine / cinchocaine (e.g., skin numbing cream, gel, spray, foam, liquid, ointment, and / or NUPERCAINAL® (Dr. Reddy's Laboratories Inc., Princeton, NJ) and Rectacaine products, etc.; tetracaine / ametocaine (e.g., skin numbing creams, gels, sprays, foams, liquids, ointments, and / or AMETOP® (Alliance Pharmaceutical Limited, Chippenham, UK), PONTOCAINE® (Hospira, Inc., Lake Forest, IL), Viractin, and ZILACTIN® (Blairex Laboratories, Inc., Columbus, IN) products, etc.); and any combinations thereof (e.g., but not limited to, combinations such as lidocaine-bupivacaine, lidocaine-tetracaine, lignocaine-prilocaine, lignocaine-tetracaine, bupivacaine-saxitoxin, etc.).

[0034] Any anti-hyperhidrosis agent known in the art or otherwise contemplated herein may be utilized in accordance with the present disclosure, so long as the anti-hyperhidrosis agent is capable of reducing sweating of the skin of a subject to which an alternating electric field is applied. One non-limiting example of an anti-hyperhidrosis agent that may be utilized in accordance with the present disclosure includes botulinum toxin.

[0035] The active agent(s)-containing composition may be provided in any form / formulation that allows for administration of the composition to a target site in a subject and for the active agent(s) to penetrate the subject's skin and reduce electrical sensations and / or skin irritation. Non-limiting examples of available forms / formulations may include creams, gels, foams, lotions, ointments, salves, oils, liquids, emulsions, sprays, aerosols, dispersions, solids (patches or bandages), adhesive plasters, etc., and any combination thereof.

[0036] In certain (but non-limiting) embodiments, the at least one active agent may comprise botulinum toxin complex A (BoNT-A). BoNT-A is currently used to treat a variety of conditions, including, but not limited to, dystonia, neuromuscular disorders, and pain. Additionally, BoNT-A has been approved for the treatment of severe axillary hyperhidrosis. The effects of BoNT-A begin 2-5 days after injection and are maintained for 3-6 months. BoNT-A acts by inhibiting the exocytosis of acetylcholine vesicles at the neuromuscular junction, resulting in flaccid paralysis (Caronetl. (2015) PLoS ONE, 10(10): e0140439; Mark Hallett (2015) Toxicon, 107:64-67). In addition to this, Li et al. (Med Eng Phys. (2017) 43:97-102) investigated the immediate effects of BoNT-A injection on the intrinsic electrical properties of spastic muscles and found that although the resistance of treated muscles was significantly reduced, no significant changes were observed in other impedance variables such as reactance, phase angle, or the anisotropy of each parameter (resistance, reactance, phase angle) after toxin injection.

[0037] Additionally, the disclosed compositions may contain both at least one topical anesthetic and at least one anti-hyperhidrosis agent. Alternatively, the disclosed methods may include applying a first composition containing at least one topical anesthetic and a second composition containing at least one anti-hyperhidrosis agent. When administered separately, the first composition may be administered simultaneously with the second composition or sequentially, in whole or in part. Additionally, it should be understood that the use of ordinal terms is for identification purposes only, and that the first composition may be administered before or after the second composition.

[0038] 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(s) to reduce electrical sensations and / or skin irritation upon application of the composition to a subject's skin. For example, and without limitation, each active agent can be present in the composition at 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%, about 31%, about 32%, about 33%, about 34%, about 35%, about 36%, about 37%, about 38%, about 39%, about 40%, about 41%, about 42%, about 43%, about 44%, about 45%, about 46%, about 47%, about 48%, about 49%, about 50%, about 51%, about 52%, about 53%, about 54%, about 55%, about 56%, about 57%, about 58%, about 59%, about 60%, about 61%, about 62%, about 63%, about It may be present at concentrations (wt%) of 2%, 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., as well as ranges formed from any of the above values ​​(e.g., a range of about 0.01% to about 20%), and ranges formed by combining two values ​​between two of the above reference values ​​(e.g., a range of about 0.025% to about 17.5%).

[0039] In certain (but not limited to) embodiments, the composition comprises a botulinum toxin at a concentration ranging from about 0.1% to about 10%. In certain (but not limited to) embodiments, the composition comprises lidocaine at a concentration ranging from about 0.1% to about 10% (particularly, but not limited to, about 1% to about 5%). In certain (but not limited to) embodiments, the composition comprises bupivacaine at a concentration ranging from about 0.1% to about 1%. In certain (but not limited to) embodiments, the composition comprises benzocaine at a concentration ranging from about 1% to about 25% (particularly, but not limited to, about 5% to about 20%). In certain (but not limited to) embodiments, the composition comprises tetracaine at a concentration ranging from about 0.1% to about 10% (particularly, but not limited to, about 0.5% to about 8%). In certain (but not limited to) embodiments, the composition comprises lignocaine at a concentration ranging from about 1% to about 15% (particularly, but not limited to, about 2% to about 10%). In certain (but not limited to) embodiments, the composition comprises proparacaine at a concentration ranging from about 0.1% to about 2%.

[0040] However, the concentration of the active agent(s) present in the composition can be measured by other mechanisms. For example, in certain non-limiting embodiments, the active agent(s) can be present in the composition at a particular molar concentration. Non-limiting examples of molar concentrations that may be utilized in accordance with the present disclosure include about 0.0001 M, about 0.0005 M, about 0.001 M, about 0.005 M, about 0.01 M, about 0.05 M, about 0.1 M, about 0.2 M, about 0.3 M, about 0.4 M, about 0.5 M, about 0.6 M, about 0.7 M, about 0.8 M, about 0.9 M, about 1 M, about 2 M, about 3 M, about 4 M, about 5 M, or more, as well as molar concentrations within a range formed by two of the above values ​​(e.g., a range of about 0.0001 M to about 1 M, a range of about 0.001 M to about 0.1 M, etc.), or concentrations within two ranges each falling between the two above values ​​(e.g., a range of about 0.007 M to about 0.86 M, etc.).

[0041] In yet another alternative, the active agent(s) may be present in the composition to deliver a specific number of units in each dosage. Non-limiting examples of unit dosages that may be utilized in accordance with the present disclosure 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 dosage ranges formed by any two of the above values ​​(e.g., a range of about 0.5 units to about 100 units), or unit dosage ranges formed by two values ​​that fall between the two above values ​​(e.g., a range of about 0.25 units to about 180 units).

[0042] The composition can be formulated for repeated administration to a patient based on the effective duration of the active agent(s). The dosage can be repeated as needed, for example (but not limited to), about every hour, about every 2 hours, about every 3 hours, about every 4 hours, about every 5 hours, about every 6 hours, about every 7 hours, about every 8 hours, about every 9 hours, about every 10 hours, about every 11 hours, about every 12 hours, about every day, about every 2 days, about every 3 days, about every 4 days, about every 5 days, about every 6 days, about every week, about every 2 weeks, about every 3 weeks, etc., as well as ranges formed by two of the above values.

[0043] 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 agent(s) using formulation techniques well known in the art. Non-limiting examples of formulation techniques include coating, polymer conjugation, the use of one or more delivery systems in which the local anesthetic(s) are disposed or encapsulated (such as, but not limited to, liposomes, lipid-based particles, microspheres, microparticles, nanoparticles, polymer conjugates, SABER (sucrose acetate isobutyrate) systems, collagen implants, depofoams, and combinations thereof), and the like, as well as combinations thereof. Various formulation methods for providing controlled release of active agents are well known in the art and therefore further description is not believed to be necessary.

[0044] The use of a modified release formulation allows one or more active agent(s) to be released from the composition over an extended 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 1 month, etc., and ranges formed from any of the above values ​​(i.e., a range of about 1 day to about 2 weeks, a range of about 2 weeks to about 3 weeks, etc.).

[0045] Specific non-limiting examples of modified release formulations of local anesthetic(s) that may be utilized in accordance with the present disclosure include liposomal formulations of saxitoxin (a liposomal mixture of saxitoxin and dexamethasone has been shown to provide nerve blockade for up to 7.5 days (Epstein-Barash et al. (2009) PNAS, 106(17):7125-7130)); polymer-tetrodotoxin conjugates (which have been shown to provide nerve blockade durations of several hours to 3 days (Elofsson et al. (2019) Nature Commun, 10:2566)); tetrodotoxin microspheres (Kohane et al. (2003) Pain, 104:415-421); liposomal formulations of bupivacaine (EXPAREL® (bupivacaine liposomal injectable suspension in DEPOFOAM®) is FDA approved and provides analgesia for up to 48-72 hours); SABER-bupivacaine (SABER was developed as a bioerodible injectable depot system with the potential to deliver the drug over days to months); bupivacaine-collagen matrix / implant (XARACOLL® implant (Innocoll Pharmaceuticals Limited, Princeton, NJ) has been shown to provide analgesia for 24-72 hours); and any combination thereof.

[0046] The compositions of the present disclosure may be administered via any route of administration that allows for localized numbing of at least a portion of the skin of a target area of ​​a 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 injection or infusion.

[0047] In certain (but non-limiting) embodiments, microneedling is used to administer at least one composition, and the active agent(s)-containing composition is coated onto the microneedles before administration to the subject. For example, but not limited to, the use of microneedling to deliver botulinum toxin is currently utilized in the art to treat various cosmetic concerns.

[0048] The at least one active agent may be placed and administered in any formulation known in the art or contemplated herein that reduces electrical sensations and / or skin irritation caused by application of an alternating current electric field to a subject. For example, but not limited to, the at least one active agent-containing composition may be administered in the form of a pharmaceutical composition comprising the at least one active agent in combination with at least one pharmaceutically acceptable carrier. Non-limiting examples of suitable pharmaceutically acceptable carriers that may be utilized in accordance with the present disclosure may include water, saline, dextrose solution, fructose or mannitol, calcium carbonate, cellulose, ethanol, oils of animal, vegetable, 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, sodium chloride, buffer solutions such as saline and phosphate-buffered saline, and / or other physiologically acceptable and / or safe substances, diluents, excipients such as polyethylene glycol (PEG), or any combination thereof. Suitable pharmaceutically acceptable carriers for pharmaceutical formulations are described, for example, in Remington: The Science and Practice of Pharmacy, 23rd ed (2020).

[0049] In addition, the composition containing at least one active agent may contain other agents that allow the composition to be administered by a specific administration route.For example, but not limited to, the composition may be formulated for administration by topical, transdermal, and / or subcutaneous routes, or other routes described or envisioned herein.Depending on the administration route, the composition may also contain one or more additional components in addition to the active agent (i.e., local anesthetic and / or anti-hyperhidrosis agent).Examples of additional secondary compounds that may be present may include, but are not limited to, fillers, salts, buffers, preservatives, stabilizers, solubilizers, wetting agents, emulsifiers, dispersants, and other substances well known in the art.

[0050] Furthermore, in certain (but not limited to) embodiments, compositions containing at least one local anesthetic and / or at least one anti-hyperhidrosis agent may further contain other active agents that are typically combined with the anesthetic / anti-hyperhidrosis agent(s) in existing formulations. For example (but not limited to), certain topical anesthetic creams may include hydrocortisone to reduce redness, itching, and swelling. In addition, certain topical anesthetic creams may include epinephrine, norepinephrine, or phenylephrine to improve the depth and duration of anesthesia at the subject site.

[0051] In certain non-limiting embodiments, a composition containing at least one active agent can be applied prior to application of the electrodes, but can also be applied substantially simultaneously with and / or after application of the electrodes.

[0052] Additionally, the composition containing at least one topical anesthetic and / or at least one anti-hyperhidrosis agent may be applied prior to application of the AC electric field, but may be applied substantially simultaneously with application of the AC electric field. For example (and not limited to), the composition may be applied for 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 42 hours, about 45 hours, about 48 hours, about 50 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 It may be administered before about 51 hours, about 54 hours, about 57 hours, about 60 hours, about 63 hours, about 66 hours, about 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., as well as ranges formed from any of the above values ​​(i.e., a range of about 1 minute to about 24 hours, etc.), and ranges formed by combining two integers between two of the above reference values ​​(i.e., a range of about 14 minutes to about 94 hours, etc.).

[0053] Also, when two or more compositions are administered, each composition may be applied independently prior to application of the alternating electric field and / or substantially simultaneously with application of the alternating electric field.

[0054] The AC electric field applied according to the method of the present disclosure can be used for any therapeutic purpose disclosed herein or otherwise contemplated herein. In one non-limiting embodiment, the AC electric field is applied to treat any type of cancer cell / cancer / tumor that responds to TT field treatment. Non-limiting examples of cancer cells / cancers / tumors that can be treated according to the present disclosure include hepatocellular carcinoma, glioblastoma, pleural mesothelioma, differentiated thyroid cancer, advanced renal cell carcinoma, ovarian cancer, breast cancer, pancreatic cancer, lung cancer (including, but not limited to, non-small cell lung cancer), and any combination thereof. In another non-limiting embodiment, the AC electric field is applied to increase the permeability of tight junctions between endothelial cells, for example, in the blood-brain barrier or in the intestine.

[0055] Any type of conductive or non-conductive electrode(s) and / or transducer array(s) known in the art or contemplated herein that can be utilized to generate an alternating electric field can be utilized to generate an alternating electric field in accordance with the methods of the present disclosure. Non-limiting examples of electrodes and transducer arrays that can be utilized to generate alternating electric fields in accordance with the present disclosure include, but are not limited to, those that function as part of the TT field systems described, for example, in 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. Pat. Nos. 2018 / 0160933, 2019 / 0117956, 2019 / 0307781, and 2019 / 0308016.

[0056] According to the present invention, the AC electric field can be generated at any frequency, for example (but not limited to) about 50 kHz, about 75 kHz, about 100 kHz, about 125 kHz, about 150 kHz, about 175 kHz, about 200 kHz, about 225 kHz, about 250 kHz, about 275 kHz, about 300 kHz, about 325 kHz, about 350 kHz, about 375 kHz, about 400 kHz, about 425 kHz, about 450 kHz, about 475 kHz, about 500 kHz, about 550 kHz, about 600 kHz, about 650 kHz, about 700 kHz, about 750 kHz, about 800 kHz, about 850 kHz, about 900 kHz, about 950 kHz, about 1 MHz, and the like. Hz, about 2 MHz, about 3 MHz, about 4 MHz, about 5 MHz, about 6 MHz, about 7 MHz, about 8 MHz, about 9 MHz, about 10 MHz, etc., as well as ranges formed from any of the above values ​​(e.g., a range of about 50 kHz to about 10 MHz, a range of about 50 kHz to about 1 MHz, a range of about 100 kHz to about 500 kHz, a range of about 150 kHz to about 300 kHz, etc.), and ranges formed by combining two integers between two of the above reference values ​​(e.g., a range of about 122 kHz to about 313 kHz, a range of about 78 kHz to about 298 kHz, etc.).

[0057] In certain (but non-limiting) embodiments, the alternating electric field may be applied at two or more different frequencies, where two or more frequencies are present, each frequency being selected from any of the values ​​listed above, or from a range formed from any of the values ​​listed above, or from a range combining two integers between any two of the values ​​listed above.

[0058] The alternating electric field can have any electric field strength within the subject / cells as long as it is capable of functioning in accordance with the present disclosure. For example (but not limited to), the alternating electric field may 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 15.5 V / cm, about 16 V / cm The electric field strength may be about 16.5 V / cm, about 17 V / cm, about 17.5 V / cm, about 18 V / cm, about 18.5 V / cm, about 19 V / cm, about 19.5 V / cm, about 20 V / cm, etc., as well as ranges formed from any of the above values ​​(e.g., a range of about 1 V / cm to about 20 V / cm, a range of about 1 V / cm to about 10 V / cm, a range of about 1 V / cm to about 4 V / cm, etc.), and a range formed by combining two integers between two of the above reference values ​​(e.g., a range of about 1.1 V / cm to about 18.6 V / cm, a range of about 1.2 V / cm to about 9.8 V / cm, a range of about 1.3 V / cm to about 4.7 V / cm, etc.).

[0059] The alternating electric field can be applied for any period of time sufficient to achieve a therapeutic objective, such as, but not limited to, reducing cancer cell viability 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 57 ...19 hours, about 20 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 57 hours, about 6 hours, about 7 hours, about 8 hours, about 8 hours, 0 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., as well as ranges formed from any of the above values ​​(e.g., a range of about 24 hours to about 72 hours), and ranges combining two integers between two of the above values ​​(e.g., a range of about 14 hours to about 68 hours).

[0060] In certain (but non-limiting) embodiments, the alternating electric field is applied for a period of at least about 24 hours.

[0061] In certain (but non-limiting) embodiments, the method includes one or more additional steps. For example, but not by way of limitation, the method may include repeating any of the steps one or more times. Each step may be repeated as many times as necessary. Repeated application of the alternating electric field may position the transducer array slightly differently from its original position on the subject, and this repositioning of the array may further aid in treating the disease / condition / tumor / cancer.

[0062] Additionally, any step of administering the active agent(s)-containing composition may be repeated at various times and intervals according to known and / or commonly accepted dosing schedules for the local anesthetic(s) / anti-hyperhidrosis agent(s). For example (but not limited to), the composition may be administered once or more times per day (or once or more times per day) for an extended period of time (such as, but not limited to, at least about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 1 month, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks, about 2 months, etc.). Additionally, if the application of the AC electric field is repeated and the transducer array is changed during the repeating step, the administration of the active agent-containing composition may be repeated each time the transducer array is changed. Also, if the transducer array is positioned slightly differently from its original position on the subject during the repeating step, the active agent-containing composition may be administered in multiple steps at different sites to which the transducer array will subsequently be attached.

[0063] For example, in certain (but non-limiting) embodiments, the method is further defined as including the following steps: (1) administering at least one composition to at least a portion of a first target area of ​​the subject, the at least one composition comprising at least one topical anesthetic and / or at least one anti-hyperhidrosis agent, (2a) applying a first AC electric field generating system transducer array to the first target area of ​​the subject, (2) applying an AC 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 comprising at least one topical anesthetic and / or at least one anti-hyperhidrosis agent to a second target area of ​​the subject, (5) applying a second AC electric field generating system transducer array to the second target area of ​​the subject, and (6) applying an AC electric field to the second target area of ​​the subject using the second transducer array. In certain (but non-limiting) embodiments, the first and second target areas are the same. In another specific (but non-limiting) embodiment, the first and second target regions are different.

[0064] The electrical sensation is typically observed for a relatively short period of time after treatment begins, e.g., during the initial treatment period, such as the first two months, the first six weeks, the first month, the first four weeks, the first three weeks, the first two weeks, or the first week. After the initial treatment period, patients typically become accustomed to the treatment and more tolerant of the electrical sensation present, reducing compliance issues with extended AC electric field treatment. Thus, the methods of the present disclosure encompass the use of compositions containing local anesthetic(s) / anti-hyperhidrosis agent(s) for extended periods of time, as well as the use of compositions containing local anesthetic(s) / anti-hyperhidrosis agent(s) for limited periods of time (e.g., 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 AC electric field treatment may be utilized for longer periods of time. Additionally, the numbness and / or reduced sweating provided by the active agent(s)-containing composition may be achieved by multiple administrations of the composition over a period of time, or by a single administration of a controlled / sustained release formulation of the composition.

[0065] In certain (but non-limiting) embodiments, a composition comprising at least one topical anesthetic and / or at least one anti-hyperhidrosis agent effectively reduces electrosensory / skin irritation for an extended period of time ranging from about 2 days to about 4 days (or more), which is approximately the same as or longer than the period during which the transducer array is applied to the patient's skin. Thus, in this non-limiting embodiment, a composition containing at least one active agent can be reapplied each time the transducer array is changed.

[0066] As described above, compositions containing at least one local anesthetic and / or at least one anti-hyperhidrosis agent can be administered to a subject separately as topical, transdermal, or injectable formulations. Alternatively, the compositions can be added to, incorporated into, or otherwise associated with one or more components of an AC electric field-generating system (e.g., but not limited to, hydrogels, adhesives for attaching electrodes disposed in the inter-electrode spaces, etc.). Thus, compositions containing at least one local anesthetic and / or at least one anti-hyperhidrosis agent can be applied directly between the subject's skin and the electrodes, or the compositions can be contained within a material surrounding the electrodes. When an active agent-containing composition is associated with a component of an AC electric field-generating system, steps (1) and (2) of the method are performed substantially simultaneously.

[0067] Specific, non-limiting embodiments of the present disclosure include components of an AC electric field generating system having any of the active agent-containing compositions associated therewith. For example, and without limitation, the present disclosure includes a polymerized conductive hydrogel that is applied to a patient's skin and disposed between the patient's skin and at least one transducer array that generates an AC electric field having a frequency in the range of about 50 kHz to about 10 MHz, and further having disposed or attached to the polymerized conductive hydrogel at least one topical anesthetic agent and / or at least one anti-hyperhidrosis agent, the agent(s) including any anesthetic / anti-hyperhidrosis agent described herein or otherwise discussed, in any formulation described herein or otherwise discussed.

[0068] The polymerized conductive hydrogel can be in any form that enables the assembly to function in accordance with the present disclosure. In certain, but non-limiting, embodiments, the hydrogel is sterilized. Additionally, in certain non-limiting embodiments, the hydrogel does not substantially degrade when exposed to sterilization conditions, including gamma radiation or ethylene oxide gas. In certain, but non-limiting, embodiments, the polymerized hydrogel is semi-solid.

[0069] The polymerized hydrogel can be formed from any hydrophilic polymer that enables the hydrogel to function according to the present disclosure. For example, but not limited to, the hydrogel can be a polyacrylic acid gel, a povidone gel, or a cellulose gel. In addition, the hydrogel can include at least one of chitosan, alginate, agarose, methylcellulose, hyaluronan, collagen, laminin, Matrigel, fibronectin, vitronectin, poly-l-lysine, proteoglycan, fibrin glue, gels produced by decellularization of artificial and / or native tissue, and any combination thereof. Additionally, the gel may comprise at least one 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), or any combination thereof.

[0070] The polymerized hydrogel can be provided at any pH that is not damaging to the patient's skin and does not cause chemical irritation to the skin even with prolonged exposure to the gel. For example (but not limited to), the pH of the gel can be about 6, about 6.5, about 7, about 7.5, about 8, and ranges formed from 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.).

[0071] The polymerized hydrogel can be provided in any thickness that allows the gel to function according to the present disclosure. Non-limiting examples of thicknesses that can be utilized according to the present disclosure 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, as well as ranges combining any two of the above values ​​(e.g., about 10 mil to about 50 mil), and ranges combining two integers between two of the above values ​​(e.g., about 12 mil to about 48 mil).

[0072] The polymerized hydrogel can be provided with any skin adhesion rate that enables the gel to function in accordance with the present disclosure. For example (but not limited to), the gel can have a skin adhesion rate of 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, 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, at least about 310 g / inch, at least about 320 g / inch, at least about 330 g / inch, at least about 340 g / inch, at least about 350 g / inch, at least about 360 g / inch, at least about 370 g / inch, at least about 380 g / inch, at least about 390 g / inch, at least about 400 g / inch, at least about 410 g / inch, at least about 420 g / inch, at least about 430 g / inch, at least about 440 g / inch, at least about 450 g / inch, at least about 460 g / inch, at least about 470 g / inch, at least about 480 g / inch, at least about 490 g / inch, at least about 500 g / inch, at least about 510 g / inch, at least about 52 The elastic modulus may be 0 g / 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, as well as ranges of any of the above values ​​(e.g., a range of about 120 g / inch to about 300 g / inch), and ranges combining two integers between the above two values ​​(e.g., a range of about 115 g / inch to about 295 g / inch).

[0073] Another component of the AC electric field generating system with which the composition comprising the local anesthetic / anti-hyperhidrosis agent(s) is associated is a transducer array. Accordingly, certain non-limiting embodiments of the present disclosure are directed to an AC electric field generating system transducer array that includes at least two insulated electrodes, each electrode generating an AC electric field having a frequency in the range of about 50 kHz to about 10 MHz (e.g., about 50 kHz to about 1 MHz, about 50 kHz to about 500 kHz, or about 100 kHz to about 300 kHz). The transducer array also includes at least one composition associated therewith, the at least one composition including any of the local anesthetic / anti-hyperhidrosis agents disclosed herein or otherwise discussed and at least one of the formulations disclosed herein or otherwise discussed.

[0074] In certain non-limiting embodiments, the active agent(s)-containing composition is disposed on or between at least two electrodes. Alternatively, the active agent(s)-containing composition can be disposed within at least one adhesive for adhering the transducer array to the patient's skin. In yet another non-limiting alternative, the system further includes at least one bandage for attaching the transducer array to the patient's skin, and the at least one active agent(s)-containing composition is incorporated within at least a portion of the at least one bandage and / or disposed on at least a portion of the underside of the at least one bandage.

[0075] In certain (but non-limiting) embodiments, each electrode may be an insulated electrode including at least one non-conductive layer, at least one conductive layer, and a high capacitance layer having an upper surface and a lower surface, and further, at least one opening may be disposed between the upper and lower surfaces of the high capacitance layer.

[0076] Specific non-limiting embodiments of the present disclosure include any of the compositions comprising at least one topical anesthetic agent and / or at least one anti-hyperhidrosis agent disclosed herein or otherwise discussed in combination with any of the formulations disclosed herein or otherwise discussed in combination with any of the components of an alternating current electric field generating system (e.g., 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. 2018 / 0160933, 2019 / 0117956, 2019 / 0307781, and The present invention relates to a kit comprising one or more transducer arrays and / or one or more hydrogel compositions (such as, but not limited to, those disclosed in US Pat. No. 2019 / 0308016). The kit may optionally further include one or more of any compositions disclosed or contemplated herein. The kit may optionally further include one or more devices (or one or more components of a device) used in one or more additional treatment steps.

[0077] In certain (but not limited to) embodiments, the kit may further include one or more elements or devices for administering a composition containing at least one local anesthetic and / or at least one anti-hyperhidrosis agent to a subject. For example (but not limited to), if the composition containing the local anesthetic / anti-hyperhidrosis agent is delivered by microneedling, the kit may further include at least one assembly containing multiple microneedles. The composition containing at least one local anesthetic and / or at least one anti-hyperhidrosis agent may be present in the kit separately from the assembly (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 the local anesthetic / anti-hyperhidrosis agent. In certain (but not limited to) embodiments, 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 multiple microneedles.

[0078] In certain (but not limited to) embodiments, the kit may further include instructions for carrying out any of the methods disclosed or contemplated herein. For example (but not limited to), the kit may include instructions for applying a composition including at least one topical anesthetic and / or at least one anti-hyperhidrosis agent to a patient's skin, instructions for applying one or more components of an alternating current electric field to the patient's skin, instructions for applying the alternating current electric field to the patient, and optionally instructions on when and how to reapply the composition including at least one active agent and / or one or more components of the alternating current electric field to the patient's skin, and / or instructions on when to activate and deactivate the alternating current electric field.

[0079] In addition to the components detailed above, the kits may further contain other component(s) / reagent(s) for carrying out any of the particular methods described herein or otherwise discussed. For example (but not limited to), the kits may further contain (i) components for preparing the skin before disposing the hydrogel composition and / or transducer array thereon (i.e., razors, cleaning compositions, or wipes / towels, etc.), (ii) components for removing the gel / transducer array(s), (iii) components for cleaning the skin after removing the gel / transducer array(s), and / or (iv) other components used in the system (i.e., conductive materials, non-conductive materials, soothing gels or creams, bandages, etc.). The nature of these additional component(s) / reagent(s) will depend on the particular treatment format, and their identification is within the skill of those of ordinary skill in the art, and therefore further description is not believed necessary. Additionally, the components / reagents in a kit may be contained in separate containers / compartments or various components / reagents may be combined in one or more containers / compartments depending on the sterility, cross-reactivity, and stability of the components / reagents.

[0080] The kit can be disposed in any packaging that enables the components contained therein to function according to the present disclosure. In certain non-limiting embodiments, the kit further comprises a sealed package into which the components are disposed. In certain (but non-limiting) embodiments, the sealed package is substantially impermeable to air and / or substantially impermeable to light.

[0081] In addition, the kits may also include a set of written instructions that describe how to use one or more components of the kit. Such kits can be used in any of the methods described herein or otherwise discussed.

[0082] 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.

[0083] Certain non-limiting embodiments of the present disclosure relate to systems that include any component of an alternating current 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 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. Any of the compositions comprising a local anesthetic agent(s) and / or anti-hyperhidrosis agent(s) disclosed herein or otherwise discussed can be used in any formulation disclosed herein or otherwise discussed in combination with at least one of any of the compositions comprising a local anesthetic agent(s) and / or anti-hyperhidrosis agent(s) disclosed herein or otherwise discussed (e.g., U.S. Patent No. 2018 / 0160933, U.S. Patent No. 2019 / 0117956, U.S. Patent No. 2019 / 0307781, and U.S. Patent No. 2019 / 0308016). The system can optionally further include one or more of any of the compositions disclosed or contemplated herein.

[0084] Certain non-limiting embodiments of the present disclosure are directed to an assembly including a plurality of microneedles, at least a portion of which have associated therewith at least one composition, the at least one composition comprising any of the topical anesthetic / anti-hyperhidrosis agents disclosed herein or otherwise discussed, and at least one of any of the formulations disclosed herein or otherwise discussed. In certain (but non-limiting) embodiments, at least a portion of the microneedles are coated with a composition containing the topical anesthetic / anti-hyperhidrosis agent(s). In certain (but non-limiting) embodiments, at least one composition comprising at least one topical 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 Exemplary Embodiments of the Inventive Concept

[0085] Exemplary Embodiment 1. A method for reducing electrical sensations and / or skin irritation in a subject caused by application of an alternating current electric field to the subject, 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 topical anesthetic agent, at least one anti-hyperhidrosis agent, and combinations thereof; and (2) applying the alternating current electric field to the target area of ​​the subject.

[0086] Exemplary Embodiment 2. A method for reducing electrical sensations in a subject caused by application of an alternating current electric field to the subject, 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 current electric field to the target area of ​​the subject.

[0087] Exemplary Embodiment 3. A method for reducing skin irritation in a subject caused by application of an alternating current electric field to the subject, 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 current electric field to the target area of ​​the subject.

[0088] Exemplary Embodiment 4. The method of exemplary embodiment 1 or 2, wherein the at least one local anesthetic comprises at least one agent selected from the group consisting of botulinum toxin, saxitoxin, tetrodotoxin, lidocaine, bupivacaine, ropivacaine, benzocaine, pramoxine, prilocaine, proparacaine, dibucaine, tetracaine, lignocaine, and combinations thereof.

[0089] Exemplary Embodiment 5 The method of any of exemplary embodiments 1, 3, or 4, wherein the at least one anti-hyperhidrosis agent comprises at least one botulinum toxin.

[0090] Exemplary Embodiment 6. The method of embodiment 4 or 5, wherein the botulinum toxin is botulinum toxin complex A.

[0091] Exemplary Embodiment 7. The method of any of Exemplary Embodiments 1-6, wherein at least one composition is administered in a form selected from the group consisting of a cream, gel, foam, lotion, ointment, salve, oil, liquid, emulsion, aerosol, dispersion, solid (patch or bandage), adhesive bandage, and combinations thereof.

[0092] Exemplary Embodiment 8 The method of any of Exemplary Embodiments 1-7, wherein at least one composition is formulated for controlled or sustained release.

[0093] Exemplary Embodiment 9. The method of exemplary 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.

[0094] Exemplary Embodiment 10. The method of exemplary embodiment 8 or 9, wherein at least one composition comprises at least one delivery system for delivering at least one anesthetic agent and / or at least one anti-hyperhidrosis agent.

[0095] Exemplary Embodiment 11. The method of exemplary embodiment 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) systems, collagen implants, and combinations thereof.

[0096] Exemplary Embodiment 12 The method of any of exemplary embodiments 1-11, wherein at least one composition is administered by injection.

[0097] Exemplary Embodiment 13 The method of any of Exemplary Embodiments 1-12, wherein at least one composition is administered topically or transdermally to the subject.

[0098] Exemplary Embodiment 14 The method of any of exemplary embodiments 1-13, wherein administering at least one composition utilizes microneedling.

[0099] Exemplary Embodiment 15. The method of any of Exemplary Embodiments 1 to 14, wherein the AC electric field is applied at a frequency in the range of about 50 kHz to about 10 MHz or about 50 kHz to about 1 MHz, the AC electric field has an electric field strength of at least about 1 V / cm in at least a portion of the cancer cells, and / or the AC electric field is applied for a period of at least about 24 hours.

[0100] Exemplary Embodiment 16. The method of any of exemplary embodiments 1-15, wherein steps (1) and (2) are repeated one or more times.

[0101] Exemplary Embodiment 17. The method of exemplary embodiment 16, wherein step (1) is repeated one or more times over a period of at least two weeks after application of the alternating electric field begins.

[0102] Exemplary Embodiment 18. The method of exemplary embodiment 16 or 17, further defined as comprising the following steps: (1) administering at least one composition to at least a portion of a target area of ​​the subject, the at least one composition comprising at least one local anesthetic agent and / or at least one anti-hyperhidrosis agent; (2a) applying a first alternating current electric field generating system transducer array to the target area of ​​the subject; (2) applying an alternating current 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 comprising at least one local anesthetic agent; (5) applying a second alternating current electric field generating system transducer array to the subject; and (6) applying an alternating current electric field to the target area of ​​the subject using the second transducer array.

[0103] Exemplary Embodiment 19. The method of exemplary embodiment 18, wherein in steps (4) and (5), at least one composition is administered and a second transducer array is applied to a target area different from the target area of ​​steps (1), (2a), and (2).

[0104] Exemplary Embodiment 20. The method of exemplary embodiment 18, wherein in steps (4) and (5), at least one composition is administered and a second transducer array is applied to the target area of ​​steps (1), (2a), and (2).

[0105] Exemplary embodiment 21. A hydrogel, the hydrogel comprising: a polymerized conductive hydrogel applied to a patient's skin and disposed between the patient's skin and at least one transducer array that generates an alternating electric field having a frequency in a range of about 50 kHz to about 10 MHz, the polymerized conductive hydrogel comprising at least one composition disposed therein or attached thereto, the composition comprising at least one active agent selected from at least one topical anesthetic agent, at least one anti-hyperhidrosis agent, and combinations thereof.

[0106] Exemplary embodiment 22. A hydrogel, the hydrogel comprising: a polymerized conductive hydrogel applied to a patient's skin and positioned 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, the polymerized conductive hydrogel comprising at least one composition disposed therein or attached thereto, the composition comprising at least one local anesthetic agent.

[0107] Exemplary embodiment 23. A hydrogel, the hydrogel comprising: a polymerized conductive hydrogel applied to a patient's skin and disposed between the patient's skin and at least one transducer array that generates an alternating electric field having a frequency in a range of about 50 kHz to about 10 MHz, the polymerized conductive hydrogel comprising at least one composition disposed therein or attached thereto, the composition comprising at least one anti-hyperhidrosis agent.

[0108] Exemplary Embodiment 24. The hydrogel of any of Exemplary Embodiments 21-23, wherein the hydrogel is sterilized; the hydrogel comprises at least one additional substance selected from the group consisting of a hydrogel that is a polyacrylic acid gel, a povidone gel, or a cellulose gel, chitosan, alginate, agarose, methylcellulose, hyaluronan, collagen, laminin, Matrigel, fibronectin, vitronectin, poly- l -lysine, proteoglycan, fibrin glue, gels made by decellularization of artificial and natural tissues, and combinations thereof; the hydrogel is selected from the group consisting of polyglycolic acid (PGA), polylactic acid (PLA), polycaprolactone (PCL), polyvinyl alcohol ( the hydrogel comprises at least one polymer selected from the group consisting of poly(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 in the range of about 6.5 to about 7.5; the hydrogel has a skin adhesion of at least about 120 g / in; the hydrogel has a thickness in the range of about 10 mils to about 50 mils; and / or the hydrogel has a shelf life of at least about 6 months.

[0109] Exemplary Embodiment 25. The hydrogel of any of Exemplary 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.

[0110] Exemplary Embodiment 26 The hydrogel of any of exemplary embodiments 21 or 23-25, wherein the at least one anti-hyperhidrosis agent comprises at least one botulinum toxin.

[0111] Exemplary Embodiment 27 The hydrogel of exemplary embodiment 25 or 26, wherein the botulinum toxin is botulinum toxin complex A.

[0112] Exemplary Embodiment 28 The hydrogel of any of Exemplary Embodiments 21-27, wherein at least one composition is formulated for controlled or sustained release.

[0113] Exemplary Embodiment 29 The hydrogel of exemplary embodiment 28, wherein the at least one composition comprises at least one delivery system for delivering at least one anesthetic agent.

[0114] Exemplary Embodiment 30. The hydrogel of exemplary 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) systems, collagen implants, and combinations thereof.

[0115] Exemplary Embodiment 31. An alternating current electric field generating system transducer array comprising: at least two insulated electrodes, each electrode generating an alternating current 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, the at least one composition comprising at least one active agent selected from the group consisting of at least one topical anesthetic agent, at least one anti-hyperhidrosis agent, and combinations thereof.

[0116] Exemplary Embodiment 32. An alternating current electric field generating system transducer array comprising at least two insulated electrodes, each electrode generating an alternating current 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, the at least one composition comprising at least one local anesthetic agent.

[0117] Exemplary Embodiment 33. An alternating current electric field generating system transducer array comprising: at least two insulated electrodes, each electrode generating an alternating current 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, the at least one composition comprising at least one anti-hyperhidrosis agent.

[0118] Exemplary Embodiment 34. A transducer array according to any of exemplary embodiments 31-33, wherein each electrode includes at least one non-conductive layer, at least one conductive layer, and a high capacitance layer having an upper surface and a lower surface, and at least one opening is disposed between the upper surface and the lower surface of the high capacitance layer.

[0119] Exemplary Embodiment 35. The transducer array of any of Exemplary Embodiments 31-34, wherein the at least one composition includes at least one adhesive for adhering the transducer array to the patient's skin.

[0120] Exemplary Embodiment 36. The transducer array of any of exemplary embodiments 31-32 or 34-35, wherein the at least one local anesthetic agent 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.

[0121] Exemplary Embodiment 37. The transducer array of any of exemplary embodiments 31 or 33-35, wherein the at least one anti-hyperhidrosis agent comprises at least one botulinum toxin.

[0122] Exemplary Embodiment 38 The transducer array of exemplary embodiment 36 or 37, wherein the botulinum toxin is botulinum toxin complex A.

[0123] Exemplary Embodiment 39. The transducer array of any of exemplary embodiments 31-38, wherein at least one composition is formulated for controlled or sustained release.

[0124] Exemplary Embodiment 40. The transducer array of exemplary embodiment 39, wherein the at least one composition comprises at least one delivery system for delivering at least one anesthetic agent.

[0125] Exemplary Embodiment 41. The transducer array of exemplary 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) systems, collagen implants, and combinations thereof.

[0126] Exemplary Embodiment 42. The transducer array of any of Exemplary Embodiments 31-41, further comprising at least one bandage for attaching the transducer array to the patient's skin, wherein the at least one composition is incorporated within at least a portion of the at least one bandage and / or disposed on at least a portion of the underside of the at least one bandage.

[0127] Exemplary Embodiment 43. A kit comprising: an AC electric field generation system transducer array, the AC electric field generation 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 having an upper surface and a lower surface, wherein at least one opening is disposed between the upper and lower surfaces of the high capacitance layer, and each electrode generates an AC electric field having a frequency in a range of about 50 kHz to about 10 MHz; and at least one composition comprising at least one active agent selected from the group consisting of at least one topical anesthetic agent, at least one anti-hyperhidrosis agent, and combinations thereof.

[0128] Exemplary Embodiment 44. A kit comprising: an AC electric field generation system transducer array, the AC electric field generation 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 having an upper surface and a lower surface, wherein at least one opening is disposed between the upper and lower surfaces of the high capacitance layer, and each electrode generates an AC electric field having a frequency in a range of about 50 kHz to about 10 MHz; and at least one composition, the at least one composition comprising at least one local anesthetic agent.

[0129] Exemplary Embodiment 45. A kit comprising: an AC electric field generation system transducer array, the AC electric field generation 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 having an upper surface and a lower surface, wherein at least one opening is disposed between the upper and lower surfaces of the high capacitance layer, and each electrode generates an AC electric field having a frequency in a range of about 50 kHz to about 10 MHz; and at least one composition, the at least one composition comprising at least one local anesthetic agent.

[0130] Exemplary Embodiment 46. The kit of exemplary embodiment 43 or 44, wherein the at least one local anesthetic comprises at least one agent selected from the group consisting of botulinum toxin, saxitoxin, tetrodotoxin, lidocaine, bupivacaine, ropivacaine, benzocaine, pramoxine, prilocaine, proparacaine, dibucaine, tetracaine, lignocaine, and combinations thereof.

[0131] Exemplary Embodiment 47 The kit of any of exemplary embodiments 43 or 45-46, wherein the at least one anti-hyperhidrosis agent comprises at least one botulinum toxin.

[0132] Exemplary Embodiment 48 The kit of exemplary embodiment 46 or 47, wherein the botulinum toxin is botulinum toxin complex A.

[0133] Exemplary Embodiment 49. The kit of any of exemplary embodiments 43-48, wherein at least one composition is formulated for controlled or sustained release.

[0134] Exemplary Embodiment 50 The kit of exemplary embodiment 49, wherein the at least one composition comprises at least one delivery system for delivering at least one anesthetic agent.

[0135] Exemplary Embodiment 51. The kit of exemplary 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) systems, and combinations thereof.

[0136] Exemplary Embodiment 52. The kit of any of Exemplary Embodiments 43-51, further comprising at least one assembly having a plurality of microneedles.

[0137] Exemplary Embodiment 53. The kit of exemplary embodiment 52, wherein at least one composition comprising at least one local anesthetic agent and / or at least one anti-hyperhidrosis agent is associated with a distal portion of at least one of the plurality of microneedles.

[0138] Exemplary embodiment 54. A composition comprising at least one local anesthetic, said composition being used in a method for reducing electrical sensations in a subject caused by application of an alternating current 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; and (2) applying the alternating current electric field to the target area of ​​the subject.

[0139] Exemplary Embodiment 55. The composition of exemplary embodiment 54, wherein the at least one local anesthetic comprises at least one agent selected from the group consisting of botulinum toxin, saxitoxin, tetrodotoxin, lidocaine, bupivacaine, ropivacaine, benzocaine, pramoxine, prilocaine, proparacaine, dibucaine, tetracaine, lignocaine, and combinations thereof.

[0140] Exemplary Embodiment 56 The composition of exemplary embodiment 55, wherein the at least one local anesthetic comprises at least one botulinum toxin.

[0141] Exemplary Embodiment 57 The composition of exemplary embodiment 56, wherein the at least one botulinum toxin comprises botulinum toxin complex A.

[0142] Exemplary embodiment 58. A composition comprising at least one anti-hyperhidrosis agent, the composition being used in a method for reducing skin irritation in a subject caused by application of an alternating current 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; and (2) applying the alternating current electric field to the target area of ​​the subject.

[0143] Exemplary Embodiment 59 The composition of exemplary embodiment 58, wherein the at least one anti-hyperhidrosis agent comprises at least one botulinum toxin.

[0144] Exemplary Embodiment 60 The composition of exemplary embodiment 59, wherein the at least one botulinum toxin comprises botulinum toxin complex A.

[0145] Exemplary embodiment 61. A composition comprising at least one botulinum toxin, the composition being used in a method for reducing electrical sensations and / or skin irritation in a subject caused by application of an alternating current 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; and (2) applying the alternating current electric field to the target area of ​​the subject.

[0146] Exemplary Embodiment 62 The composition of exemplary embodiment 61, wherein the at least one botulinum toxin comprises botulinum toxin complex A.

[0147] Exemplary Embodiment 63. The composition of any of Exemplary Embodiments 54-62, wherein 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), a bandage, and combinations thereof.

[0148] Exemplary Embodiment 64 The composition of any of exemplary embodiments 54-63, wherein at least one composition is formulated for controlled or sustained release.

[0149] Exemplary Embodiment 65 The composition of exemplary 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.

[0150] Exemplary Embodiment 66. The composition of exemplary embodiment 64 or 65, wherein at least one composition comprises at least one delivery system for delivering at least one anesthetic agent and / or at least one anti-hyperhidrosis agent.

[0151] Exemplary Embodiment 67. The composition of exemplary 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) systems, collagen implants, and combinations thereof.

[0152] Exemplary Embodiment 68 The composition of any of exemplary embodiments 54-67, wherein at least one composition is administered by injection.

[0153] Exemplary Embodiment 69 The composition of any of exemplary embodiments 54-68, wherein at least one composition is administered topically or transdermally to a subject.

[0154] Exemplary Embodiment 70. The composition of any of exemplary embodiments 54-69, wherein microneedling is utilized to administer at least one of the compositions.

[0155] Exemplary Embodiment 71. The composition of any of exemplary embodiments 54-70, wherein the alternating electric field is applied at a frequency ranging from about 50 kHz to about 10 MHz, or from 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 duration of the alternating electric field is at least about 24 hours.

[0156] Exemplary Embodiment 72 The composition of any of Exemplary Embodiments 54-71, wherein the method steps are repeated one or more times.

[0157] Exemplary Embodiment 73 The composition of exemplary embodiment 72, wherein application of the composition is repeated one or more times over a period of at least two weeks after application of the alternating electric field is initiated.

[0158] While the above disclosure, in conjunction with specific experiments, results, and written language, describes the inventive concept(s), it is evident that many alternatives, modifications, and variations will be apparent to those skilled in the art. Accordingly, it is intended to embrace all such alternatives, modifications, and variations that fall within the spirit and broad scope of this disclosure.

Claims

1. 1. A method for reducing electrical sensations and / or skin irritation in a subject caused by application of an alternating current electric field to the subject, comprising: (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 topical anesthetic agent, at least one anti-hyperhidrosis agent, and combinations thereof; (2) applying the alternating electric field to a target area of ​​the subject.

2. The at least one local anesthetic agent is and / or comprising 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; The method of claim 1 , wherein the at least one anti-hyperhidrosis agent comprises at least one botulinum toxin, and combinations thereof.

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

4. 4. The method of any one of claims 1 to 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 (patch or bandage), a bandage, and combinations thereof.

5. 5. The method of any one of claims 1 to 4, wherein the at least one composition is formulated for controlled or sustained release and comprises at least one delivery system for delivering the at least one active agent, the delivery system being 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.

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

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

8. The method of any one of claims 1 to 7, wherein microneedling is utilized to administer the at least one composition.

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

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

11. A hydrogel comprising:

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

12. The hydrogel is It is sterilized, the hydrogel is a polyacrylic acid gel, a povidone gel, or a cellulose gel; the hydrogel comprises at least one additional substance selected from the group consisting of chitosan, alginate, agarose, methylcellulose, hyaluronan, collagen, laminin, Matrigel, fibronectin, vitronectin, poly-l-lysine, proteoglycan, fibrin glue, gels made by decellularization of artificial and natural tissues, 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 thickness of the hydrogel ranges from about 10 mils to about 50 mils; and / or The hydrogel of claim 11, wherein the hydrogel has a shelf life of at least about six months.

13. The at least one local anesthetic agent is and / or comprising 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; 13. The hydrogel of claim 11 or 12, wherein the at least one anti-hyperhidrosis agent comprises at least one botulinum toxin, and combinations thereof.

14. 14. The hydrogel of any one of claims 11 to 13, wherein the at least one composition is formulated for controlled or sustained release and comprises at least one delivery system for delivering at least one active agent, the delivery system being 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.

15. 1. A transducer array of an AC electric field generating system, comprising: at least two insulated electrodes, each of which 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, the at least one composition comprising at least one active agent selected from at least one anesthetic agent, at least one anti-hyperhidrosis agent, and combinations thereof.

16. The at least one local anesthetic agent is and / or comprising 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; 16. The transducer array of claim 15, wherein the at least one anti-hyperhidrosis agent comprises at least one botulinum toxin, and combinations thereof.

17. 17. The transducer array of claim 15 or 16, wherein the at least one composition is formulated for controlled or sustained release and comprises at least one delivery system for delivering at least one anesthetic agent, the delivery system being 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. 1. A method for reducing electrical sensations in a subject caused by application of an alternating current electric field to the subject, comprising: (1) administering at least one composition to at least a portion of a target area of ​​the subject, the at least one composition comprising at least one local anesthetic; (2) applying an alternating electric field to a target region of the subject.

19. 19. The method of claim 18, wherein the at least one local anesthetic agent 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. 20. The method of claim 19, wherein the botulinum toxin is toxin complex A.

21. 21. The method of any one of claims 18 to 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), a bandage, and combinations thereof.

22. 22. The method of any one of claims 18 to 21, wherein the at least one composition is formulated for controlled or sustained release and comprises at least one delivery system for delivering the at least one active agent, the delivery system being 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 to 22, wherein the at least one composition is administered by injection.

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

25. The method of any one of claims 18 to 24, wherein microneedling is utilized to administer the at least one composition.

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

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

28. A hydrogel comprising:

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

29. The hydrogel It is sterilized, the hydrogel is a polyacrylic acid gel, a povidone gel, or a cellulose gel; the hydrogel comprises at least one additional substance selected from the group consisting of chitosan, alginate, agarose, methylcellulose, hyaluronan, collagen, laminin, Matrigel, fibronectin, vitronectin, poly-l-lysine, proteoglycan, fibrin glue, gels made by decellularization of artificial and natural tissues, 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 thickness of the hydrogel ranges from about 10 mils to about 50 mils; and / or 30. The hydrogel of claim 28, wherein the hydrogel has a shelf life of at least about six months.

30. 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. 31. The hydrogel of any one of claims 28 to 30, wherein the at least one composition is formulated for controlled or sustained release and comprises at least one delivery system for delivering at least one active agent, the delivery system being 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.

32. 1. A transducer array of an AC electric field generating system, comprising: at least two insulated electrodes, each of which 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, the at least one composition comprising at least one local anesthetic agent.

33. 33. The transducer array of claim 32, wherein the at least one local anesthetic agent 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. 34. The transducer array of claim 32 or 33, wherein the at least one composition is formulated for controlled or sustained release and comprises at least one delivery system for delivering at least one anesthetic agent, the delivery system being 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. 1. A method for reducing electrical sensations and / or skin irritation in a subject caused by application of an alternating current electric field to the subject, comprising: (1) administering at least one composition to at least a portion of a target area of ​​the subject, the at least one composition comprising at least one anti-hyperhidrosis agent; (2) applying an alternating electric field to a target region of the subject.

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

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

38. 38. The method of any one of claims 35 to 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), a bandage, and combinations thereof.

39. 39. The method of any one of claims 35 to 38, wherein the at least one composition is formulated for controlled or sustained release and comprises at least one delivery system for delivering the at least one active agent, the delivery system being 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 of any one of claims 35 to 39, wherein the at least one composition is administered by injection.

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

42. 42. The method of any one of claims 35 to 41, wherein microneedling is utilized to administer the at least one composition.

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

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

45. A hydrogel comprising:

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

46. The hydrogel is It is sterilized, the hydrogel is a polyacrylic acid gel, a povidone gel, or a cellulose gel; the hydrogel comprises at least one additional substance selected from the group consisting of chitosan, alginate, agarose, methylcellulose, hyaluronan, collagen, laminin, Matrigel, fibronectin, vitronectin, poly-l-lysine, proteoglycan, fibrin glue, gels made by decellularization of artificial and natural tissues, 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 thickness of the hydrogel ranges from about 10 mils to about 50 mils; and / or 46. ​​The hydrogel of claim 45, wherein the hydrogel has a shelf life of at least about six months.

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

48. 48. The hydrogel of any one of claims 45 to 47, wherein the at least one composition is formulated for controlled or sustained release and comprises at least one delivery system for delivering the at least one active agent, the delivery system being 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.

49. 1. A transducer array of an AC electric field generating system, comprising: at least two insulated electrodes, each of which 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, the at least one composition comprising at least one anti-hyperhidrosis agent.

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

51. 51. The transducer array of claim 49 or 50, wherein the at least one composition is formulated for controlled or sustained release and comprises at least one delivery system for delivering the at least one anesthetic agent, the delivery system being 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.

Images