Transdermal drug delivery compositions

Abstract

The present disclosure relates to transdermal drug delivery compositions for delivering brivaracetam, and uses, processes, methods of preparation and delivery thereof. The present disclosure also relates to iontophoresis drug delivery devices and systems, and methods of treatment comprising such compositions.

Description

[0001] TRANSDERMAL DRUG DELIVERY COMPOSITIONS

[0002] CROSS REFERENCE TO RELATED APPLICATIONS

[0003] The present application claims priority from United States Provisional Patent Application No. 63 / 604,652 filed 30 November 2023, the contents of which are incorporated herein by reference in their entirety.

[0004] TECHNICAL FIELD

[0005] The present disclosure is related to transdermal drug delivery compositions for delivering brivaracetam, and uses, processes, methods of preparation and delivery thereof. The present disclosure is also related to iontophoresis drug delivery devices and systems, and methods of treatment comprising such compositions.

[0006] BACKGROUND

[0007] Brivaracetam is a third generation antiepileptic racetam derivative with chemical formula (2S)-2-[(4R)-2-oxo-4-propyltetrahydro-lH-pyrrol-l-yl]butanamide. Despite its therapeutic effectiveness, the complexity of its delivery presents a significant barrier to improved efficacy and patient outcomes.

[0008] Although oral formulations of brivaracetam are known, their use is associated with a variety of problems limiting efficacy. Oral delivery requires the patient to be compliant, in that they must adhere to the prescribed administrative regime in order for the treatment to be effective. Moreover, oral delivery of brivaracetam invariable does not result in stable levels of the drug in the patient’s blood over time. A maximum level of the drug is achieved immediately after ingestion and absorption, which decreases over time to a minimum level immediately prior to a subsequent administration. Maintaining a therapeutically effective level of brivaracetam is critical to patient management and to reduce the incidence of e.g. seizures. Furthermore, initial absorption of brivaracetam in oral formulations is limited by the bioavailability of the drug , which is affected by factors such as solubility, first-pass metabolism in the liver, and interactions with food or other medicament.

[0009] Accordingly, there is a pressing need for alternative formulations, including formulations that are suitable for delivery via other methods (for example, transdermal delivery). In particular, there is an unmet need to improve the delivery of brivaracetam. SUMMARY

[0010] The inventors of the present disclosure have undertaken research and development into transdermal drug delivery compositions for delivering brivaracetam to subjects, including by iontophoresis. In particular, the inventors have developed a transdermal composition comprising brivaracetam, which can surprisingly be delivered transdermally in an effective manner, particularly by iontophoresis.

[0011] In one aspect, the present disclosure provides for a transdermal drug delivery composition, comprising brivaracetam or a pharmaceutically acceptable salt, hydrate or solvate thereof and optionally one or more carriers and / or excipients.

[0012] In another aspect, the present disclosure provides for a transdermal drug delivery composition, comprising a porous carrier; and brivaracetam or a pharmaceutically acceptable salt, hydrate or solvate thereof and optionally one or more excipients interspersed on or within the porous carrier.

[0013] In another aspect, the present disclosure provides for a transdermal drug delivery composition, comprising: a polymer; and brivaracetam or a pharmaceutically acceptable salt, hydrate or solvate thereof, a solubility enhancer, and optionally one or more excipients interspersed on or within the polymer.

[0014] In another aspect, the present disclosure provides for a transdermal drug delivery composition, comprising: a polymer gel and brivaracetam or a pharmaceutically acceptable salt, hydrate or solvate thereof, a solubility enhancer, and optionally one or more additives interspersed on or within the polymer gel.

[0015] In another aspect, the present disclosure provides for a method for preparing a transdermal drug delivery composition according to any aspect, embodiment or example described herein, comprising the step of mixing brivaracetam or a pharmaceutically acceptable salt, hydrate or salt thereof and one or more carriers and / or excipients.

[0016] In another aspect, the present disclosure provides for a method for preparing a transdermal drug delivery composition according to any aspect, embodiment or example described herein, comprising contacting a polymer with brivaracetam or a pharmaceutically acceptable salt, hydrate or salt thereof, a solubility enhancer; and optionally one or more excipients.

[0017] In another aspect, the present disclosure provides for a method for preparing a transdermal drug delivery composition according to any aspect, embodiment or example described herein, comprising the step of contacting the carrier with brivaracetam or a pharmaceutically acceptable salt, hydrate or salt thereof, optionally a solubility enhancer; and optionally one or more excipients. In another aspect, the present disclosure provides for a method for preparing a transdermal drug delivery composition according to any aspect, embodiment or example described herein, comprising the step of mixing an aqueous solution comprising: a polymer; brivaracetam or a pharmaceutically acceptable salt, hydrate or salt thereof; a solubility enhancer; and optionally one or more excipients, under conditions effective to form a polymer gel.

[0018] In another aspect, the present disclosure provides for an iontophoresis drug delivery device, comprising: a) a delivery electrode; and b) a reservoir holding a composition according to any of the above aspects or the composition prepared by a method according to any aspect, embodiment or example described herein.

[0019] In another aspect, the present disclosure provides for an iontophoresis drug delivery system, comprising: a) at least one iontophoresis drug delivery device according to any aspect, embodiment, or example described herein; and b) a control circuit configured to generate an electrical control signal and provide the electrical control signal to the delivery electrode of the one or more iontophoresis drug delivery device to transdermally deliver brivaracetam by iontophoresis to a subject.

[0020] In another aspect, the present disclosure provides for a use of a transdermal drug delivery composition according to any aspect, embodiment, or example described herein or a composition prepared by a method according to any aspect, embodiment, or example described herein, for delivering brivaracetam or a pharmaceutically acceptable salt, hydrate or solvate thereof across the skin of a subject.

[0021] In some embodiments, the use is for treating and / or preventing a disease in a subject in need thereof, comprising transdermally delivering a therapeutically effective amount of brivaracetam across the skin to the subject.

[0022] In some embodiments, the disease is epilepsy.

[0023] In another aspect, the present disclosure provides for a method for delivering brivaracetam or a pharmaceutically acceptable salt, hydrate or solvate thereof across the skin of a subject, comprising contacting a composition according to any aspect, embodiment, or example described herein or a composition prepared by a method according to any aspect, embodiment, or example described herein, to the skin to transdermally deliver brivaracetam by iontophoresis across the skin to the subject.

[0024] In some embodiments, the method is for treating and / or preventing a disease in a subject in need thereof, comprising transdermally delivering a therapeutically effective amount of brivaracetam across the skin to the subject.

[0025] In some embodiments, the disease is epilepsy. In another aspect, the present disclosure provides for a transdermal drug delivery composition for treating and / or preventing a disease, wherein the composition comprising: a polymer gel and brivaracetam or a pharmaceutically acceptable salt, hydrate or solvate thereof, a solubility enhancer, and optionally one or more excipients interspersed on or within the polymer gel.

[0026] In some embodiments, the treating and / or preventing comprises transdermally delivering a therapeutically effective amount of brivaracetam across the skin to the subject.

[0027] In some embodiments, the disease is epilepsy.

[0028] In another aspect, the present disclosure provides for a use of a transdermal drug delivery composition according to according to any aspect, embodiment or example described herein in the manufacture of a medicament for treating and / or preventing a disease in a subject, wherein the medicament is formulated for transdermal delivery of a therapeutically effective amount of brivaracetam. In another aspect, there is provided a transdermal drug delivery composition according to according to any aspect, embodiment or example described herein, for use in treating and / or preventing a disease in a subject. In some embodiments, the disease is epilepsy.

[0029] BRIEF DESCRIPTION OF DRAWINGS

[0030] So that the manner in which the above recited features of the present disclosure can be understood in detail, a more particular description of the disclosure, briefly summarised above, may be had by reference to embodiments, some of which are illustrated in the appended drawings. It is to be noted, however, that the appended drawings illustrate only typical embodiments of this disclosure and are therefore not to be considered limiting of its scope, for the disclosure may admit to other equally effective embodiments. It is to be understood that elements and features of one embodiment may be in other embodiments without further recitation. It is further understood that, where possible, identical reference numerals have been used to indicate comparable elements that are common to the figures.

[0031] FIGURE 1 describes the iontophoresis patch Franz Cell setup for the permeation studies.

[0032] FIGURE 2 depicts an example of porcine skin sample impedance measurements taken prior to the iontophoretic transdermal delivery experiment.

[0033] FIGURE 3 describes the viscosity profile of carbomer hydrogel formulation.

[0034] FIGURE 4 describes the shear stress profile of carbomer hydrogel formulation. FIGURE 5 describes solubility of brivaracetam in various formulations.

[0035] FIGURE 6 describes the controlled release of brivaracetam by switching polarity. FIGURE 7 describes the iontophoretic delivery of brivaracetam with constant current and constant voltage modes.

[0036] FIGURE 8 describes the iontophoretic enhancement coefficient with constant voltage and constant current modes.

[0037] DETAILED DESCRIPTION

[0038] The present disclosure describes the following various non-limiting embodiments, which relate to transdermal compositions for iontophoretic drug delivery.

[0039] General terms

[0040] With regards to the definitions provided herein, unless stated otherwise, or implicit from context, the defined terms and phrases include the provided meanings. Unless explicitly stated otherwise, or apparent from context, the terms and phrases below do not exclude the meaning that the term or phrase has acquired by a person skilled in the relevant art. The definitions are provided to aid in describing particular embodiments, and are not intended to limit the claimed invention, because the scope of the invention is limited only by the claims.

[0041] All technical and scientific terms used herein have the usual meaning conventionally understood by persons skilled in the art to which this disclosure pertains, unless context defines otherwise.

[0042] All references, including publications, patent applications, and patents, cited herein, unless described otherwise, are hereby incorporated by reference to the same extent as if each reference were individually and specifically indicated to be incorporated by reference and were set forth in its entirety herein.

[0043] Any discussion of documents, acts, materials, devices, articles or the like which has been included in the present specification is not to be taken as an admission that any or all of these matters form part of the prior art base or were common general knowledge in the field relevant to the present disclosure as it existed before the priority date of each of the appended claims.

[0044] Unless otherwise required by context, singular terms shall include pluralities and plural terms shall include the singular. Throughout this disclosure, unless specifically stated otherwise or the context requires otherwise, reference to a single step, composition of matter, group of steps or group of compositions of matter shall be taken to encompass one and a plurality (i.e., one or more) of those steps, compositions of matter, groups of steps or groups of compositions of matter. Thus, as used herein, the singular forms “a”, “an” and “the” include plural aspects unless the context clearly dictates otherwise. For example, reference to “a” includes a single as well as two or more; reference to “an” includes a single as well as two or more; reference to “the” includes a single as well as two or more and so forth. Those skilled in the art will appreciate that the disclosure herein is susceptible to variations and modifications other than those specifically described. It is to be understood that the disclosure includes all such variations and modifications. The disclosure also includes all of the examples, steps, features, methods, compositions, articles, formulations, uses and processes, referred to or indicated in this specification, individually or collectively, and any and all combinations or any two or more of said steps or features.

[0045] The term “and / or”, e.g., “X and / or Y” shall be understood to mean either “X and Y” or “X or Y” and shall be taken to provide explicit support for both meanings or for either meaning.

[0046] Unless otherwise indicated, the terms “first,” “second,” etc. are used herein merely as labels, and are not intended to impose ordinal, positional, or hierarchical requirements on the items to which these terms refer. Moreover, reference to a “second” item does not require or preclude the existence of lower-numbered item (e.g., a “first” item) and / or a higher-numbered item (e.g., a “third” item).

[0047] As used herein, the phrase “at least one of’ or “one or more of’ when used with a list of items, means different combinations of one or more of the listed items may be used and only one of the items in the list may be needed. The item may be a particular object, thing, or category. In other words, “at least one of’ means any combination of items or number of items may be used from the list, but not all of the items in the list may be required. For example, “at least one of item A, item B, and item C” may mean item A; item A and item B; item B; item A, item B, and item C; or item B and item C. In some cases, “at least one of item A, item B, and item C” may mean, for example and without limitation, two of item A, one of item B, and ten of item C; four of item B and seven of item C; or some other suitable combination.

[0048] It is to be appreciated that certain features that are, for clarity, described herein in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features that are, for brevity, described in the context of a single embodiment, may also be provided separately or in any sub-combination.

[0049] Throughout the present specification, various aspects and components of the disclosure can be presented in a range format. The range format is included for convenience and should not be interpreted as an inflexible limitation on the scope of the present disclosure. Accordingly, the description of a range should be considered to have specifically disclosed all the possible sub-ranges as well as individual numerical values within that range, unless specifically indicated. For example, description of a range such as from 1 to 5 should be considered to have specifically disclosed sub-ranges such as from 1 to 3, from 1 to 4, from 1 to 5, from 2 to 4, from 2 to 5, from 3 to 5 etc., as well as individual and partial numbers within the recited range, for example, 1, 2, 3, 4, 4.5 and 5, unless where integers are required or implicit from context. This applies regardless of the breadth of the disclosed range. Where specific values are required, these will be indicated in the specification.

[0050] Generally, the term “about” will be understood and determined by a person skilled in the art in the context of each given aspect, embodiment, example, claim or feature, to encompass variance within which a person skilled in the art would not expect significant alteration of function or purpose of the invention. However, where a tolerance in any value connected to this term is required, unless otherwise specified, the term “about” can encompass a 10%, 15%, 20%, 25% or even 30% tolerance in any value or values connected to the term. Throughout this specification the word "comprise", or variations such as "comprises" or "comprising", will be understood to imply the inclusion of a stated element, integer or step, or group of elements, integers or steps, but not the exclusion of any other element, integer or step, or group of elements, integers or steps. The terms "comprising", "comprise" and "comprises" herein are intended to be optionally substitutable with the terms "consisting essentially of, "consist essentially of, "consists essentially of, "consisting of, "consist of and "consists of, respectively, in every instance.

[0051] Specific terms

[0052] As used herein, “administer” or “administration” shall refer to the means by which brivaracetam is delivered to a subject's body. It will be appreciated that in some embodiments “administer” or “administration” may refer to delivery of a dose of brivaracetam, and in some embodiments to the multiplicity of delivered (or intended to be delivered) doses of brivaracetam according to a “course of treatment”, such that it may be said that the “course of treatment” is administered.

[0053] As used herein, the term “subject” refers to any organism susceptible to a disease or condition that requires therapy. For example, the subject can be a mammal, primate, livestock (e.g., sheep, cow, horse, pig), companion animal (e.g., dog, cat), or laboratory animal (e.g., mouse, rabbit, rat, guinea pig, hamster). In one example, the subject is a mammal. In one embodiment, the subject is human.

[0054] As used herein, the term “transdermal” means relating to or denoting the application of a drug via absorption through the skin, or across the stratum comeum of the epidermis and into the dermis for absorption into the systemic circulation or for local effects. This may be achieved passively or through one or more active means, such as iontophoresis.

[0055] As used herein, the term “treating” or “treatment” includes alleviation of the symptoms associated with a specific disease or condition and reducing and / or eliminating said symptoms. For example, the term “treating epilepsy” refers to alleviating the symptoms associated with epilepsy and / or eliminating the symptoms associated with epilepsy. In certain embodiments, the terms refer to minimizing the advancement or worsening of the disease, disorder, or condition resulting from the administration of a formulation of the invention to a patient with such a disease, disorder, or condition. The terms “treat,” “treating”, “treatment”, or the like, as used herein covers the treatment of a disease, disorder, or condition in a subject, e.g., a mammal, and includes at least one of: (i) inhibiting the disease, disorder, or condition, i.e., partially or completely halting its progression; (ii) relieving the disease, disorder, or condition, i.e. causing regression of symptoms of the disease, disorder, or condition, or ameliorating a symptom of the disease, disorder, or condition; and (iii) reversal or regression of the disease, disorder, or condition, preferably eliminating or curing of the disease, disorder, or condition. In some embodiments, the terms refer to the administration of a radiopharmaceutical, after the onset of symptoms of the particular disease, disorder, or condition. As is known in the art, adjustments for age, body weight, general health, sex, diet, time of administration, drug interaction and the severity of the condition may be necessary, and will be ascertainable with routine experimentation by one of ordinary skill in the art based on the invention described herein.

[0056] As used herein, the term “preventing” or “prevention” includes prophylaxis of the specific disorder or condition. For example, the term “preventing epilepsy” refers to preventing the onset or duration of the symptoms associated with epilepsy.

[0057] As would be understood by the person skilled in the art, brivaracetam can be administered in a therapeutically effective amount. The term “therapeutically effective amount”, as used herein, refers to an amount (e.g. of brivaracetam) sufficient to achieve a desired pharmacological effect or therapeutic improvement, e.g. an amount sufficient alleviate or prevent to some extent one or more of the symptoms of a disorder or condition being treated. The result can be the reduction and / or alleviation of the signs, symptoms, or causes of a disease or condition, or any other desired alteration of a biological system. For example, one result may be the reduction of one or more symptoms associated with e.g. epilepsy. A “therapeutically effective amount” may refer to an amount effective to achieve a desired pharmacologic effect or therapeutic improvement without undue adverse side effects. By way of example only, “therapeutically effective amounts” may be determined by routine experimentation, including but not limited to a dose escalation clinical trial. The term “therapeutically effective amount” includes, for example, a prophylactically effective amount. In one embodiment, a prophylactically effective amount is an amount sufficient to prevent epilepsy. It is understood that “an effective amount” or “a therapeutically effective amount” can vary from subject to subject, due to variation in metabolism of the compound and any one or combination of the age, weight, general condi tion / heal th of the subject, the condition being treated, the severity of the condition being treated, and the judgment of the prescribing physician. Thus, it is not always possible to specify an exact “effective amount”. However, an appropriate “effective amount” in any individual case may be determined by one of ordinary skill in the art using routine experimentation. Where one or more other therapeutic agents are used in combination with brivaracetam, a “therapeutically effective amount” of each therapeutic agent can refer to an amount of the therapeutic agent that would be therapeutically effective when used on its own, or may refer to an adjusted (e.g., reduced) amount that is therapeutically effective by virtue of its combination with one or more additional therapeutic agents.

[0058] The terms “excipient”, “carrier”, “pharmaceutically acceptable excipient” and “pharmaceutically acceptable carrier” refer to a substance that directly or indirectly aids the transdermal administration of an active agent to and absorption by a subject and can be included in the compositions of the present invention, typically without causing a significant adverse effect on the patient. For example, “carriers” or “pharmaceutically acceptable carriers" as used herein can refer to carrier materials suitable for transdermal drug administration, and include any such materials known in the art, e.g., any liquid, polymer, including a polymeric adhesive or polymer gel such as hydrogel, solvent, liquid diluent, solubilizer, or the like, which can act as a reservoir for an active agent, such as that for a transdermal patch. Non-limiting examples of excipients include water, NaCl, normal saline solutions, lactated Ringer's, normal sucrose, normal glucose, binders, fillers, disintegrants, lubricants, coatings, sweeteners, flavors, salt solutions (such as Ringer's solution), alcohols, oils, gelatins, carbohydrates such as lactose, amylose or starch, fatty acid esters, hydroxymethycellulose, polyvinyl pyrrolidine, colors, lubricants, preservatives, stabilizers, scavengers (e.g. metal chelators such as diethylenetriaminepentaacetic acid (DTP A), ethylenediaminetetraacetic acid [EDTA]), wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, coloring, and / or aromatic substances and the like (collectively referred to herein as “excipients”) that do not deleteriously react with the active component(s) of the composition. One of skill in the art will recognise that other pharmaceutically acceptable excipients are useful in the present invention.

[0059] The term “pharmaceutically acceptable salt” refers to salts derived from a variety of organic and inorganic counter ions well known in the art and include, by way of example only, sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium, and the like; and when the molecule contains a basic functionality, salts of organic or inorganic acids, such as hydrochloride, hydrobromide, tartrate, mesylate, acetate, maleate, oxalate and the like.

[0060] The term “solvate” refers to a complex formed by combining brivaracetam with a solvent or a crystalline solid containing an amount of solvent incorporated into the crystal structure. Examples of solvates include, but are not limited to, complexes of the compounds of the present invention with ethanol, methanol or water. The term “hydrate” refers to a specific form of solvate where the solvent is water.

[0061] The term “isoelectric point” (pl) refers to the pH at which a molecule does not carry a net electrical charge or is electrically neutral in the statistical mean.

[0062] The term “polymer” refers to a macromolecule composed of one or more structural repeat units. The term "polymer gel" refers to a gel whose network component is a polymer. Generally, although not necessarily, a polymer gel is a wet (aqueous or non-aqueous) three-dimensional structure consisting of a polymer formed from a natural or synthetic precursor or polymer precursor.

[0063] . The term "gel" refers to a non-fluid colloidal network or polymer network that is expanded throughout its whole volume by a fluid. The fluid trapped inside the gel may comprise e.g. brivaracetam or a pharmaceutically acceptable salt, hydrate or solvate thereof. The network structure may result from physical bonds (physical gels) or chemical bonds (chemical gels), as well as crystallites or other junctions that remain intact within the extending fluid. The network structure may also comprise components of the composition according to any aspect, embodiment, or example described herein.

[0064] The term "hydrogel" refers to a crosslinked porous polymeric network that can absorb liquid, such as water, and can contain at least 10% by weight of water within its porous polymer matrix when fully hydrated.

[0065] The term “acid” refers to any substance that is capable of lowering the pH of a solution. Acids include Arrhenius, Bronsted and Lewis acids. A “solid acid” refers to a dried or granular compound that yields an acidic solution when dissolved in a solvent. The term “acidic” means having the properties of an acid.

[0066] The term “base” refers to any substance that is capable of raising the pH of a solution. Bases include Arrhenius, Bronsted and Lewis bases. A “solid base” refers to a dried or granular compound that yields basic solution when dissolved in a solvent. The term “basic” means having the properties of a base.

[0067] The term “amphiphilic” refers to a property where a molecule has both a polar portion and a non-polar portion. The polar portion may have either a formal positive charge, or a formal negative charge. Alternatively, the polar portion may have both a formal positive and a negative charge, and be a zwitterion or inner salt. For purposes of the invention, the amphiphilic compound can be, but is not limited to, one or a plurality of the following: naturally derived lipids, surfactants, or synthesized compounds with both hydrophilic and hydrophobic moieties. In one particular example, cyclodextrins as described herein are considered to be amphiphilic.

[0068] It will be appreciated by persons skilled in the art that numerous variations and / or modifications may be made to the below-described embodiments, without departing from the broad general scope of the present disclosure. The described embodiments are, therefore, to be considered in all respects as illustrative and not restrictive.

[0069] Compositions

[0070] The present disclosure provides for a transdermal drug delivery composition, comprising brivaracetam or a pharmaceutically acceptable salt, hydrate or solvate thereof and optionally one or more carriers and / or excipients. The present disclosure provides for a transdermal drug delivery composition, comprising brivaracetam or a pharmaceutically acceptable salt, hydrate or solvate thereof and one or more carriers and / or excipients. In some embodiments, the transdermal drug delivery composition comprises a porous carrier, wherein the brivaracetam or a pharmaceutically acceptable salt, hydrate or solvate thereof, and optionally one or more excipients are interspersed on or within the porous carrier. In some embodiments, the transdermal drug delivery composition comprises a solubility enhancer. In some embodiments, the transdermal drug delivery composition comprises: a polymer; and brivaracetam or a pharmaceutically acceptable salt, hydrate or solvate thereof, a solubility enhancer, and optionally one or more excipients, interspersed on or within the polymer. In some embodiments, the transdermal drug delivery composition comprises: a polymer gel; and brivaracetam or a pharmaceutically acceptable salt, hydrate or solvate thereof, a solubility enhancer, and optionally one or more excipients, interspersed on or within the polymer gel.

[0071] Transdermal compositions

[0072] The compositions for transdermal drug delivery include an effective amount of brivaracetam or its pharmaceutically acceptable salts, hydrates or solvates, along with carriers and / or excipients. The compositions can be in the form of patches containing the brivaracetam, or a pharmaceutically acceptable salt, hydrate or solvate thereof. The compositions can optionally include components such as carriers and / or excipients, including not but limited to porous carriers including polymers (such as polymer gels such as hydrogels, polymeric adhesives), solvents, solubility enhancers, buffers, permeation enhancers, adhesive, chelating agents, stabilizers, preservatives, humectants, surfactants, ionic species (including ions) or an alcohols, and means for providing instantaneous and / or sustained release of the active ingredients. The compositions may or may not include a membrane to modulate the release of the active ingredient from a device to the skin. In one embodiment, the composition is configured for transdermal delivery of brivaracetam, or a pharmaceutically acceptable salt, hydrate or solvate thereof.

[0073] Porous carriers

[0074] In some embodiments, the transdermal drug delivery composition comprises a porous carrier. As used herein, “porous carrier” refers to any carrier characterised by interconnected pores or void spaces that may encapsulate, adsorb, absorb or load brivaracetam. The brivaracetam or a pharmaceutically acceptable salt, hydrate or solvate thereof may be interspersed on or within the porous carrier. Additionally, in some cases, a solubility enhancer, and optionally one or more excipients may also be interspersed on or within the porous carrier (including as complexes with brivaracetam). Porous carriers may be described, at least in part, by their porosity, which refers to the fraction or percentage of its total volume that consists of void spaces (pores). Porosity may be measured according to any method known in the art, including nitrogen adsorptiondesorption (BET analysis).

[0075] Porous carriers suitable for transdermal drug delivery will be known to persons skilled in the art, and for example include, but are not limited to, polymers such as hydrogels. Thus, in one example, the porous carrier is a polymer. However, other non- polymeric porous carriers are also envisaged such that in an alternative embodiment or example, the porous carrier is not a polymer. In another alternative embodiment, the carrier is a non-polymeric carrier.

[0076] In some embodiments, the porous carrier is in the form of a gel, colloid, suspension, solution, liquid, dispersion, emulsion, ointment, paste, form, or a solid.

[0077] In some embodiments, the composition comprises (in % w / w) about 0.1, 0.3, 0.5, 0.7, 0.9, 1.1, 1.3, 1.5, 1.7, 1.9, 2.1, 2.3, 2.5, 2.7, 2.9, 3.1, 3.3, 3.5, 3.7, 3.9, 4.1, 4.3, 4.5,

[0078] 4.7, 4.9, 5.1, 5.3, 5.5, 5.7, 5.9, 6.1, 6.3, 6.5, 6.7, 6.9, 7.1, 7.3, 7.5, 7.7, 7.9, 8.1, 8.3, 8.5,

[0079] 8.7, 8.9, 9.1, 9.3, 9.5, 9.7, 9.9 or 10 of the porous carrier based on the total weight of the composition. In some embodiments, the composition comprises (in % w / w) greater than about 0.1, 0.3, 0.5, 0.7, 0.9, 1.1, 1.3, 1.5, 1.7, 1.9, 2.1, 2.3, 2.5, 2.7, 2.9, 3.1, 3.3, 3.5, 3.7,

[0080] 3.9, 4.1, 4.3, 4.5, 4.7, 4.9, 5.1, 5.3, 5.5, 5.7, 5.9, 6.1, 6.3, 6.5, 6.7, 6.9, 7.1, 7.3, 7.5, 7.7,

[0081] 7.9, 8.1, 8.3, 8.5, 8.7, 8.9, 9.1, 9.3, 9.5, 9.7, 9.9 or 10 of the porous carrier based on the total weight of the composition. In some embodiments, the composition comprises (in % w / w) less than about 10.0, 9.8, 9.6, 9.4, 9.2, 9.0, 8.8, 8.6, 8.4, 8.2, 8.0, 7.8, 7.6, 7.4, 7.2,

[0082] 7.0, 6.8, 6.6, 6.4, 6.2, 6.0, 5.8, 5.6, 5.4, 5.2, 5.0, 4.8, 4.6, 4.4, 4.2, 4.0, 3.8, 3.6, 3.4, 3.2,

[0083] 3.0, 2.8, 2.6, 2.4, 2.2, 2.0, 1.8, 1.6, 1.4, 1.2, 1.0, 0.8, 0.6, 0.4, 0.2 or 0.1 of the porous carrier based on the total weight of the composition. In some embodiments, the composition comprises (in % w / w) an amount of porous carrier in a range provided by any two of the previously described upper and / or lower amounts, for example, in some embodiments the composition comprises (in % w / w) between about 0.1 and about 10, or between about 0.1 and about 5, or between about 0.1 and 2, of the porous carrier based on the total weight of the composition. It will be understood that in this context “% w / w” refers to the weight of the porous carrier as a percentage of the total weight of the composition.

[0084] It will be understood that the porous carrier, particularly when in certain forms e.g. a gel, may be in part described by its viscosity, which may be measured in pascal- seconds (Pa s). In some embodiments, the porous carrier has a viscosity of between 0.1 Pa s to about 100 Pa s at a shear rate of 100 1 / s when measured using an MCR 702 twin drive rheometer (Anton Paar). In some embodiments, the porous carrier has a viscosity of between 1 Pa s to about 10 Pa s at a shear rate of 100 1 / s when measured using an MCR 702 twin drive rheometer (Anton Paar). Polymer and polymer gels

[0085] In some embodiments, the transdermal drug delivery composition comprises a polymer. The brivaracetam or a pharmaceutically acceptable salt, hydrate or solvate thereof may be interspersed on or within the polymer. Additionally, in some cases, a solubility enhancer, and optionally one or more excipients may also be interspersed on or within the polymer.

[0086] In some embodiments, the transdermal drug delivery composition comprises: a polymer gel; and brivaracetam or a pharmaceutically acceptable salt, hydrate or solvate thereof, a solubility enhancer, and optionally one or more excipients, interspersed on or within the polymer gel.

[0087] It will be understood that there is no particular limitation as to the polymers that may be suitable for the present invention.

[0088] In some embodiments, the polymer comprises a natural polymer. In some embodiments, the polymer comprises a synthetic polymer. In some embodiments, the polymer is a naturally occurring polymer or a synthetic polymer. Suitable natural occurring polymers include, for example, polysaccharides such as alginate, carboxymethylcellulose, carrageenan, cellulose, gellan gum, chitosan, and chitin. The polymer may also comprise an adhesive polymer. In example devices and systems described herein, by using an adhesive polymer comprising the brivaracetam and other excipients, all but a small portion of the device or system area can be devoted to brivaracetam delivery, given that the site of adhesion to a subject’s skin can also function as a site of drug delivery. This is an advantage over other devices that face a trade-off between how much of the device area is devoted to substance delivery versus the area used to adhere the device to the skin.

[0089] In some embodiments, the polymer is a hydrophilic polymer. In some embodiments, the hydrophilic polymer is a non-ionic hydrophilic polymer. In some embodiments, the hydrophilic polymer is at least partially ionised, for example, such that a least a portion of the polymer has been protonated, deprotonated or metalated, such as lithiated or sodiated. It will be understood that in such cases, the ionisation state of the polymer is that at the pH of the composition. In some embodiments, at least a portion of the polymer, for example poly(acrylic acid), is deprotonated. In some embodiments, the the hydrophilic polymer is non-ionic. In some embodiments, the hydrophilic polymer is a naturally occurring polymer or a synthetic polymer.

[0090] In some embodiments, the hydrophilic polymer comprises a polymer selected from the group consisting of poly(acrylic acids), poly(methacrylic acids), poly(acrylamides), poly(amidoamines), poly(dimethylaminoethyl methacrylate), poly(dimethylaminoethyl methacrylate), polyethylene glycols), poly(amidoamines), poly (dimethyl siloxanes), poly(hydroxyethyl methacrylates), poly(N-isopropyl acrylamides), poly(vinyl alcohols), and polyvinylpyrrolidones) or a copolymer or combination thereof. In some embodiments, the hydrophilic polymer comprises poly(acrylic acid) or a copolymer thereof. Carbomer may be an example of a suitable poly(acrylic acid).

[0091] In some embodiments, the hydrophilic polymer is a carbomer. Examples of suitable commercially available carbomers include, but are not limited to those marketed under the names Carbopol®, Noveon®, Pemulen®, Polygel®, Synthalen®, Acritamer® or Tego Carbomer®. For example, the Carbopol® polymer series includes Carbopol® Aqua SF-1 (acrylate copolymer, lightly cross-linked acrylate copolymer), Carbopol® Aqua SF-2 (acrylate crosspolymer-4), Carbopol® Aqua CC (poly acrylate- 1 crosspolymer), Carbopol® 934 (carbomer, acrylate homopolymer cross-linked with allyl ether of sucrose), Carbopol® 934P NF, Carbopol® 940 (carbomer), Carbopol®) 941 (carbomer), Carbopol® 97 IP (carbomer, lightly crosslinked with allylpentaerythritol), Carbopol® 71 (Carbopol® 971P free flowing granule form for use in direct compression formulations), Carbopol® 974P (carbomer, highly cross-linked), Carbopol® 980 (carbomer), Carbopol® 980 (carbomer), Carbopol® 981 (carbomer, allyl pentaerythritol cross-linked), Carbopol® 1342 (acrylate / C10-30 alkyl acrylate cross polymer, allyl pentaerythritol cross-linked) Copolymer of acrylic acid and C10-C30 alkyl acrylate) Carbopol® 1382 (acrylate / Cl 0-30 alkyl acrylate crosspolymer, allylpentaery Copolymers of acrylic acid and C10-C30 alkyl acrylate cross-linked with lithol), Carbopol® 2984 (carbomer), Carbopol® 5984 (carbomer), Carbopol® Ultrez 10 (carbomer), Carbopol® Ultrez 20 (acrylate / Cl 0-30 alkyl acrylate crosspolymer), Carbopol® Ultrez 21 (acrylate I Cl 0-30 alkyl acrylate crosspolymer), Carbopol® Ultrez 30 (carbomer), Carbopol (registered trademark) Trademarks) ETD 2001, Carbopol® ETD 2020 (acrylate / Cl 0-30 alkyl acrylate), Ross polymers, interpolymers containing block copolymers of polyethylene glycol and long chain alkyl acid esters), homopolymers, copolymers, interpolymers, exemplified by Carbopol® ETD 2050 (carbomer).

[0092] In some embodiments, the hydrophilic polymer is selected from Carbopol® 934P NF, Carbopol® Ultrez 30, or a combination thereof.

[0093] In some embodiments, the polymer is in the form of a gel, colloid, suspension, solution, liquid, dispersion, emulsion, ointment, paste, form, or a solid. It will be understood that the polymer may be a polymeric adhesive (e.g. where the composition is configured for use in a “drug-in-adhesive” patch). In some embodiments, the polymer is in the form of a gel. That is to say, in some embodiments, the polymer is a polymer gel.

[0094] In some embodiments, the polymer gel is a hydrogel, that is a matrix comprising a suitable polymer. Hydrogels can be classified as a three-dimensional cross-linked porous network of polymers, typically of cross-linked hydrophilic polymers, capable of retaining liquid therein. The porous network of the hydrogel typically comprises of open and / or closed pores. Open pores are physically interconnected and can induce capillary action, while closed pores are controlled by the diffusion of liquid. In some embodiments, the hydrogel comprises a physically crosslinked hydrophilic polymer. In some embodiments, the hydrogel comprises a chemically crosslinked hydrophilic polymer. As used herein, the term “cross-link, “cross-linked” or “cross-linking” refers to the formation of interactions within or between a hydrophilic polymer which result in the formation of a three-dimensional matrix, i.e. a hydrogel. The term “physically cross-linked” refers to a type of cross-linking that is reversible in nature (i.e. not permanent). Examples of physical cross-linking includes molecular entanglement of the hydrophilic polymer, ionic interactions, hydrogen bonding and hydrophobic interaction. The term “chemically cross-linked” refers to a type of crosslinking that is non-reversible in nature (i.e. permanent).

[0095] In some embodiments, the composition comprises (in % w / w) about 0.1, 0.3, 0.5, 0.7, 0.9, 1.1, 1.3, 1.5, 1.7, 1.9, 2.1, 2.3, 2.5, 2.7, 2.9, 3.1, 3.3, 3.5, 3.7, 3.9, 4.1, 4.3, 4.5,

[0096] 4.7, 4.9, 5.1, 5.3, 5.5, 5.7, 5.9, 6.1, 6.3, 6.5, 6.7, 6.9, 7.1, 7.3, 7.5, 7.7, 7.9, 8.1, 8.3, 8.5,

[0097] 8.7, 8.9, 9.1, 9.3, 9.5, 9.7, 9.9 or 10 of the polymer based on the total weight of the composition. In some embodiments, the composition comprises (in % w / w) greater than about 0.1, 0.3, 0.5, 0.7, 0.9, 1.1, 1.3, 1.5, 1.7, 1.9, 2.1, 2.3, 2.5, 2.7, 2.9, 3.1, 3.3, 3.5, 3.7,

[0098] 3.9, 4.1, 4.3, 4.5, 4.7, 4.9, 5.1, 5.3, 5.5, 5.7, 5.9, 6.1, 6.3, 6.5, 6.7, 6.9, 7.1, 7.3, 7.5, 7.7,

[0099] 7.9, 8.1, 8.3, 8.5, 8.7, 8.9, 9.1, 9.3, 9.5, 9.7, 9.9 or 10 of the polymer based on the total weight of the composition. In some embodiments, the composition comprises (in % w / w) less than about 10.0, 9.8, 9.6, 9.4, 9.2, 9.0, 8.8, 8.6, 8.4, 8.2, 8.0, 7.8, 7.6, 7.4, 7.2, 7.0,

[0100] 6.8, 6.6, 6.4, 6.2, 6.0, 5.8, 5.6, 5.4, 5.2, 5.0, 4.8, 4.6, 4.4, 4.2, 4.0, 3.8, 3.6, 3.4, 3.2, 3.0,

[0101] 2.8, 2.6, 2.4, 2.2, 2.0, 1.8, 1.6, 1.4, 1.2, 1.0, 0.8, 0.6, 0.4, 0.2 or 0.1 of the polymer based on the total weight of the composition. In some embodiments, the composition comprises (in % w / w) an amount of polymer in a range provided by any two of the previously described upper and / or lower amounts, for example, in some embodiments the composition comprises (in % w / w) between about 0.1 and about 10, or between about 0.1 and about 5, or between about 0.1 and 2, of the polymer based on the total weight of the composition. It will be understood that in this context “% w / w” refers to the weight of the polymer as a percentage of the total weight of the composition.

[0102] In some embodiments where the polymer is a polymer gel, the polymer gel comprises an aqueous solution, such as water. In consequence, it will be understood that in some embodiments, the composition may comprise an aqueous solution, such as water. In some embodiments, the polymer gel or composition comprises an aqueous solution in an amount (in % w / w) greater than about 50, 60, 70, 80, 90, 95, 98, 98.5, 99 or 99.5. In some embodiments, the polymer gel or composition comprises an aqueous solution in an amount (in % w / w) between about 90 and 99.5, or between about 95 and about 99.5, between about 98 and about 99.5, or between about 98.5 and about 99.5. The aqueous solution may be water. The aqueous solution may further comprise one or more excipients, such as buffers, and other excipients described herein. It will be understood that the polymer, particularly when in certain forms e.g. a gel, may be in part described by its viscosity, which may be measured in pascal-seconds (Pa s). In some embodiments, the polymer has a viscosity of between 0.1 Pa s to about 100 Pa s at a shear rate of 100 1 / s when measured using an MCR 702 twin drive rheometer (Anton Paar). In some embodiments, the polymer has a viscosity of between 1 Pa s to about 10 Pa s at a shear rate of 100 1 / s when measured using an MCR 702 twin drive rheometer (Anton Paar).

[0103] Brivaracetam

[0104] The composition comprises brivaracetam, or a pharmaceutically acceptable salt, hydrate, or solvate thereof. In some embodiments, the composition comprises brivaracetam, or a pharmaceutically acceptable salt or hydrate thereof. In some embodiments, the composition comprises brivaracetam or a pharmaceutically acceptable salt thereof.

[0105] As used herein, “brivaracetam” refers to the compound with structure depicted in Formula 1, which may also be referred to as (2S)-2-[(4R)-2-oxo-4-propylpyrrolidin-l- yl]butanamide, and having CAS Number: 357336-20-0. A reference to brivaracetam shall be understood to also include a reference to any and all tautomers and / or conformational isomers thereof.

[0106] Formula 1

[0107] In some embodiments, the concentration of brivaracetam (in mg / mL) is about 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 185, 190, 195 or 200. In some embodiments, the concentration of brivaracetam (in mg / mL) is greater than about 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 185, 190, 195 or 200. In some embodiments, the concentration of brivaracetam (in mg / mL) is less than about 200, 195, 190, 185, 180, 175, 170, 165, 160, 155, 150, 145, 140, 135, 130, 125, 120, 115, 110, 105, 100, 95, 90, 85, 80, 75, 70, 65, 60, 55, 50, 45, 40, 35, 30, 25, 20, 15, 10, 5 or 1. In some embodiments, the concentration of brivaracetam (in mg / mL) is in a range provided by any two of the previously described upper and / or lower amounts, for example, in some embodiments the concentration of brivaracetam (in mg / mL) is between about 1 and about 200, between about 5 and about 100, between about 10 and about 50, or between about 30 and about 40. It will be understood that in this context “mg / mL” refers to the mass of brivaracetam (in mg) based on the total volume of the composition (in mL).

[0108] The concentration of brivaracetam may be alternatively described on a weight percentage basis. Thus, in some embodiments, the concentration of brivaracetam (in % w / w) is about 0.1, 0.2, 0.3, 0.4 0.5, 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 5.5, 6.0, 6.5, 7.0, 7.5, 8.0, 8.5, 9.0, 9.5, 10.0, 10.5, 11.0, 11.5, 12.0, 12.5, 13.0, 13.5, 14.0, 14.5, 15.0,

[0109] 15.5, 16.0, 16.5, 17.0, 17.5, 18.0, 18.5, 19.0, 19.5, 20.0, 20.5, 21.0, 21.5, 22.0, 22.5, 23.0,

[0110] 23.5, 24.0, 24.5, 25.0, 25.5, 26.0, 26.5, 27.0, 27.5, 28.0, 28.5, 29.0, 29.5 or 30.0. In some embodiments, the concentration of brivaracetam (in % w / w) is greater than about 0.1, 0.2, 0.3, 0.4 0.5, 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 5.5, 6.0, 6.5, 7.0, 7.5, 8.0, 8.5, 9.0, 9.5, 10.0, 10.5, 11.0, 11.5, 12.0, 12.5, 13.0, 13.5, 14.0, 14.5, 15.0, 15.5, 16.0, 16.5, 17.0, 17.5, 18.0, 18.5, 19.0, 19.5, 20.0, 20.5, 21.0, 21.5, 22.0, 22.5, 23.0, 23.5, 24.0, 24.5, 25.0, 25.5, 26.0, 26.5, 27.0, 27.5, 28.0, 28.5, 29.0, 29.5 or 30.0. In some embodiments, the concentration of brivaracetam (in % w / w) is less than about 30.0, 29.5, 29.0, 28.5, 28.0, 27.5, 27.0, 26.5, 26.0, 25.5, 25.0, 24.5, 24.0, 23.5, 23.0, 22.5, 22.0, 21.5, 21.0, 20.5, 20.0, 19.5, 19.0, 18.5, 18.0, 17.5, 17.0, 16.5, 16.0, 15.5, 15.0, 14.5, 14.0, 13.5, 13.0, 12.5, 12.0, 11.5, 11.0, 10.5, 10.0, 9.5, 9.0, 8.5, 8.0, 7.5, 7.0, 6.5, 6.0, 5.5, 5.0, 4.5, 4.0, 3.5, 3.0,

[0111] 2.5, 2.0, 1.5, 1.0, 0.5, 0.4, 0.3, 0.2 or 0.1. In some embodiments, the concentration of brivaracetam (in % w / w) is in a range provided by any two of the previously described upper and / or lower amounts, for example, in some embodiments the concentration of brivaracetam (in % w / w) is between about 0.1 and about 30, between about 0.1 and about 20, or between about 0.5 and about 15. It will be understood that in this context “% w / w” refers to the weight of brivaracetam as a percentage of the total weight of the composition.

[0112] It will be appreciated by persons skilled in the art that the solubility of the brivaracetam in the composition may depend on the components of the composition and concentrations thereof. In some embodiments, the solubility of brivaracetam (in mg / mL) in the composition is at least about 10, 20, 30, 40 or 50. In some embodiments, the solubility of brivaracetam (in mg / mL) in the composition is at least about 50.

[0113] The person skilled in the art will appreciate that analogues of brivaracetam may also be suitable for the transdermal drug delivery compositions. Such analogues will be apparent to persons skilled in the art, examples of which include but are not limited to, racetams such as levetiracetam, piracetam, oxiracetam, phenylpiracetam, and seletracetam. As such, the present disclosure also provides for a transdermal drug delivery composition, comprising brivaracetam or a pharmaceutically acceptable salt, analogue, hydrate or solvate thereof and one or more carriers and / or excipients.

[0114] The present disclosure also provides for a transdermal drug delivery composition, comprising brivaracetam or a stereoisomer thereof, or a pharmaceutically acceptable salt, hydrate or solvate thereof and one or more carriers and / or excipients. Solubility Enhancer

[0115] Of the excipients contemplated by the present disclosure, according to some embodiments or examples described herein, the present inventors have surprisingly identified that a solubility enhancer, such as cyclodextrin, can enhance the transdermal delivery of brivaracetam from the compositions described herein.

[0116] The person skilled in the art will appreciate that there is no particular limitation as to suitable solubility enhancers. The solubility enhancer may be any molecule capable of increasing the solubility of the brivaracetam within the composition. This can be achieved either by modulating the possible interactions between the brivaracetam (or a portion thereof) and the other components present in the composition, by additionally incorporating suitable excipients.

[0117] In some embodiments, at least a some of the solubility enhancer is attached to, or associated with, brivaracetam, forming a complex.

[0118] Without intending to be limited by theory and according to some embodiments or examples described herein, it is believed that during use, the flow of the solubility enhancer or ions from the polymer (e.g. at the delivery electrode) across the skin by iontophoresis, either transports, carries or entrains a portion of the brivaracetam, so as to deliver the brivaracetam to the subject. It will be understood that in some embodiments, a portion of the total brivaracetam is attached to, or associated with the solubility enhancer. The solubility enhancer can therefore also act as a transporter.

[0119] In some embodiments, the solubility enhancer is selected from a surfactant or an amphiphilic molecule. In some embodiments, the solubility enhancer is selected from a surfactant, an amphiphilic molecule, or a combination thereof. In some embodiments, the solubility enhancer is an amphiphilic molecule.

[0120] In some embodiments, the solubility enhancer is neutral or an ionic solubility enhancer. Thus, in some embodiments, the solubility enhancer is neutral or comprises one or more ionic groups. In some embodiments, the solubility enhancer is an ionic solubility enhancer. That is to say, the solubility enhancer is formally charged, e.g. at the pH of the composition.

[0121] In some embodiments, the solubility enhancer is a micelle, such as an anionic micelle or a cationic micelle. Micelles, and components from which they may be formed (such as polymers, surfactants, and lipids including phospholipids), are well known to persons skilled in the art, as well as their use in solubilising active agents.

[0122] In some embodiments, the solubility enhancer is a cyclodextrin. In some embodiments, the solubility enhancer is a cyclodextrin, at least a portion of which forms an inclusion complex with brivaracetam. The term “inclusion complex” refers to a complex wherein one chemical compound, the host, forms a cavity within which at least a portion of the molecules of a second compound, the guest, either passes through or is located. In other words, the host compound surrounds at least a portion of the guest compound via the cavity in the host compound. In embodiments, a single host compound may be combined with a single guest compound to form an inclusion complex. In embodiments, a plurality of host compounds may share a common guest compound to form a series of inclusion complexes. In other embodiments, a single host compound may share a plurality of guest compounds to form an inclusion complex. In still other embodiments, a plurality of host compounds may be combined with a plurality of guest compounds to form a plurality of inclusion complexes.

[0123] Cyclodextrin is a cyclic oligosaccharide comprising a macrocyclic ring formed from anywhere from 6-32 glucose residue subunits connected by a- 1,4 glycosidic bonds. In some embodiments, the cyclodextrin comprises 6 to 32 glucose residue subunits. In some embodiments, the cyclodextrin comprises 6 to 28 glucose residue subunits. In some embodiments, the cyclodextrin comprises 6 to 24 glucose residue subunits. In some embodiments, the cyclodextrin comprises 6 to 20 glucose residue subunits. In some embodiments, the cyclodextrin comprises 6 to 16 glucose residue subunits. In some embodiments, the cyclodextrin comprises 6 to 12 glucose residue subunits. In some embodiments, the cyclodextrin comprises 6 to 10 glucose residue subunits. In some embodiments, the cyclodextrin comprises 6 to 8 glucose residue subunits.

[0124] The cyclodextrin has a ring or donut form and unique amphipathic character, i.e., the inner cavity exhibits predominantly hydrophobic properties while the outer functional groups contributing to a hydrophilic property. Without intending to be limited by theory, it is believed that drugs such as brivaracetam are capable of being “enclosed” within the cyclodextrin cavity inside, forming enclosure compound with excellent physical character. The stability of the enclosure compound is mainly dependent on the stereocompatibility between the cyclodextrin and the brivaracetam, and various forces which act independently or cooperatively as a bonding force in the enclosure compound.

[0125] In some embodiments, the cyclodextrin is a water soluble cyclodextrin. In some embodiments, the cyclodextrin is a natural cyclodextrin. In some embodiments, the cyclodextrin is a synthetic cyclodextrin.

[0126] In some embodiments, the cyclodextrin is an ionic cyclodextrin. In some embodiments, the cyclodextrin is a positive ionic cyclodextrin (that is to say, that at the pH of the composition, a substantial portion of the cyclodextrin has a formal net positive charge). In some embodiments, the cyclodextrin is a negative ionic cyclodextrin (that is to say, that at the pH of the composition, a substantial portion of the cyclodextrin has a formal net negative charge). According to some embodiments or examples described herein, some of the ionic cyclodextrin can associate or complex with brivaracetam, the flow of the solubility enhancer or ions from the polymer (e.g. at the delivery electrode via repulsion) across the skin by iontophoresis, either transports, carries or entrains a portion of the brivaracetam, so as to deliver the brivaracetam to the subject.

[0127] It will be understood that an ionic cyclodextrin may have one or more positive ionic groups, and / or one or more negative ionic groups. In some embodiments, the cyclodextrin comprises one or more positive ionic groups. In some embodiments, the cyclodextrin comprises one or more negative ionic groups.

[0128] Hydrophobic, hydrophilic, polymerized, ionized, non-ionized and many other modified cyclodextrins have been developed, and their use in various industries has been established. Cyclodextrins comprising one or more positive ionic groups and / or one or more negative ionic groups may be obtained by various methods that will be known to persons skilled in the art, for example and without intending to limit the scope of the invention, positive ionic groups and negative ionic groups may be introduced to a cyclodextrin core by chemical modification at one or more of the hydroxyl groups. It will be understood that the positive or negative ionic group may be tethered to the cyclodextrin core via a linking group, suitable examples of which include but are not limited to, alkyl (such as C1-C20), or alkylether (such as butylether). It will be understood, the positive ionic groups or negative ionic groups may be, in at least a portion thereof, associated with a counterion, examples of which may include but are not limited to, e.g. lithium, sodium, bromide, chloride.

[0129] In some embodiments, the one or more positive ionic groups are selected from the group consisting of quadrivalent ammonium, imine, amide.

[0130] In some embodiments, the one or more negative ionic groups are selected from the group consisting of sulfate, carboxylate, phosphate, nitrate.

[0131] In some embodiments, the cyclodextrin is selected from the group consisting of an a-cyclodextrin, a P-cyclodextrin, a y-cyclodextrin, and derivatives or combinations thereof.

[0132] In some embodiments, the cyclodextrin is selected from the group consisting of sulfoalkylether-P-cyclodextrin (SAE-P-CD), including sulfobutylether-P-cyclodextrin (SBE-P-CD), hydroxyalkyl-P-cyclodextrins, including hydroxypropyl-P-cyclodextrin (e.g. HP-P-CD), hydroxyalkyl-y-cyclodextrins, methylated-P-cyclodextrin, y- cyclodextrin sulfobutyl ether, branched P-cyclodextrin and branched y-cyclodextrins.

[0133] In some embodiments, the cyclodextrin is an SBA-P-CD, such as sulfobutylether- P-cyclodextrin (SBE-P-CD).

[0134] In some embodiments, the cyclodextrin is SBE-P-CD.

[0135] Accordingly, in some embodiments, the composition comprises a carbomer hydrogel; and brivaracetam or a pharmaceutically acceptable salt, hydrate or solvate thereof and SBE-P-CD interspersed on or within the hydrogel.

[0136] In some embodiments, the composition comprises two or more solubility enhancers. In some embodiments, the composition comprises two or more cyclodextrins.

[0137] In some embodiments, the concentration of the solubility enhancer (in % w / w) is about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39 or 40. In some embodiments, the concentration of the solubility enhancer (in in % w / w) is greater than about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39 or 40. In some embodiments, the concentration of the solubility enhancer (in in % w / w)is less than about 40, 39, 38, 37, 36, 35, 34, 33, 32, 31, 30, 29, 28, 27, 26, 25, 24, 23, 22, 21, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2 or 1. In some embodiments, the concentration of the solubility enhancer (in in % w / w) is in a range provided by any two of the previously described upper and / or lower amounts, for example, in some embodiments the concentration of the solubility enhancer (in % w / w) is between about 1 and about 40, between about 1 and about 30, or between about 1 and about 10. It will be understood that in this context “% w / w” refers to the weight of the solubility enhancer as a percentage of the total weight of the composition.

[0138] In some embodiments, the concentrations of the solubility enhancer and brivaracetam are in a ratio of about 80:1, 70:1, 60:1, 50:1, 40:1, 30:1, 20:1, 10:1: 5:1, 1:1, 1:5, 1:10, 1:20, 1:30, 1:40, 1:50, 1:60, 1:70 or 1:80. In some embodiments, the concentrations of the solubility enhancer and brivaracetam are in a ratio less than about 80:1, 70:1, 60:1, 50:1, 40:1, 30:1, 20:1, 10:1: 5:1, 1:1, 1:5, 1:10, 1:20, 1:30, 1:40, 1:50, 1:60, 1:70 or 1:80. In some embodiments, the concentrations of the solubility enhancer and brivaracetam are in a ratio greater than about 80:1, 70:1, 60:1, 50:1, 40:1, 30:1, 20:1, 10:1: 5:1, 1:1, 1:5, 1:10, 1:20, 1:30, 1:40, 1:50, 1:60, 1:70 or 1:80. In some embodiments, the concentrations of the solubility enhancer and brivaracetam are in a ratio between about 80:1 and about 1:80, between about 60:1 and about 1:60, between about 40:1 and about 1:40, between about 20:1 and about 1:20, between about 10:1 and about 1:10, between about 5:1 and about 1:5, between about 2:1 and about 1:2, between about 1.5:1 and about 1 : 1.5, or about 1:1.

[0139] In some embodiments, the concentrations of the solubility enhancer and polymer are in a ratio of about 80:1, 70:1, 60:1, 50:1, 40:1, 30:1, 20:1, 10:1: 5:1, 1:1, 1:5, 1:10, 1:20, 1:30, 1:40, 1:50, 1:60, 1:70 or 1:80. In some embodiments, the concentrations of the solubility enhancer and polymer are in a ratio less than about 80:1, 70:1, 60:1, 50:1, 40:1, 30:1, 20:1, 10:1: 5:1, 1:1, 1:5, 1:10, 1:20, 1:30, 1:40, 1:50, 1:60, 1:70 or 1:80. In some embodiments, the concentrations of the solubility enhancer and polymer are in a ratio greater than about 80:1, 70:1, 60:1, 50:1, 40:1, 30:1, 20:1, 10:1: 5:1, 1:1, 1:5, 1:10, 1:20, 1:30, 1:40, 1:50, 1:60, 1:70 or 1:80. In some embodiments, the concentrations of the solubility enhancer and polymer are in a ratio between about 80:1 and about 1:80, between about 60:1 and about 1:60, between about 40:1 and about 1:40, between about 20:1 and about 1:20, between about 10:1 and about 1:10, between about 5:1 and about 1:5, between about 2:1 and about 1:2, between about 1.5:1 and about 1:1.5, or about 1:1.

[0140] In some embodiments, the concentrations of the solubility enhancer and porous carrier are in a ratio of about 80:1, 70:1, 60:1, 50:1, 40:1, 30:1, 20:1, 10:1: 5:1, 1:1, 1:5, 1:10, 1:20, 1:30, 1:40, 1:50, 1:60, 1:70 or 1:80. In some embodiments, the concentrations of the solubility enhancer and porous carrier are in a ratio less than about 80:1, 70:1, 60:1,50:1,40:1,30:1,20:1, 10:1:5:1, 1:1, 1:5, 1:10, 1:20, 1:30, 1:40, 1:50, 1:60, 1:70 or 1:80. In some embodiments, the concentrations of the solubility enhancer and porous carrier are in a ratio greater than about 80: 1, 70: 1, 60: 1, 50: 1, 40: 1, 30: 1, 20: 1, 10: 1 : 5:1, 1 : 1, 1 :5, 1 : 10, 1 :20, 1 :30, 1 :40, 1 :50, 1 :60, 1 :70 or 1 :80. In some embodiments, the concentrations of the solubility enhancer and porous carrier are in a ratio between about 80: 1 and about 1 :80, between about 60: 1 and about 1 :60, between about 40: 1 and about 1 :40, between about 20: 1 and about 1 :20, between about 10: 1 and about 1 : 10, between about 5: l and about 1 :5, between about 2:1 and about 1 :2, between about 1.5: 1 and about 1 : 1.5, or about 1 : 1. pH

[0141] It will be understood by the skilled person that the pH of the composition and / or the pH of the polymer or porous carrier affects the efficacy of the composition toward transdermal drug delivery. It will be further understood that a skilled person will be capable of determining a suitable pH of the composition and / or the polymer in order to maximise delivery of brivaracetam, according to the particulars of the composition and intended method and parameters of delivery. To this end, it will be understood that there may be a particular relationship between the pH of the composition and / or polymer or porous carrier, and the isoelectric point (pl) of brivaracetam.

[0142] Accordingly, in some embodiments, the porous carrier has a pH of between about

[0143] 1 and about 14, between about 2 and about 10, between about 3 and about 7, between about 2 and about 5, or between about 3 and about 5. In some embodiments, the porous carrier has a pH greater than about 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14. In some embodiments, the polymer has a pH less than about 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3,

[0144] 2 or 1.

[0145] Accordingly, in some embodiments, the polymer has a pH of between about 1 and about 14, between about 2 and about 10, between about 3 and about 7, between about 2 and about 5, or between about 3 and about 5. In some embodiments, the polymer has a pH greater than about 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14. In some embodiments, the polymer has a pH less than about 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2 or 1.

[0146] In some embodiments, the composition has a pH of between about 1 and about 14, between about 2 and about 10, between about 3 and about 7, between about 2 and about 5, or between about 3 and about 5. In some embodiments, the composition has a pH greater than about 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14. In some embodiments, the composition has a pH less than about 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2 or 1.

[0147] In some embodiments, the pH of the porous carrier or composition is at or near the pl of brivaracetam. In some embodiments, the pH of the polymer or composition is at or near the pl of brivaracetam.

[0148] In some embodiments, the pH of the porous carrier or composition is less than the pl of brivaracetam. In some embodiments, the pH of the porous carrier or composition is less than the pl of brivaracetam, wherein the pH is effective to ionize a non-insignificant amount of brivaracetam to an overall positive charge. In some embodiments, the pH of the polymer or composition is less than the pl of brivaracetam. In some embodiments, the pH of the polymer or composition is less than the pl of brivaracetam, wherein the pH is effective to ionize a non-insignificant amount of brivaracetam to an overall positive charge. For example, in some embodiments, the pH of the polymer of composition is less than the pl of brivaracetam, wherein the pH is effective to ionize about or at least about 0.5, 1, 2, 3, 4, 5, 10, 20, 30, 40 or 50% of brivaracetam in the composition to an overall positive charge.

[0149] In some embodiments, the pH of the porous carrier or composition is greater than the pl of brivaracetam. In some embodiments, the pH of the porous carrier or composition is greater than the pl of brivaracetam, wherein the pH is effective to ionize a non- insignificant amount of brivaracetam to an overall negative charge. In some embodiments, the pH of the polymer or composition is greater than the pl of brivaracetam. In some embodiments, the pH of the polymer or composition is greater than the pl of brivaracetam, wherein the pH is effective to ionize a non-insignificant amount of brivaracetam to an overall negative charge. For example, in some embodiments, the pH of the polymer of composition is greater than the pl of brivaracetam, wherein the pH is effective to ionize about or at least about 0.5, 1, 2, 3, 4, 5, 10, 20, 30, 40 or 50% of brivaracetam in the composition to an overall negative charge.

[0150] In some embodiments, the difference between the pH of the porous carrier or the composition and the pl of brivaracetam is about or greater than about 0, 0.2, 0.4, 0.6, 0.8, 1.0, 1.2, 1.4, 1.6, 1.8, 2.0, 2.5, 3.5, 4.0, 4.5, 5.0 or 6.0. In some embodiments, the difference between the pH of the porous carrier or the composition and the pl of brivaracetam is about or less than about 6.0 or 5.0, 4.5, 4.0, 3.5, 2.5, 2.0, 1.8, 1.6, 1.4, 1.2, 1.0, 0.8, 0.6, 0.4, 0.2, 0. In some embodiments, the difference between the pH of the polymer or the composition and the pl of brivaracetam is about or greater than about 0, 0.2, 0.4, 0.6, 0.8, 1.0, 1.2, 1.4, 1.6, 1.8, 2.0, 2.5, 3.5, 4.0, 4.5, 5.0 or 6.0. In some embodiments, the difference between the pH of the polymer or the composition and the pl of brivaracetam is about or less than about 6.0 or 5.0, 4.5, 4.0, 3.5, 2.5, 2.0, 1.8, 1.6, 1.4, 1.2, 1.0, 0.8, 0.6, 0.4, 0.2, 0.

[0151] Excipients

[0152] It will understood that various excipients may be present in the composition in order to improve aspects such as, but not limited to, physical properties (e.g. viscosity), thermal stability, and chemical stability.

[0153] In some embodiments, the composition further comprises one or more excipients selected from a buffer, a permeation enhancer, an adhesive, a chelating agent, a stabilizer, a preservative, a humectant, a surfactant, an ionic species (e.g. ions) or an alcohol.

[0154] In some embodiments, the composition comprises a buffer. The term "buffer" refers to solutions of compounds that are known to be safe for pharmaceutical or veterinary use in formulations and that have the effect of maintaining or controlling the pH of the formulation in the pH range desired for the composition. Acceptable buffers for controlling pH at a moderately acidic pH to a moderately basic pH include, but are not limited to, such compounds as phosphate, acetate, citrate, borate, arginine, TRIS, and histidine. "TRIS" refers to 2-amino-2- hydroxymethyl- 1,3, -propanediol, and to any pharmacologically acceptable salt thereof. Preferred buffers include phosphate or borate buffers with saline or an acceptable salt.

[0155] Suitable permeation enhancers include any compounds capable of increasing the permeability of the skin in respect of the brivaracetam in the composition. Due to this increase in skin permeability, the rate at which the active agent(s) permeate(s) through the skin and enter(s) the blood circulation is also increased. The enhanced permeation effected by the use of said skin permeation enhancers can be assayed and confirmed by measuring the rate of active agent diffusion through animal or human skin using a diffusion cell apparatus generally known in the art. Suitable examples of permeation enhancers include, but are not limited to, dimethylsulfoxide (DMSO), N,N- dimethylacetamide (DMA), decylmethylsulfoxide (CIO MSO), polyethylene glycol monolaurate (PEGML), propylene glycol (PG), propylene glycol monolaurate (PGML), glycerol monolaurate (GML), sodium laural sulfate, transcutol, cineole, lecithin, the I- substituted alkyl-azacycloalkyl-2-ones (for example, l-n-dodecylcylazacycloheptan-2- one), alcohols, and the like. The permeation enhancer may also be selected from vegetable oils, e. g. safflower oil, cotton seed oil, or corn oil. Combinations comprising two or more different permeation enhancers may also be used.

[0156] Chelating agents may be used to control metal ions, stabilize formulations, enhance solubility, prevent drug interactions, improve drug stability, and avoid precipitation, thereby contributing to the overall stability, efficacy, and safety of the drug product. The term "chelating agent" (or “chelator”) as used herein refers to a molecule that binds metal ions, usually by binding to two or more complexing groups within the molecule. Chelators are well known in the art, and include certain proteins and polypeptides, as well as small molecules including, but not limited to, ethylenediaminetetraacetic acid (EDTA), ethylene glycol-bis(P-aminoethyl ether)- N,N,N',N' -tetraacetic acid (EGTA), nitrilotriacetic acid, oxalate, citric acid, 1,2- diaminocyclohexane-N,N,N'N' -tetracetic acid, 4,5- dihydroxybenzene-l,3-disulfonic acid, pyrocatechol-3, 5 -di sulfonate, salicylic acid, 5-sulfosalicylic acid, xylenol orange, 2,2'-pyridyl ethylene diamine, glycine, 8-hydroxyquinoline-5-sulfonic acid, lactic acid, 1,10- phenanthroline, pyridine, pyridine-2,6-dicarboxylic acid, 8-quinolinol, succinic acid, tartaric acid, thiogly colic acid, l,l,l-trifluoro-3,2'-thenolyacetone, triethylenetetramine and the like.

[0157] Stabilizers may be used to enhance the stability of components of the composition, prevent degradation processes, and maintain the physical and chemical integrity of the composition, ensuring the overall effectiveness and safety of the drug product. The term "stabilizer" is intended to mean a compound used to stabilize brivaracetam against physical, chemical, or biochemical process that would otherwise reduce the therapeutic activity of the agent. Suitable stabilizers include, but are not limited to, albumin, sialic acid, creatinine, glycine and other amino acids, niacinamide, sodium acetyltryptophonate, zinc oxide, sucrose, glucose, lactose, sorbitol, mannitol, glycerol, polyethylene glycols, sodium caprylate and sodium saccharin and others known to those of ordinary skill in the art.

[0158] Humectants may be used to retain and regulate moisture levels, preventing dehydration and maintaining the physical stability of the formulation, thereby ensuring the efficacy and shelf life of the drug product. Suitable examples of humectants include, but are not limited to, glycerin, propylene glycol, sorbitol and urea, and the like.

[0159] Surfactants serve as excipients in pharmaceutical formulations to lower surface tension, facilitate emulsification and dispersion of hydrophobic substances, enhance solubility, and improve bioavailability, contributing to the overall stability and effectiveness of the drug product. Suitable examples of surfactants include, but are not limited to, L-a-phosphatidylcholine (PC), 1,2-dipalmitoylphosphatidylcholine (DPPC), oleic acid, sorbitan trioleate, sorbitan monooleate, sorbitan monolaurate, monolauric acid polyoxyethylene sorbitan, polyoxyethylene sorbitan monooleate, natural lecithin, oleyl polyoxyethylene ether, stearyl polyoxyethylene ether, lauryl polyoxyethylene ether, block copolymer of oxyethylene and oxypropylene, synthetic lecithin, diethylene glycol dioleate, tetrahydrofurfuryl oleate, ethyl oleate, isopropyl myristate, glyceryl monooleate, glyceryl monostearate, glyceryl monoricinoleate, cetyl alcohol, stearyl alcohol, polyethylene glycol 400, cetylpyridinium chloride, benzalkonium chloride, olive oil , glyceryl monolaurate, corn oil, cottonseed oil, and sunflower seed oil.

[0160] Alcohol may be used for various purposes, including enhancing solubility of brivaracetam, serving as a co-solvent, aiding in drug dissolution, and acting as a preservative or antimicrobial agent, contributing to the formulation's stability and efficacy. Suitable examples of alcohols include, but are not limited to, ethanol, isopropyl alcohol, propylene glycol, glycerin (glycerol), sorbitol, benzyl alcohol, polyethylene glycols (PEGs), butanol, and hexylene glycol.

[0161] Ionic species may be used to adjust tonicity, regulate pH, enhance solubility, provide buffering capacity, ensure compatibility with biological systems, and influence controlled drug release, contributing to the overall efficacy, stability, and safety of the drug product. Suitable examples include, but are not limited to, sodium chloride, potassium chloride, calcium chloride, sodium phosphate, potassium phosphate, calcium phosphate, sodium acetate, potassium acetate, magnesium sulfate, sodium bicarbonate, potassium bicarbonate, zinc sulfate, copper sulfate, iron chloride, aluminum chloride, ammonium chloride, sodium citrate, potassium citrate, calcium citrate, and magnesium chloride.

[0162] In some embodiments, the composition further comprises one or more diluents. Diluents are incorporated as excipients in pharmaceutical formulations to increase the bulk volume of a dosage form, aid in the uniform distribution of the active pharmaceutical ingredient (API), and ensure accurate dosing, supporting the overall manufacturing and dosing characteristics. Suitable examples of diluents include, but are not limited to, lactose, starch, pregelatinized starch, microcrystalline cellulose, silicified microcrystalline cellulose, cellulose acetate, dextrose, mannitol, sodium phosphate, potassium phosphate, calcium phosphate, fructose, maltose, sorbitol, or sucrose.

[0163] In some embodiments, the composition further comprises one or more preservatives. Suitable preservatives include, but are not limited to, antimicrobial agents that kill and / or inhibit the proliferation and / or growth of microbes, particularly bacteria, fungi and yeast. Preservatives can be synthetic compounds, semisynthetic compounds, and naturally produced compounds. Suitable dermatologically absorbable preservatives include erythromycin, bacitracin, zinc bacitracin, polymycin, neomycin, chloramphenicol, tetracycline, sulfacetamide, minocycline, clindamycin, doxycycline, undecylenic acid and salts thereof, propionic acid and salts thereof, caprylic acid and salts thereof, ciprofloxacin, cephlasporins, benzoic acid, ciclopiroxolamine, clotrimazole, econazole nitrate, metronizadole, miconazole nitrate, ketacanazole, oxiconazole, tolnaftate, benzalkonium chloride, parabens, methyl paraben, benzethonium chloride, NeoIone 950, sodium benzoate, sodium bisulfite, phenol, alkyl esters of parahydroxybenzoic acid, o-phenylphenol benzoic acid and salts thereof, boric acid and salts thereof, sorbic acid and salts thereof, chlorobutanol, benzyl alcohol, thimerosal, phenylmercuric acetate and nitrate, nitromersol, and cetylpyridinium chloride. In some embodiments, the composition further comprises sodium benzoate.

[0164] In some embodiments, the composition further comprises one or more viscosity modulating agents. A viscosity modulating agent includes any agent that is capable of modulating the viscosity of a gel, optimisation of which may be required in order to maximise efficacy. Viscosity modulating agents useful in the practice of the invention include but are not limited to, ionic and non-ionic, high viscosity, water soluble polymers; crosslinked acrylic acid polymers such as the "carbomer" family of polymers, e.g., carboxypolyalkylenes that may be obtained commercially under the Carbopol® trademark; hydrophilic polymers such as polyethylene oxides, polyoxyethylenepolyoxypropylene copolymers, and polyvinylalcohol; cellulosic polymers and cellulosic polymer derivatives such as hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropyl methylcellulose, hydroxypropyl methylcellulose phthalate, methyl cellulose, carboxymethyl cellulose, and etherifted cellulose; gums such as tragacanth and xanthan gum; sodium alginate; gelatin, hyaluronic acid and salts thereof, chitosans, gellans or any combination thereof. If a uniform gel is desired, dispersing agents such as alcohol, sorbitol or glycerin can be added, or the gelling agent can be dispersed by trituration, mechanical mixing, or stirring, or combinations thereof.

[0165] In some embodiments, the composition further comprises one or more antioxidants. Antioxidants may be added to inhibit oxidative degradation, protect the brivaracetam and other components from oxidation, and enhance the stability and shelf life of the drug product, contributing to its overall efficacy and quality. Suitable examples of antioxidants include, but are not limited to, cysteine, methionine, tryptophan, and mixtures thereof. In some embodiments, the composition further comprises one or more antimicrobial, antibacterial or antifungal agents to mitigate against the growth of microbes.

[0166] Methods of Preparing Compositions

[0167] The present disclosure provides for a method of preparing a composition according to any aspect, embodiment, or example described herein.

[0168] The person skilled in the art will appreciate that there are multiple suitable methods for the preparation of the composition. That is to say, there is no particular order to which the components of the composition may be combined.

[0169] In some embodiments, the method comprises mixing brivaracetam or a pharmaceutically acceptable salt, hydrate or salt thereof and one or more carriers and / or excipients. In some embodiments, the method comprises contacting a carrier with brivaracetam or a pharmaceutically acceptable salt, hydrate or salt thereof, optionally a solubility enhancer; and optionally one or more excipients. In some embodiments, the method comprises contacting a polymer with brivaracetam or a pharmaceutically acceptable salt, hydrate or salt thereof, a solubility enhancer; and optionally one or more excipients.

[0170] In some embodiments, the method comprises preparation of the porous carrier. In some embodiments, the method comprises preparation of the polymer gel. Typically, although not necessarily, this will involve dispersing the polymer in water (e.g. MilliQ water) to form a colloidal suspension of low viscosity. Optionally, the added polymer is in a powder form. Optionally, the formed colloidal suspension is acidic. Optionally, the dispersion may be vortexed and / or shaken (e.g. in an orbital shaker) for a period of time (e.g. overnight) in order to facilitate wetting of the powder.

[0171] After the colloidal suspension is formed and optionally vortexed and / or shaken, further components are added, including the brivaracetam, and any other excipients, including the solubility enhancer.

[0172] In some embodiments, the method further comprises the addition of brivaracetam. In some embodiments, the method further comprises addition of the solubility enhancer. In some embodiments, the method further comprises the addition of brivaracetam, and the solubility enhancer. The brivaracetam and / or solubility enhancer may be according to any aspect, embodiment, or example described herein.

[0173] In some embodiments, the method further comprises the addition of one or more excipients. The one or more excipients may be according to any aspect, embodiment, or example described herein. In some embodiments, the one or more excipients include permeation enhancers. Examples of suitable permeation enhancers include, but are not limited to, e.g. propylene glycol, Transcutol®, cineole or sodium lauryl sulfate. Such permeation enhancers may be according to any aspect, embodiment, or example described herein.

[0174] Following addition of the brivaracetam, solubility enhancer, and the one or more excipients (which may optionally include permeation enhancers) to the colloidal suspension, the suspension is thoroughly mixed until a uniform consistency has been formed.

[0175] In some embodiments, the pH of the colloidal suspension is then adjusted to a desired pH by the slow addition of e.g. a base or acid, in order to trigger gel formation. A non-limiting example of a suitable base is sodium hydroxide. A non-limiting example of a suitable acid is hydrogen chloride. For example, where an acidic colloidal suspension has been formed form a carbomer, sodium hydroxide may be used to adjust the pH to e.g. 4-7, where upon the gel matrix will turn from a cloudy suspension to a slightly white translucent gel, constituting the composition of the present invention.

[0176] Devices

[0177] While the transdermal compositions of the present disclosure are suitable for passive delivery of brivaracetam, in one embodiment, they are particularly suitable for iontophoresis.

[0178] Iontophoresis delivers a medicine or other chemical through the skin, colloquially referred to as “an injection without a needle”. Iontophoresis is non-invasive and different from passive transdermal patches, which do not rely on an electric field or current. During iontophoresis a delivery system drives a substance, usually an active agent, transdermally by electromotive force, through the skin. The active agent may itself be charged (i.e. ionised) and therefore repelled by the electric field or one or more excipients present with the active agent may be charged and either transports, carries or entrains a portion of the active agent through the skin. A small electric signal is applied to an iontophoretic chamber adhered to the skin, containing an active agent in a suitable formulation, wherein either the active agent, components of the formulation, or both, are charged (i.e. the formulation comprises one or more charged species). A return electrode carries the return current. The positively charged electrode, called the anode, repels a positively and attracts a negatively charged chemical species into or from the skin, whereas the negatively charged electrode, called the cathode, repels a negatively and attracts positively charged species into or from the skin.

[0179] The present disclosure provides for an iontophoresis drug delivery device, comprising: a) a delivery electrode; and b) a reservoir for holding a transdermal drug delivery composition according to any aspect, embodiment, or example described herein. In some embodiments, the iontophoresis drug delivery device is integrated into an adhesive patch for transdermal application. In some embodiments, the iontophoresis drug delivery device further comprises an adhesive to adhere to the skin of a subject.

[0180] The delivery electrode (also known as the “drug” or “active” electrode) is the electrode which, when polarised by a suitable electrical control signal (such as a negative voltage), generates an electrical field which repels a charged chemical species into the skin. The charged species may be brivaracetam or one or more other excipients present in the composition, such as the solubility enhancer. If positively charged (i.e. polarised with a positive voltage), the delivery electrode can be called the anode, and repels a positively and attracts a negatively charged chemical species into or from the skin. If negatively charged (i.e. polarised with a negative voltage), the delivery electrode can be called the cathode, and repels a negatively and attracts positively charged species into or from the skin.

[0181] In most cases, the drug delivery composition according to any aspect, embodiment, or example described herein is in electrical communication with the delivery electrode (that is to say, the composition and delivery electrode is configured in a way such within the device that the delivery electrode, when polarised, generates an electrical field which can interact (e.g. contact) the drug delivery composition and repel charged chemical species (e.g. ionised brivaracetam or other charged species such as ionic cyclodextrin etc.) from the composition and into the skin).

[0182] Examples of suitable materials used as the delivery electrode include, but are not limited to, polydimethylsiloxane (PDMS), which is an elastomer with excellent optical, electrical and mechanical properties and is biocompatible. Other examples include polyethylene terephthalate (PET). Both PDMS and PET provide for flexible substrates, which is useful as the patch can then adapt to the shape of the skin, gold (Au), including electroless nickel immersion gold coated copper (Cu), silver (Ag) and silver chloride (AgCl), iridium oxide (EO2) or platinum (Pt) can be used for electrodes. Other examples include liquid metal and Ag nanowires for interconnects. Various types of masking materials can be used to define specific areas to hold the composition / reservoir described herein. Another example includes the use of poly(3,4-ethylenedi oxythiophene) (PEDOT). The electrodes may then be deposited onto that substrate, which may be made of platinum, iridium oxide or another biocompatible conductor.

[0183] The reservoir is configured / adapted to hold the transdermal drug delivery composition. In some embodiments, the reservoir may be proximal to the skin surface of a subject. The reservoir may be configured such that the drug delivery composition is in direct contact or in fluidic communication with the skin surface so that brivaracetam can pass from the composition in the reservoir into the skin surface. That is, the skin may be touching the drug delivery composition, or there may be a permeable membrane or outer layer between the reservoir and the skin surface, but that layer is permeable to brivaracetam. One such membrane could be an ion-transducing material. In some embodiments, the delivery electrode, reservoir or indeed the iontophoresis drug delivery device, may be coated with an ion-transducing material such as PEDOT:PSS. When the reservoir or drug delivery device (which comprises the delivery electrode and composition described herein) is coated with an ion-transducing material, when in use, the skin-device interface is via the ion-transducing material, such that ionised molecules within the drug delivery composition (e.g. ionised solubility enhancer associated with brivaracetam) can pass from drug delivery composition housed in the reservoir through the ion-transducing material and into the skin.

[0184] In some embodiments, the iontophoresis drug delivery device or system further comprises a mechanical skin permeator to improve transport of the pharmaceutical through the skin. In some embodiments, the device further comprises hollow microneedles that puncture the skin and the brivaracetam can then more readily enter the skin through those punctures.

[0185] The iontophoresis drug delivery device may further comprise additional components, such as one or more electrodes, including a return electrode (which may or may not be located in or near a reservoir housing a charge balancing fluid) and / or a reference electrode, both of which are described below.

[0186] Systems

[0187] The iontophoresis drug delivery device can be considered a sub-component of an iontophoresis drug delivery system. The present disclosure therefore also provides for an iontophoresis drug delivery system, comprising: a) at least one iontophoresis drug delivery device according to any aspect, embodiment, or example described herein; b) a return electrode; and c) a control circuit configured to generate and provide an electrical control signal to the delivery electrode of the one or more iontophoresis drug delivery device to transdermally deliver brivaracetam by iontophoresis to the subject.

[0188] In some embodiments, the system comprises two or more iontophoresis drug delivery devices. In this embodiment, the two or more iontophoresis drug delivery devises can be individually addressable. In some embodiments, where there is more than one iontophoresis drug delivery device, the delivery electrode of each iontophoresis drug delivery device may be insulated from electrodes of other iontophoresis drug delivery devices. In some embodiments, the reservoir is also separated from the reservoirs of the other iontophoresis drug delivery devices.

[0189] In some embodiments, the system is integrated into a patch comprising an adhesive to affix the patch on the skin of a patient. The patch may integrate all components that are part of the system, including the control circuit, battery (if present) and the electrodes. Thus, in some embodiments, the system is integrated into an adhesive patch for transdermal application. The return electrode may be selected from any electrode material described herein, including that described for the delivery electrode. As noted above, a return electrode carries the return current.

[0190] In some embodiments, the system may further comprise a reference electrode to provide a stable fluid electrode potential (or stable fluid electrode potential interface). The reference electrode can also provide a measurement of the electrode-skin interface or impedance between the electrode and the skin. Advantageously, the reference electrode may be located closely to the delivery electrode and return electrode so that the measurement on the reference electrode provides a reasonably accurate indication of the interface condition of the electrode and return electrode. In other words, if the reference electrode provides a measurement that indicates good skin contact, it can be assumed that the skin contact is also good for electrode and return electrode. In some embodiments, the return electrode is provided with a reservoir for a charge balancing fluid.

[0191] The electrical control signal may be an electrical charge, such as a positive or negative voltage. In some embodiments, the control circuit is configured to generate a positive voltage or a negative voltage. A positive voltage, when applied to the delivery electrode, renders the delivery electrode positively charged, which is suitable to repel positively and attract negatively charged chemical species into or from the skin. Conversely, a negative voltage, when applied to the delivery electrode, will render the delivery electrode negatively charged, which is suitable to repel negatively and attract positively charged chemical species into or from the skin.

[0192] In one embodiment, the control circuit is configured to generate a negative voltage, for example between about -10 V to less than 0 V, e.g. about -5 V, -4 V, -3 V, -

[0193] 2 V, or -1 V, which polarises the delivery electrode such that it is capable of repelling negatively charged chemical species into the skin. In an alternative embodiment, the control circuit is configured to generate an electrical control signal by application of a positive voltage, for example between greater than 0 V up to about 10 V, e.g. 1 V, 2 V,

[0194] 3 V, 4 V or 5 V, which polarises the delivery electrode such that it is capable of repelling positively charged chemical species into the skin. In some embodiments, the control circuit is configured to generate a constant positive or negative voltage and / or constant current.

[0195] The control circuit may be a microprocessor, field programmable gate array, application specific integrated circuit or other type of circuit and may incorporate a wireless communications system. Typically, the control circuit is configured, such as by way of program code stored on program memory or by way of hardware design, to generate and provide an electrical control signal the delivery electrode of the one or more iontophoresis drug delivery device to transdermally deliver brivaracetam by iontophoresis to the subject. The control circuit may be powered by a battery. In some embodiments, the system comprises an integrated battery. In some embodiments, the system is integrated into an adhesive patch for transdermal application. This integration means the control circuit as well as the devices and control signals are integrated within the patch. Therefore, no further components are required, and no further components need to be connected to the patch to commence application, which is why the patch may also integrate a battery. Thus, in some embodiments, the system comprises an integrated battery.

[0196] The method for manufacturing the system commences by providing a substrate and creating the required metal layers on the substrate as well as making vias, which provide an electrical connection between the top side of substrate to the bottom side of substrate. The metal layers comprise the signal lines as well as electrodes and may include an antenna. Next, the reservoirs are created and incorporated into a membrane or adhesive laminate or directly onto a protective liner. Further, the control circuit and the battery are added, noting that there may only be one control circuit and one battery for the entire system. Finally, the top side of the substrate is encapsulated in an encapsulating layer, such as epoxy cured with ultraviolet (UV) light and covered with an encapsulation foil or backing.

[0197] As will be appreciated by the person skilled in the art, various devices and systems may be utilised to transdermally deliver the composition, which includes, although is not limited to, those described by United States of American Provisional Patent Application No. 63 / 469047 filed 25 May 2023 and corresponding international application No. PCT / AU2024 / 050540 filed 24 March 2024 and published as WO2024 / 239072 on 28 November 2024, the contents of which is incorporated by reference herein in its entirety. It will also be appreciated that the above description of the devices and systems comprising the iontophoresis drug delivery composition is non-limiting and it is envisaged that the compositions described herein can be applied to any iontophoresis delivery system / patch.

[0198] Transdermal patches

[0199] In some embodiments, the composition, devices and / or systems according to any aspect, embodiment, or example described herein is integrated into a patch for transdermal application (i.e. a transdermal patch). The person skilled in the art will appreciate that there is no particular limitation as to transdermal patches that are suitable for integration with the composition. In some embodiments, this patch comprises an adhesive for fixation on the skin of a subject. The physical architecture of the patch may include specific adhesives, methods to store drug matrices, bio-resolvable layers, and wireless communication and measurement apparatus. The adhesive of the transdermal patch may be a polymeric adhesive, and in some embodiments forms part of or is the polymer of the composition according to some aspects, embodiments or examples described herein. Methods of Delivery and Treatment

[0200] The present disclosure provides a use of a transdermal drug delivery composition according to any aspect, embodiment, or example described herein or a composition prepared by a method according to any aspect, embodiment, or example described herein, for delivering brivaracetam or a pharmaceutically acceptable salt, hydrate or solvate thereof across the skin of a subject.

[0201] The present disclosure also provides a method for delivering brivaracetam or a pharmaceutically acceptable salt, hydrate or solvate thereof across the skin of a subject, comprising contacting a composition according to any aspect, embodiment, or example described herein or a composition prepared by a method according to any aspect, embodiment, or example described herein to the skin to transdermally deliver brivaracetam by iontophoresis across the skin to the subject.

[0202] In one embodiment, the transdermal delivery of brivaracetam is by iontophoresis.

[0203] In one embodiment, the method or use comprises: providing an iontophoresis drug delivery system according to any aspect, embodiment, or example described herein; contacting the system to the skin of a subject; and generating and providing an electrical control signal to the delivery electrode to transdermally deliver brivaracetam by iontophoresis to the subject.

[0204] In some embodiments, the method or use comprises generating and providing a voltage to the delivery electrode to transdermally delivery brivaracetam by iontophoresis to the subject (i.e. the method or use comprises polarising the delivery electrode with a negative voltage). In some embodiments, the voltage is between -10 V to about 10V, for example between about -5 V to about 5 V. In some embodiments, the voltage is a negative voltage, including for example between about -10 V to less than 0 V, e.g. between about -5V to less than 0V e.g. about -5 V, -4 V, -3 V, -2 V, or -1 V, which polarises the delivery electrode such that it is capable of repelling negatively charged chemical species into the skin. In an alternative embodiment, the voltage is a positive voltage (i.e. the method or use comprises polarising the delivery electrode with a negative voltage), for example between greater than 0 V up to about 10 V, e.g. greater than 0 V up to about 5 V, e.g. 1 V, 2 V, 3 V, 4 V or 5 V, which polarises the delivery electrode such that it is capable of repelling positively charged chemical species into the skin. In some embodiments, the control circuit is configured to generate a constant positive or negative voltage and / or constant current.

[0205] In some embodiments, the method or use comprises generating and providing a negative voltage described herein to the delivery electrode and cumulatively delivering between about 500 pg to about 2000 pg of brivaracetam per cm2of skin of the subject. According to some embodiments or examples described herein, polarising the delivery electrode with a negative voltage has surprisingly been found to deliver brivaracetam in higher cumulative amounts compared to passive delivery or under reverse polarity conditions using positive voltages.

[0206] In some embodiments, the method or use comprises generating a constant positive or negative voltage and / or constant current to the delivery electrode to transdermally deliver brivaracetam by iontophoresis to the subject.

[0207] In some embodiments, the method or use is for treating and / or preventing a disease in a subject in need thereof, comprising transdermal delivery of a therapeutically effective amount of brivaracetam across the skin to the subject.

[0208] The present disclosure also provides a method of treating and / or preventing a disease in a subject in need thereof, comprising administering to the subject a composition according to any aspect, embodiment, or example described herein.

[0209] The present disclosure also provides a use of a transdermal drug delivery composition according to according to any aspect, embodiment or example described herein in the manufacture of a medicament for treating and / or preventing a disease in a subject, wherein the medicament is formulated for transdermal delivery of a therapeutically effective amount of brivaracetam across the skin to the subject.

[0210] In some embodiments, the method or use comprises transdermally delivering a therapeutically effective amount of brivaracetam across the skin of a subject by iontophoresis according to any aspect, embodiment, or example as described herein.

[0211] In some embodiments, the disease is selected from the group consisting of epileptogenesis, seizure disorders, convulsions, Parkinson's disease, dyskinesia induced by dopamine replacement therapy, tardive dyskinesia induced by administration of neuroleptic drugs, Huntington Chorea, and other neurological disorders including bipolar disorders, mania, depression, anxiety, attention deficit hyperactivity disorder (ADHD), migraine, cluster headache, trigeminal and other neuralgia, chronic pain, neuropathic pain, cerebral ischemia, cardiac arrhythmia, myotonia, cocaine and other substance abuse (e.g. alcohol, benzodiazepines, opiates, marijuana, barbiturates, amphetamines, other stimulants), stroke, myoclonus, dystonia, dyskinesia, tremor, essential tremor, simple or complex tics, Tourette syndrome, restless leg syndrome and other movement disorders, neonatal cerebral haemorrhage, amyotrophic lateral sclerosis, spasticity and degenerative diseases.

[0212] In some embodiments, the disease is selected from the group consisting of epilepsy, Parkinson's disease, dyskinesia, migraine, tremor, essential tremor, bipolar disorders, chronic pain, neuropathic pain, or bronchial, asthmatic or allergic conditions.

[0213] In some embodiments, the disease is epilepsy.

[0214] The present disclosure also provides a transdermal drug delivery composition according to according to any aspect, embodiment or example described herein for delivering brivaracetam or a pharmaceutically acceptable salt, hydrate or solvate thereof across the skin of a subject. The present disclosure also provides a transdermal drug delivery composition according to according to any aspect, embodiment or example described herein for treating and / or preventing a disease in a subject in need thereof, comprising transdermally delivery a therapeutically effective amount of brivaracetam across the skin to the subject.

[0215] The present disclosure also provides a transdermal drug delivery composition according to according to any aspect, embodiment or example described herein when used for treating and / or preventing a disease in a subject in need thereof, comprising transdermally delivery a therapeutically effective amount of brivaracetam across the skin to the subject. It will be appreciated that the embodiments and examples described herein in relation to the method or use equally apply to the for use / when used aspects / embodiments of the composition described herein.

[0216] ***

[0217] The present disclosure can also be described by reference to one or more of the following example embodiments. It will be appreciated that the specific embodiments presented below are not intended to be limiting to the scope. It will also be appreciated that persons skilled in the art may incorporate one or more of the elements, features or embodiments in the listing below (indeed, any such aspect or embodiment described herein) into combinations not specifically set forth herein. All such embodiments are considered to be within the scope of the disclosure.

[0218] 1. A transdermal drug delivery composition comprising a polymer and brivaracetam or a pharmaceutically acceptable salt, hydrate or solvate thereof, a solubility enhancer and optionally one or more excipients interspersed on or within the polymer.

[0219] 2. The composition of example embodiment 1, wherein at least some of the solubility enhancer is attached or associated to brivaracetam forming a complex.

[0220] 3. The composition of example embodiment 1 or example embodiment 2, wherein the solubility enhancer is an amphiphilic molecule.

[0221] 4. The composition of any one of example embodiments 1 to 3, wherein the solubility enhancer is neutral or comprises one or more ionic groups. 5. The composition of any one of example embodiments 1 to 4, wherein the solubility enhancer is a cyclodextrin and at least some of the cyclodextrin forms an inclusion complex with brivaracetam.

[0222] 6. The composition of example embodiment 5, wherein the cyclodextrin is selected from the group consisting of a-cyclodextrin, P-cyclodextrin, y-cyclodextrin, or a derivative or combination thereof.

[0223] 7. The composition of example embodiment 5 or example embodiment 6, wherein the cyclodextrin comprises one or more positive ionic groups or one or more negative ionic groups.

[0224] 8. The composition of example embodiment 7, wherein the one or more negative ionic groups of the cyclodextrin is selected from the group consisting of sulfate, carboxylate, phosphate and nitrate group, or combinations thereof.

[0225] 9. The composition of any one of example embodiments 5 to 8, wherein the cyclodextrin is selected from the group consisting of a sulfoalkylether- P-cyclodextrin (SAE- P -CD), including sulfobutylether-P-cyclodextrin (SBE-P-CD), hydroxyalkyl-P- cyclodextrins, including hydroxypropyl-P-cyclodextrin (e.g. HP-P-CD), hydroxyalkyl-y- cyclodextrins, methylated-P-cyclodextrin, y-cyclodextrin sulfobutyl ether, branched P- cyclodextrin and branched y-cyclodextrins.

[0226] 10. The composition of example embodiment 9, wherein the cyclodextrin is a SAE- P-CD, preferably SBE-P-CD.

[0227] 11. The composition of any one of example embodiments 1 to 10, wherein the composition comprises (in % w / w) between about 1 to about 40 of the solubility enhancer based on the total weight of the composition, preferably between 1 to about 30, more preferably between about 1 to about 10.

[0228] 12. The composition of any one of 1 to 11, wherein the polymer is a polymer gel.

[0229] 13. The composition of any one of 1 to 12, wherein the polymer gel is a hydrogel. 14. The composition of example embodiment 12 or example embodiment 13, wherein the polymer comprises a hydrophilic polymer.

[0230] 15. The composition of example embodiment 14, wherein the hydrophilic polymer is a naturally occurring polymer or a synthetic polymer.

[0231] 16. The composition of example embodiment 14 or example embodiment 15, wherein the hydrophilic polymer comprises a polymer selected from the group consisting of poly(acrylic acids), poly(methacrylic acids), poly(acrylamides), poly(amidoamines), poly(dimethylaminoethyl methacrylate), polyethylene glycols), poly(amidoamines), poly (dimethyl siloxanes), poly(hydroxyethyl methacrylates), poly(N-isopropyl acrylamides), poly(vinyl alcohols), and polyvinylpyrrolidones) or copolymers thereof.

[0232] 17. The composition of any one of example embodiments 14 to 16, wherein the hydrophilic polymer comprises poly(acrylic acid), or a copolymer thereof.

[0233] 18. The composition of example embodiment 17, wherein the poly(acrylic acid) is a carbomer, preferably Carbomer 934P or Carbomer Ultrez 30.

[0234] 19. The composition of any one of example embodiments 1 to 18, wherein the composition comprises (in % w / w) between about 0.1 to about 10 of the polymer based on the total weight of the composition, preferably between about 0.1 to about 5, more preferably between about 0.1 to about 2.

[0235] 20. The composition of any one of example embodiments 1 to 19, wherein the polymer has a viscosity of between 0.1 Pa.s to about 100 Pa.s at a shear rate of 100 1 / s when measured using a MCR 702 twin drive rheometer (Anton Paar), preferable between 1 to about 10 Pa.s.

[0236] 21. The composition of any one of example embodiments 1 to 20, wherein the concentration of brivaracetam (in % w / w) is between about 0.5% to about 15% based on the total weight of the composition.

[0237] 22. The composition of any one of example embodiments 1 to 21, wherein the solubility of brivaracetam (in mg / mL) in the composition is at least about 20 based on the total volume of the composition, preferably at least about 50. 23. The composition of any one of example embodiments 1 to 22, wherein the composition further comprises one or more excipients selected from a buffer, a permeation enhancer, a chelating agent, an adhesive, a stabilizer, a preservative, a humectant, a surfactant, an ionic species (e.g. ions) or an alcohol.

[0238] 24. The composition of any one of example embodiments 1 to 23, wherein the composition comprises: a carbomer hydrogel; and brivaracetam or a pharmaceutically acceptable salt, hydrate or solvate thereof and SBE-P-CD interspersed on or within the hydrogel.

[0239] 25. The composition of any one of example embodiments 1 to 24, wherein composition has a pH of between about 3 to about 7, preferably between about 3 to about 5.

[0240] 26. The composition of any one of example embodiments 1 to 25, wherein the composition is integrated into a patch for transdermal application.

[0241] 27. A method for preparing a transdermal drug delivery composition of any one of example embodiments 1 to 26, comprising the step of contacting a polymer with brivaracetam or a pharmaceutically acceptable salt, hydrate or salt thereof, a solubility enhancer; and optionally one or more excipients.

[0242] 28. An iontophoresis drug delivery device, comprising: a) a delivery electrode; and b) a reservoir for holding the transdermal drug delivery composition of any one of example embodiments 1 to 26 or the composition prepared by the method of example embodiment 27.

[0243] 29. An iontophoresis drug delivery system, comprising: a) at least one iontophoresis drug delivery device of example embodiment 28; and b) a control circuit configured to generate an electrical control signal and provide the electrical control signal to the delivery electrode of the one or more iontophoresis drug delivery device to transdermally deliver brivaracetam by iontophoresis to a subject. 30. The system of example embodiments 29, wherein the system is integrated into a patch for transdermal application.

[0244] 31. Use of a transdermal drug delivery composition of any one of example embodiments 1 to 26 or a composition prepared by the method of example embodiment 27, for delivering brivaracetam or a pharmaceutically acceptable salt, hydrate or solvate thereof across the skin of a subject.

[0245] 32. A method for delivering brivaracetam or a pharmaceutically acceptable salt, hydrate or solvate thereof across the skin of a subject, comprising contacting a composition of any one of example embodiments 1 to 26 or a composition prepared by the method of example embodiment 27 to the skin to transdermally deliver brivaracetam by iontophoresis across the skin to the subject.

[0246] 33. The method or use of example embodiment 31 or example embodiment 32, wherein the transdermal delivery of brivaracetam is by iontophoresis.

[0247] 34. The method or use of example embodiment 33, comprising: providing an iontophoresis drug delivery system of example embodiment 29 or example embodiment 30; contacting the system to the skin of a subject; and generating and providing an electrical control signal to the delivery electrode to transdermally deliver brivaracetam by iontophoresis across the skin to the subject.

[0248] 35. The method or use of example embodiment 34, wherein the electrical control signal is a negative voltage.

[0249] 36. The method or use of any one of example embodiments 31 to 35, for treating and / or preventing a disease in a subject in need thereof, comprising transdermally delivery a therapeutically effective amount of brivaracetam across the skin to the subject.

[0250] 37. The method or use of example embodiment 36, wherein the disease is epilepsy. EXAMPLES

[0251] In order that the disclosure may be more clearly understood, particular embodiments of the invention are described in further detail below by reference to the following nonlimiting experimental materials, methodologies and examples.

[0252] General

[0253] An iontophoresis patch is typically placed in a suitable in vitro setup, such as a Franz diffusion cell, which typically consists of two compartments (donor and receptor chambers) separated by the skin membrane. The donor chamber is replaced by an iontophoresis patch loaded with the targeted drug (Figure 1), while the receptor compartment contains a receiving medium that simulates physiological conditions. An electrical current is applied to facilitate drug transport through the skin layers. The content in the receptor chamber is sampled at regular intervals and analyzed using techniques such as ultra-high-performance liquid chromatography (UHPLC), UV-visible spectrophotometry or liquid chromatography mass spectrometry (LCMS). By analyzing the drug release data such as drug flux, lag time, penetration index, and release consistency, the patch's ability to deliver the drug in a controlled and sustained manner can be assessed.

[0254] Example 1 - Impedance Measurements

[0255] In order to determine suitable current / voltage parameters for use with the iontophoresis patch, impedance measurements were conducted on skin samples prior to the iontophoresis experiment. Impedance spectroscopy was performed by applying a range of frequencies and measuring the corresponding impedance values. This helps characterize the skin's electrical behaviour, including resistance and capacitance, and provides insights into the optimal current / voltage parameters for effective drug delivery. By analyzing impedance data, the iontophoresis patch can be tailored to deliver the required electrical stimulus for drug permeation while minimizing skin resistance and ensuring patient safety. Figure 2 depicts an example of porcine skin sample impedance measurements taken prior to the iontophoretic transdermal delivery experiment.

[0256] Example 2 - Hydrogel Formulation

[0257] This study aimed to optimize the hydrogel formulation for optimum viscosity to remain inside the designated well on the iontophoresis patch.

[0258] Carbomer hydrogels were prepared by dispersing carbomer 934P or Ultrez 30 powder (both of which are FDA approved) in MilliQ water at a concentration of 0.5% w / w and 1.0% w / w (respectively). After vortexing for 3 minutes, the mixture was placed in an orbital shaker overnight at approximately 134 rpm to ensure complete dispersion and swelling of the hydrogel. Additives such as solubility enhancers like sulfobutylether- P-cyclodextrin (SBE-P-CD) and permeation enhancers were incorporated into the mixture before adjusting the pH to the desired value using 1.25 M sodium hydroxide. Optimum gelling occurs between pH 3.5 and pH 7.

[0259] The viscosity and shear stress profile were determined using MCR 702 twin drive rheometer (Anton Paar). 250 pL of the formulation was placed on the stage and trimmed once in contact with the cone-plate measuring system (CP25). The shear rate was set from 0.1 to 100 s'1with 21 data points taken in this interval. Figure 3 and 4 respectively depict the hydrogel formulation viscosity and shear stress profile.

[0260] Example 3 - Drug solubility

[0261] A drug solubility study provides information about the ability of a drug to dissolve in a particular solvent under specific conditions. The solubility of active ingredient in each formulation may be determined by suspending an excess of active ingredient in a solvent mixture and keeping the suspension under constant agitation at 37 °C for 24 h. Samples are withdrawn with syringe filter (0.45 pm pore size) and assayed spectrophotometrically. The solubility of brivaracetam in a variety of formulations comprising varying amounts of a cyclodextrin and / or a carbomer was determined. The results are depicted in Figure 5.

[0262] Example 4 - lontophoretic in vitro skin permeation study

[0263] A study was undertaken to investigate the iontophoresis parameter(s) and the optimum patch configuration for efficient delivery of brivaracetam, ultimately evaluating the drug release profile.

[0264] The carbomer hydrogel was prepared by dispersing the fine carbomer powder (0.5 - 1% w / w) in MilliQ water to form acidic colloidal suspension of low viscosity. The mixture was vortexed and placed in an orbital shaker overnight to allow ample wetting of the powder. The active ingredient (e.g. 0.5 - 15% of brivaracetam), solubility enhancer (e.g. 2.5 - 10% of SBE-P-CD), permeation enhancers (e.g. 0.5 - 5% of propylene glycol / transcutol / cineole / sodium lauryl sulfate), and other additives (e.g. 0.5 - 1% sodium benzoate) were thoroughly mixed with the gel matrix until uniform consistency has formed. The gelling of carbomer occurs during the neutralization process using a base (e.g. sodium hydroxide) to the desired pH (e.g. pH 4 - 7), and the appearance of the gel matrix will turn from a cloudy suspension to a slightly white translucent gel.

[0265] The setup for in vitro skin permeation study is outlined in Figure 1, using a formulation of 1% carbomer (934P) with 3.5% Brivaracetam at pH 4.0 as a proof-of- concept experiment. Franz cells water bath temperature was set to 37 °C. lontophoretic transdermal delivery was performed using constant voltage and constant current modes, with passive permeation as a control. Samples of the receptor chamber fluid (phosphate buffered saline) were taken at selected time intervals and analyzed by UHPLC. The brivaracetam assay was performed using a Shimadzu Nexera UHPLC system endowed with a L-2400 UV-vis detector and an L-2130 isocratic pump. A Raptor Biphenyl (2.1 x 100mm 2.7pm) column was used in the assay. A mobile phase of 0.1% formic acid in MilliQ and 0.105% of formic acid in acetonitrile were used in a gradient flow method (up to 10:80% v / v). UV detection was performed at 227 nm, with an injection volume of 10 pl, flow rate of 1 ml / min, column temperature of 40 °C, 5.5 min run time and 3.2 min retention time. The data from the study is presented in Figures 6 to 8.

[0266] The polarity of iontophoresis has an effect in achieving controlled release of brivaracetam. Figure 6 illustrates that a negative voltage (-1 V) for iontophoresis delivery enhanced delivery, resulting in a more than 2.5 times increase in cumulative brivaracetam permeation through the skin sample within 3 hours, compared to the passive control. Conversely, applying a reversed polarity (+1V) led to drug retention, wherein the cumulative brivaracetam permeating through the skin decreased by 2.8 times compared to the passive control.

Claims

CLAIMS1. A transdermal drug delivery composition, comprising brivaracetam or a pharmaceutically acceptable salt, hydrate or solvate thereof, and optionally one or more carriers and / or excipients.

2. The transdermal drug delivery composition of claim 1, comprising: a porous carrier; and wherein the brivaracetam or a pharmaceutically acceptable salt, hydrate or solvate thereof, and the optional one or more excipients are interspersed on or within the porous carrier.

3. The transdermal drug delivery composition of claim 2, wherein the porous carrier is a polymer.

4. The transdermal drug delivery composition of any one of claims 1 to 3, comprising a solubility enhancer.

5. A transdermal drug delivery composition, comprising: a polymer; and brivaracetam or a pharmaceutically acceptable salt, hydrate or solvate thereof, a solubility enhancer and optionally one or more excipients interspersed on or within the polymer.

6. The composition of claim 4 or claim 5, wherein at least some of the solubility enhancer is attached to, or associated with, brivaracetam, forming a complex.

7. The composition of any one of claims claim 4 to 6, wherein the solubility enhancer is an amphiphilic molecule.

8. The composition of any one of claims 4 to 7, wherein the solubility enhancer is neutral or comprises one or more ionic groups.

9. The composition of any one of claims 4 to 8, wherein the solubility enhancer is a cyclodextrin and at least some of the cyclodextrin forms an inclusion complex with brivaracetam.

10. The composition of claim 9, wherein the cyclodextrin is selected from the group consisting of a-cyclodextrin, P-cyclodextrin, y-cyclodextrin, or a derivative or combination thereof.

11. The composition of claim 9 or claim 10, wherein the cyclodextrin comprises one or more positive ionic groups or one or more negative ionic groups.

12. The composition of claim 11, wherein the one or more negative ionic groups of the cyclodextrin is selected from the group consisting of sulfate, carboxylate, phosphate and nitrate group, or combinations thereof.

13. The composition of any one of claims 9 to 12, wherein the cyclodextrin is selected from the group consisting of a sulfoalkylether- P-cyclodextrin (SAE-P-CD), including sulfobutylether-P-cyclodextrin (SBE-P-CD), hydroxyalkyl-P- cyclodextrins, including hydroxypropyl-P-cyclodextrin (e.g. HP-P-CD), hydroxyalkyl-y-cyclodextrins, methylated-P-cyclodextrin, y-cyclodextrin sulfobutyl ether, branched P-cyclodextrin and branched y-cyclodextrins.

14. The composition of claim 13, wherein the cyclodextrin is a SAE-P-CD, preferably SBE-P-CD.

15. The composition of any one of claims 4 to 14, wherein the composition comprises (in % w / w) between about 1 to about 40 of the solubility enhancer based on the total weight of the composition, preferably between 1 to about 30, more preferably between about 1 to about 10.

16. The composition of any one of 3 to 14, wherein the polymer is a polymer gel.

17. The composition of any one of claim 16, wherein the polymer gel is a hydrogel.

18. The composition of claim 16 or claim 17, wherein the polymer comprises a hydrophilic polymer.

19. The composition of claim 18, wherein the hydrophilic polymer is a naturally occurring polymer or a synthetic polymer.

20. The composition of claim 18 or claim 19, wherein the hydrophilic polymer comprises a polymer selected from the group consisting of poly(acrylic acids), poly(methacrylic acids), poly(acrylamides), poly(amidoamines), poly(dimethylaminoethyl methacrylate), poly(ethylene glycols), poly(amidoamines), poly(dimethylsiloxanes), poly(hydroxyethyl methacrylates), poly(N-isopropyl acrylamides), poly(vinyl alcohols), and poly(vinylpyrrolidones) or copolymers thereof.

21. The composition of any one of claims 18 to 20, wherein the hydrophilic polymer comprises poly(acrylic acid), or a copolymer thereof.

22. The composition of claim 21, wherein the poly(acrylic acid) is a carbomer, preferably Carbomer 934P or Carbomer Ultrez 30.

23. The composition of any one of claims 3to 22, wherein the composition comprises (in % w / w) between about 0.1 to about 10 of the polymer based on the total weight of the composition, preferably between about 0.1 to about 5, more preferably between about 0.1 to about 2.

24. The composition of any one of claims 3 to 23, wherein the polymer has a viscosity of between 0.1 Pa.s to about 100 Pa.s at a shear rate of 100 1 / s when measured using a MCR 702 twin drive rheometer (Anton Paar), preferably between 1 to about 10 Pa.s.

25. The composition of any one of claims 1 to 24, wherein the concentration of brivaracetam (in % w / w) is between about 0.5% to about 15% based on the total weight of the composition.

26. The composition of any one of claims 1 to 25, wherein the solubility of brivaracetam (in mg / mL) in the composition is at least about 20 based on the total volume of the composition, preferably at least about 50.

27. The composition of any one of claims 1 to 26, wherein the composition further comprises one or more excipients selected from a buffer, a permeation enhancer, a chelating agent, an adhesive, a stabilizer, a preservative, a humectant, a surfactant, an ionic species (e.g. ions) or an alcohol.

28. The composition of any one of claims 1 to 27, wherein the composition comprises: a carbomer hydrogel; and brivaracetam or a pharmaceutically acceptable salt, hydrate or solvate thereof and SBE-P-CD interspersed on or within the hydrogel.

29. The composition of any one of claims 1 to 28, wherein composition has a pH of between about 3 to about 7, preferably between about 3 to about 5.

30. The composition of any one of claims 1 to 29, wherein the composition is integrated into a patch for transdermal application.

31. A method for preparing a transdermal drug delivery composition of any one of claims 1 to 30, comprising the step of contacting the carrier with brivaracetam or a pharmaceutically acceptable salt, hydrate or salt thereof, optionally a solubility enhancer; and optionally one or more excipients.

32. An iontophoresis drug delivery device, comprising: a) a delivery electrode; and b) a reservoir holding the transdermal drug delivery composition of any one of claims 1 to 30 or the composition prepared by the method of claim 31.

33. An iontophoresis drug delivery system, comprising: a) at least one iontophoresis drug delivery device of claim 32; and b) a control circuit configured to generate an electrical control signal and provide the electrical control signal to the delivery electrode of the one or more iontophoresis drug delivery device to transdermally deliver brivaracetam by iontophoresis to a subject.

34. The system of claim 33, wherein the system is integrated into a patch for transdermal application.

35. Use of a transdermal drug delivery composition of any one of claims 1 to 30 or a composition prepared by the method of claim 31, for delivering brivaracetam or a pharmaceutically acceptable salt, hydrate or solvate thereof across the skin of a subject.

36. A method for delivering brivaracetam or a pharmaceutically acceptable salt, hydrate or solvate thereof across the skin of a subject, comprising contacting a composition of any one of claims 1 to 30 or a composition prepared by the method of claim 31 to the skin to transdermally deliver brivaracetam by iontophoresis across the skin to the subject.

37. The method or use of claim 35 or claim 36, wherein the transdermal delivery of brivaracetam is by iontophoresis.

38. The method or use of claim 37, comprising: providing an iontophoresis drug delivery system of claim 33 or claim 34; contacting the system to the skin of a subject; and generating and providing an electrical control signal to the delivery electrode to transdermally deliver brivaracetam by iontophoresis across the skin to the subject.

39. The method or use of claim 38, wherein the electrical control signal is a negative voltage.

40. The method or use of any one of claims 35 to 39, for treating and / or preventing a disease in a subject in need thereof, comprising transdermally delivery a therapeutically effective amount of brivaracetam across the skin to the subject.

41. The method or use of claim 40, wherein the disease is epilepsy.

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