Sustained release compositions of mexiletine for oral administration

Abstract

The present invention relates to a controlled release pharmaceutical composition of mexiletine comprising an ion exchange resin and a method of making said composition. More particularly, the present invention relates to a controlled release suspension of mexiletine or a pharma- ceutically acceptable salt thereof complexed with an ion exchange resin. In particular, the present invention provides a controlled release suspension of mexiletine administered once daily for the treatment of myotonic disorders. Furthermore, the present invention improves bioavailability, dosing frequency and patient compliance.

Description

[Technical field]

[0001] Related Applications This application has been filed as a PCT (International) Patent Application and claims priority to Indian Patent Application No. 202131026198 filed on June 11, 2021, the entire contents of which refer to the priority application are incorporated herein by reference.

[0002] Technical Field The present invention relates to a once-daily oral controlled release pharmaceutical composition of mexiletine or a pharma- ceutically acceptable salt thereof suitable for oral administration. The present invention also relates to methods of preparation and use of said composition for the treatment of myotonic disorders. [Background technology]

[0003] Myotonia describes a neuromuscular condition in which muscle relaxation does not function normally. Myotonia can mildly or severely interfere with daily activities such as walking, climbing stairs, or opening and closing the eyelids. Myotonia is caused by abnormalities in the muscle membrane and is often associated with inherited neuropathies. It is prevalent in individuals affected by myotonic dystrophy, myotonia congenita, and in people affected by one of a group of neuropathies called channelopathies. Myotonia can be acquired or congenital and is due to mutations in the chloride, sodium, or potassium ion transport channels in the muscle membrane, among others. In addition, affected individuals have proximal muscle weakness that spreads until all muscle groups are eventually involved, including the oropharyngeal muscles, and thus dysphagia is widespread in myotonic patients.

[0004] Mexiletine hydrochloride is a class 1b antiarrhythmic drug with high affinity for muscle sodium channels and is currently used to treat arrhythmias. One commercial product, mexiletine hydrochloride, sold under the trade name MEXITIL® by Boehringer Ingelheim Pharmaceuticals, Inc., is available in 150 mg, 200 mg, and 250 mg capsules administered three times daily.

[0005] The structure of mexiletine hydrochloride is shown below: [ka]

[0006] Mexiletine is rapidly and completely absorbed after oral administration with a bioavailability of approximately 90%. Labbe L, Turgeon J. Clinical pharmacokinetics of mexiletine. Clin Pharmacokinet. 1999 Nov; 37(5): 361-84. doi:10.2165 / 00003088-199937050-00002.

[0007] Peak plasma concentrations after oral administration occur within 1-4 hours, with a linear relationship between dose and plasma concentration observed within the dose range of 100 mg to 600 mg (ibid.). Mexiletine is slowly eliminated in humans (elimination half-life of 10 hours) (ibid.). Mexiletine is a weak base (pKa of approximately 9.1) and is absorbed in the intestine, with absorption in the stomach reported to be negligible. European Medicines Agency, Assessment Report: Namuscla (October 18, 2018) (EMA / 831802 / 2018) (“EMA 2018”). Food reportedly has no effect on the rate of absorption of the aforementioned mexiletine products (ibid., p. 38).

[0008] In recent years, mexiletine has become increasingly useful in the treatment of myotonia. For example, mexiletine hydrochloride immediate release capsules NaMuscla® by Lupin Limited are used for the treatment of symptomatic myotonia in adults suffering from non-dystrophic myotonia disease. The approved maintenance dose is 167 mg to 500 mg, i.e., 1 to 3 capsules administered at 8 hour intervals. Almost all trials in support of the European approval of NaMuscla include three times daily (TID) administration (EMA, 2018).

[0009] In general, drug therapy using immediate release oral dosage forms must be administered at intervals to maintain the desired therapeutic effect, and therefore patients suffering from myotonia or similar conditions often have difficulty complying with this dosing regimen. In myotonia patients, the muscles of the face, mouth and throat are affected, causing swallowing problems, especially during the use of high doses and frequent administration of immediate release dosage forms. Furthermore, mexiletine acts by blocking fast sodium channels, and therefore high peak trough plasma levels of mexiletine from repeated administration regimes of immediate release compositions have been associated with cardiac events. In addition, the tendency of such formulations to release their entire volume in the early part of the gastrointestinal tract when administered as immediate release compositions is prone to other gastrointestinal-related side effects, such as vomiting.

[0010] The desire to extend the duration of therapeutic effects of active pharmaceutical ingredients has often led to the proposal or realization of controlled drug release formulation development, which is often associated with a reduced frequency of administration. Various techniques for the development of such formulations are known. For example, ion exchange resins are an approach that has been utilized to obtain controlled release dosage forms, and various attempts have been made to further utilize the technology of powders, liquids, suspensions, and dispersible tablet compositions as well. Ion exchange resins are crosslinked water-insoluble polymers with ionizable functional groups, which have attracted considerable attention from pharmaceutical scientists due to their versatile properties as drug delivery carriers. Not all drugs are suitable for ion exchange resins. For example, active pharmaceutical ingredients with biological half-lives of greater than 8 hours, such as mexiletine, are generally considered to be unsuitable for such formulations (see, e.g., Dp, Venkatesh & Karki, Roopa & Goli, Divakar & Jha, Sajal. (2013). JOURNAL OF PHARMACY AND PHARMACEUTICAL SCIENCES. Vol. 2, Issue 6, pp. 4764-77). There are other factors that may suggest that mexiletine is a poor candidate for such an approach (ibid.).

[0011] Other types of sustained release formulation concepts have been proposed for application to mexiletine products in the art. For example, China Patent Application Publication No. 101032462 discloses a sustained release formulation of mexiletine hydrochloride with a dual release profile, i.e., immediate release and sustained release, requiring twice-daily administration for the treatment of arrhythmia. US Patent No. 4,459,279 discloses a method for making mexiletine immediate release mini-tablets by mixing mexiletine with conventional pharmaceutical excipients such as lactose, polyvinylpyrrolidone, and magnesium stearate. Furthermore, the tablets are coated with a release-retarding spray solution to produce sustained release mini-tablets. However, the disclosures of the above references do not appear to disclose a suitable once-daily controlled release composition of mexiletine suitable for the treatment of myotonia. For example, when administered in high doses or once-daily, the formulations disclosed in the above references are expected to be too bulky and therefore not suitable, especially for myotonia patients, as they are very difficult to swallow. Dose dumping is further a known problem associated with sustained release that may make such formulations unsuitable for use in conjunction with mexiletine products for the treatment of conditions such as myotonia. Indeed, despite the known utility of mexiletine for treating myotonia, and the existence of such proposed formulations in the art, there appears to be a lack of market and active development of mexiletine formulations that provide these or other important benefits for myotonia patients. Such facts demonstrate that the development of improved mexiletine formulations with advantageous properties for patients suffering from myotonia or similar conditions will require inventive ingenuity.

[0012] Structure, Terms, and Acronyms This section provides guidelines for reading this disclosure. The intended audience of this disclosure ("reader") is one skilled in the art of practicing the techniques discussed or used herein. Readers are also referred to as "persons of ordinary skill in the art" and such techniques are referred to as "the art." Terms such as "understood," "known," and "ordinary meaning" refer to the general knowledge of a person of ordinary skill in the art.

[0013] The term "not inconsistent" means not inconsistent with the present disclosure, logic, or validity based on the knowledge of one of ordinary skill in the art.

[0014] Several different but related exemplary aspects of the invention are disclosed herein (e.g., also referred to as "cases," "aspects," or "embodiments"). The invention encompasses all aspects described individually and that can be achieved by combining any of such individual aspects. The breadth and scope of the invention should not be limited by any of the exemplary embodiments. The language of the present disclosure should not be construed as indicating any element / step as essential to the practice of the invention unless such requirement is expressly stated. Any aspect can be combined with any other aspect, unless inconsistent.

[0015] Unless inconsistent, technical / scientific terms used herein generally have the same meaning as broadly understood by one of ordinary skill in the art, regardless of any narrower examples or descriptions provided herein. However, aspects characterized by including elements, steps, etc. associated with specific descriptions provided herein are different embodiments of the invention. Unless inconsistent, the disclosure of any aspect using known terms, examples, or terms otherwise narrowed in this disclosure implicitly discloses the relevant aspects where such terms are instead interpreted using the broadest reasonable interpretation of one of ordinary skill in the art.

[0016] Unless contradictory, as used herein, "or" means "and / or" regardless of the occasional inclusion of either "and / or."

[0017] Unless contradictory, "also" means "also or alternatively." Unless contradictory, "here" and "herein" mean "in this disclosure." The term "ia" means "inter alia" or "among other things." "Also known as" is abbreviated as "aka" or "AKA." "Elsewhere" means "elsewhere herein."

[0018] For brevity, symbols are used where necessary. For example, "&" is used for "and" and "~" is used for "about." Symbols such as < and > are given their ordinary meaning (e.g., "≦" means "less than or equal to" and "≧" means "greater than or equal to"). When clear from the context, a slash " / " can indicate "or" (e.g., "A / B" means "A or B") or specify synonyms of elements.

[0019] The inclusion of "(s)" after an element or step indicates that > ​​1 of such elements are present, > 1 of such steps are performed, and the like. For example, "element(s)" means both 1 element or > 2 elements, each of which is understood to be an independent aspect of the invention.

[0020] Use of the abbreviation "etc." (or "et cetera") in connection with a list of elements / steps means any or all suitable combinations of the listed elements / steps or known equivalents of any of such listed elements / steps to obtain the functions of such elements / steps that are known in the art. Terms such as "and combinations" or "or combinations" in connection with listed elements / steps mean any or all possible / suitable combinations of such elements / steps.

[0021] An embodiment may be described as suitable for use as disclosed herein. Unless inconsistent, terms such as "suitability" mean acceptable or suitable for performing a particular function / obtaining a particular condition / result, and typically mean effective, practical, and non-detrimental / harmful in the context in which the use is used. For example, unless inconsistent, the term "suitable" may mean suitable, acceptable, or sufficient in the context, or providing at least generally or substantially all of the intended function without causing or having a significant negative / adverse effect.

[0022] Unless inconsistent, headings (e.g., "Structure, Terms...") and subheadings are included for convenience and do not limit the scope of any aspect. Without conflict, any aspect, step, or element described under one heading may be applicable to other aspects or steps / elements herein.

[0023] Ranges of values ​​are used to express each value within a range that is within an order of magnitude of the smallest endpoint of the range without the need to explicitly write out each value in the range. For example, a range of 1 to 2 implicitly discloses each of 1.0, 1.1, 1.2, . . . 1.9, and 2.0, and a range of 10 to 100 implicitly discloses each of 10, 11, 12, . . . 98, 99, and 100. Unless inconsistent, all ranges include the endpoints of the range, regardless of how the range is stated. For example, "1 to 5" includes 1 and 5 in addition to 2, 3, and 4 (and all numbers between such numbers within an order of magnitude of such endpoints, e.g., 1.0, 1.1, . . . 4.9, and 5.0). For the avoidance of doubt, any number within a range is encompassed by the range, regardless of the order of magnitude of the number (e.g., a range of 2 to 20 encompasses 18.593).

[0024] Approximate terminology (e.g., "about," "~," or "approximately") may be used to (1) express a set of related values ​​or (2) where exact values ​​are difficult to determine (e.g., due to limitations in measurement). Unless contradictory, all exact values ​​defined herein also / implicitly disclose the corresponding approximate value, and vice versa (e.g., disclosure of "about 10" provides explicit support for the use of exactly 10 in such embodiment / description). Ranges recited with approximate values ​​are intended to be within the meaning of each approximate value, regardless of format. It includes all values ​​encompassed by its endpoints (e.g., "about 10 to 20" has the same meaning as "about 10 to about 20"). The range of values ​​encompassed by approximation terms will generally depend on the context of the disclosure, the relevance or operability, the statistical significance, and the understanding in the art. In the absence of guidance herein or in the art regarding the element, terms such as "about" when used in the context of an element should be construed as implicitly disclosing ±10% of the indicated value, as well as ±5%, ±2%, ±1%, and ±0.5%.

[0025] Lists of aspects, elements, steps, and features may be used for brevity. Unless otherwise indicated, each number in each list should be viewed as an independent aspect. Each aspect defined by any individual number in the list can, and often will, have non-obvious characteristics relative to aspects characterized by other numbers in the list.

[0026] Unless inconsistent, the terms "a" and "an" as well as "the" and similar referents encompass both the singular and plural of the referenced element, step, or aspect. Unless inconsistent, singular terms herein implicitly convey the plural, and vice versa (in other words, disclosure of an element / step implicitly discloses the corresponding use of such / similar elements / steps, and vice versa).

[0027] "Significant" and "significantly" mean a result / characteristic that is statistically significant in a given context using ≧1 approximate test / trial (e.g., p≦0.05 / 0.01). "Detectable" means measurably present / different using known detection tools / techniques. The acronym "DOS" (or "DoS") means "detectably or significantly."

[0028] Unless inconsistent, for any values ​​herein without a unit of measurement (e.g., weight of 50 or length of 20), the units previously provided for the same element / step or same type of element / step shall apply, or, in the absence of such disclosure, the units most commonly used in association with such element / step in the art shall apply.

[0029] Unless inconsistent, the terms "including," "containing," "comprising," and "having" mean "including, but not limited to" or "including, without limitation." Unless inconsistent, use of terms such as comprising and including, regardless of elements / steps, means including any detectable number or amount of the elements or including any detectable performance of the step / several steps (with or without other elements / steps).

[0030] Unless inconsistent, the term "one" means a singular type, a singular iteration / replica / thing of the described element or step, or both, as will be clear from the context. For example, the referent "one" used in a component of a composition represents one type of element (which may be present in multiple copies, in the case of a component in a composition), one unit of the element, or both. Similarly, "one" component, "single" component, or "only component" of a system typically refers to one type of element (which may be present in multiple copies), one instance / unit of the element, or both. Furthermore, "one" step of a method means performing one type of action (step), one iteration of the step, or both. Unless inconsistent, a disclosure of "one" element provides support for both, but unless inconsistent, any claim to any "one" element refers to one type of such element (e.g., a component of a composition / system).

[0031] The term "some" means that ≧2 copies / occasions or ≧5% / all of the listed collection are or consist of the element. In the context of a method, some indicates that ≧5% of the effect, outcome, or both consist of or are contributed to a step (e.g., "some of the method is performed by step Y") or that a step is performed ≧2 times (e.g., "step X is repeated several times"). "Predominately," "most," or "mostly" means detectably >50% (e.g., mostly comprises, predominately includes, etc. means >50%) (e.g., a system that mostly comprises element X includes >50% of element X).

[0032] Unless inconsistent, changes to the tense or form of a term (e.g., using "comprises predominately" instead of "predominately comprises") do not change the meaning of the corresponding term / phrase.

[0033] Unless inconsistent, all methods provided herein can be performed in any suitable order, regardless of format (e.g., a method including steps A, B, and C can be performed in the order C, B, and A; B and A and C simultaneously, etc.). Unless inconsistent, the elements of the composition can be assembled in any suitable manner by any suitable method. Generally, any methods and materials similar or equivalent to those described herein can be used in the practice of the embodiments. Unless inconsistent, the use of ordinal numbers such as "first," "second," "third," etc. is to identify each element rather than to indicate a particular order of those elements.

[0034] Unless otherwise stated, each embodiment and all variations thereof, or any other element, step, component, or feature, is within the scope of the invention.

[0035] Unless expressly indicated or clearly indicated by context, "improved" herein means "increased." In some embodiments, "improved" means "reduced," such as with respect to toxicity of the composition. Unless inconsistent, terms such as "enhanced," "improved," and the like, are used interchangeably.

[0036] All references cited herein (e.g., publications, patent applications, and patents) are incorporated herein by reference as if each reference was individually and in detail incorporated by reference and set forth in its entirety herein. Any appropriate principles, methods, or elements (collectively, "teachings") of such references may be combined with or adapted to the embodiments, unless inconsistent. However, the citation / incorporation of a patent document is limited to its technical disclosure and does not reflect any opinion as to its validity, patentability, or otherwise. In the event of any inconsistency between this disclosure and the teachings of such documents, the contents of the present disclosure shall control with respect to the embodiments of the present invention. Many references are cited herein to succinctly incorporate known information and to aid those of skill in the art in practicing the embodiments. While an effort has been made to include the most relevant references for such purpose, readers will understand that not all aspects of all cited documents may apply to all aspects of the present invention.

[0037] Further Terms, Concepts, and Acronyms The compositions and practices described herein are generally pharma- ceutically suitable. "Pharmaceutically suitable," "pharma- ceutically suitable," and the like, are phrases commonly used to describe compositions / formulations or practices that are safe and effective for pharmaceutical administration and application, particularly in the case of the eye, with sufficient potency, purity, strength, quality, and safety for pharmaceutical use, as may be determined by regulatory review and, for example, as established by one or more well-controlled and sufficient clinical studies conducted in accordance with generally prevailing regulatory compliance. Generally, "pharma-ceutically acceptable" materials describe materials that are suitable for use in contact with human and lower animal tissues without undue toxicity, irritation, allergic response, and the like, while maintaining a reasonable risk-benefit ratio, and being effective for these intended uses.

[0038] Unless inconsistent, terms such as "carrier" and "excipient" refer to any physiologically inert, pharmacologically inert material known to those of skill in the art that is compatible with the physical and chemical properties of the mexiletine compound, generally or the specific mexiletine or pharma- ceutically acceptable salt described in connection therewith as the active ingredient. Pharmaceutically acceptable excipients include polymers, resins, plasticizers, fillers, binders, lubricants, glidants, disintegrants, suspending agents, anti-agglomerating agents, solvents, co-solvents, buffer systems, surfactants, preservatives, sweeteners, flavorings, pharmaceutical grade dyes or pigments, and viscosity agents.

[0039] As used herein, terms such as "pharmaceutical composition," "formulation," and the like, when used to describe compositions generally described or referenced herein, include solid dosage forms such as granules, multi-unit particulate systems (MUPS), pellets, spheres, tablets, dispersible tablets, soft capsules, hard capsules, mini-tablets, beads, particles, and the like; and liquid dosage forms such as solutions, suspensions, emulsions, colloids, and the like, that are for enteral administration.

[0040] The excipients and active pharmaceutical ingredients (e.g., mexiletine) described in the embodiments herein are generally "effective" and present in "effective amounts," and unless inconsistent, the excipient or any described class of specific excipient is present in the relevant composition / formulation in an effective amount, which in this context generally means an amount that is effective for the described function associated with the excipient (it is understood that some excipient compounds / components may exhibit more than one effect).

[0041] Unless inconsistent, the term "standard" as used herein with respect to a technology or component / element not further described or exemplified means the standard applied by a major regulatory agency (e.g., US FDA, EU EMA, China NMPA Japan PMDA, Health Canada, India CDSCO, and the like) or the most commonly used in the art.

[0042] Unless inconsistent, any reference herein to a compound capable of forming a salt shall be construed as implicitly disclosing the compound and any or all suitable pharma- ceutically acceptable salts thereof. The term "pharma-ceutically acceptable salts" includes suitable salts prepared from pharma-ceutically acceptable bases or acids, including inorganic or organic bases and inorganic or organic acids. Examples of such salts that may be appropriate in the context include acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate, acid tartrate, borate, bromide, camsylate, carbonate, chloride, clavulanate, citrate, dihydrochloride, edetate, edisylate, estolate, esylate, fumarate, gluceptate, gluconate, glutamate, glycolyl arsenate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isothionate, lactate, lactobisulfate, lactobic acid ... Examples of salts derived from inorganic bases include, but are not limited to, aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic, manganous, potassium, sodium, and zinc salts.

[0043] Unless otherwise stated, the term "controlled release" refers to a composition in which the time course of drug appearance in the medium surrounding the composition is DOS modified, usually significantly modified, compared to other corresponding / related immediate release compositions. Unless otherwise stated, immediate release compositions exhibit detectable or significant release within minutes of administration, and usually achieve ≧85% of release within about 30 minutes of administration. Controlled release encompasses "delayed release" and "sustained release" formulations. Unless otherwise stated, the term "sustained release" refers to a composition characterized by having detectable or significant release over a period of at least about 24 hours.

[0044] As used herein, the term "wt. %" means percent by weight. As used herein, the term "wt. / wt." means the weight ratio of one component to another.

[0045] As used herein, the term "T1 or Test Product 1" refers to a product having composition 1 as described in the appropriate Examples. As used herein, the term "T2 or Test Product 2" refers to a product having composition 2 as described in the appropriate Examples. As used herein, the term "T3 or Test Product 3" refers to a product having composition 3 as described in the appropriate Examples.

[0046] Unless otherwise stated, "subject" means any vertebrate animal, but preferably is a mammal, such as, for example, a human.

[0047] "Relative bioavailability" can be understood as the ratio of the plasma or serum AUC of a control composition, as determined from a plot of plasma or serum drug concentration versus time measured for a composition or method of the present composition. 0~24 " can be understood as the area under the curve relating blood plasma concentration to time from 0 to 24 hours after administration, determined using the linear trapezoidal method and expressed in units of (ng·h / ml). The term "AUC 0~∞" can be understood as the area under the curve relating blood plasma concentration to time from 0 hours to infinity (∞) and is expressed in units of (ng·h / ml). The term "AUC 0~τ " can be understood as the area under the curve for blood plasma concentration versus time curve from time 0 to time τ over a dosing interval at steady state, where τ is the length of the dosing interval, and the AUC 0~τ is expressed in units of (ng·h / ml). max " can be understood as the maximum observed blood serum concentration or the maximum blood plasma concentration calculated or estimated from the concentration versus time curve, and is expressed in units of ng / ml. max " is C max occurs and is expressed in units of time (hours (h)). A term such as "single dose" may be understood to indicate that a human patient receives a single dose of a drug formulation and the drug plasma concentration does not reach steady state (e.g., 7.5 mL of the 80 mg / mL suspension described herein). "Steady state" may be understood to indicate that the blood serum concentration curve for a given drug does not shift substantially after repeated administration up to a dose of the formulation. The elimination rate coefficient "Kel" may be understood to describe the fraction of drug eliminated per unit of time or rate at which the plasma concentration decays during the elimination phase. The term "half-life (t 1 / 2 )" is 50%t 1 / 2 This can be understood to mean that the time required for the plasma concentration of the drug to decrease by depends on the rate constant (k). The term "food effect" refers to the difference in AUC, C, or C-value of an active substance when said substance or a formulation thereof, such as a tablet or capsule or suspension, is orally administered to a mammal, preferably a human, with food or in the fed state, compared to the same value when the same formulation is administered in the fasted state. max , and / or T max The food effect F can be understood to mean the relative difference between the fed -Y fasted ) / Y fasted where Y fed and Y fasted are the AUC and C in the fed and fasted states, respectively. max, or T max are the actual measured values.

[0048] The term "myotonia" may be generally understood to include myotonic dystrophy types 1 and 2, as well as dystrophic and / or non-dystrophic myotonic diseases. Examples of such myotonic diseases are provided, for example, in EMA, 2018. However, each such condition may be a specific embodiment to the exclusion of one, some, or all of the other such conditions. The present invention also includes methods of symptomatic treatment of myotonia in adult patients suffering from non-dystrophic and / or dystrophic myotonic diseases.

[0049] Unless inconsistent, "ion exchange resin" may be understood to mean either anionic or cationic ion exchange resin or both. Unless inconsistent, "drug ion exchange resin complex" may be understood to mean a drug-containing ion exchange resin particle where there is an ionic bond between the drug and the ion exchange resin particle. Unless inconsistent, "mexiletine ion exchange resin complex" means a complex formed by loading mexiletine or a pharma- ceutically acceptable salt thereof onto an ion exchange resin. Summary of the Invention

[0050] The following aspects and embodiments described and exemplified below are intended to be exemplary and illustrative and not limiting in scope.

[0051] In one aspect, the invention provides a pharmaceutical composition adapted for oral administration comprising a therapeutically effective amount of mexiletine or a pharma- ceutically acceptable salt thereof, and a release retarding agent, wherein the release retarding agent effectively controls the release of the mexiletine or pharma- ceutically acceptable salt thereof from the composition after administration to a human patient, such that a single dose of the composition administered daily releases the mexiletine or pharma- ceutically acceptable salt thereof from the composition at a rate that is effective to treat a statistically significant number of myotonia patients for a treatment period of at least about one month, such as at least about three months (e.g., at least about six, twelve, eighteen, twenty-four, thirty, or thirty-six months or more). In some embodiments, the invention provides methods of using such compositions to treat conditions such as myotonia, the methods comprising administering an effective amount of such compositions to a patient once a day for a period of at least one month, or such as about 3, 6, 9, 12, 18, 24, 30, or 36 months or more, the methods not comprising administering the composition to the patient more than once a day. In some embodiments, the methods and compositions are as effective as Nasmuscla, as described in the EMA, 2018 publication cited herein and in the Background, if not detectably or significantly more effective than a control drug such as a known commercial product. Such compositions are distinguishable from Nasmuscla, which is effective throughout the treatment period with only once-a-day administration. In some embodiments, the number of patients for whom the compositions of the invention are effective with only once-a-day administration is significantly greater than the number of patients treatable with once-a-day administration of Nasmuscla.

[0052] In some embodiments, each dose of the composition described in the preceding paragraph contains from about 100 mg to about 600 mg of mexiletine hydrochloride, such as from about 200 mg to about 600 mg of mexiletine hydrochloride (e.g., about 225 to 600 mg, about 250 to 600 mg, about 275 to 600 mg, about 300 to 600 mg, about 350 to 600 mg, about 400 to 600 mg, or about 450 to 600 mg, such as about 100 to 550 mg, about 100 to 500 mg, about 100 to 450 mg, about 100 to 400 mg, about 100 to 300 mg, or about 100 to 250 mg). In some embodiments, each dose of the composition comprises at least about 200 mg, 250 mg, or about 300 mg up to about 600 mg, 550 mg, 500 mg, 450 mg, 400 mg, or about 350 mg.

[0053] In an embodiment, the present invention provides a composition according to any of the preceding paragraphs of this section, comprising T max whether the median is about 5 hours to about 8 hours (e.g., about 5.5 hours to 7.5 hours, such as about 6 hours to 7 hours, about 5.75 hours to 6.75 hours, about 5.75 hours to 6.25 hours, or about 6 hours); 1 / 2 The compositions can be further characterized as having an average value of about 10 hours to about 13.5 hours (e.g., about 10.5-13 hours, about 11-12.5 hours, about 10.5-12.5 hours, about 11-12 hours, about 10.5-12 hours, about 11 hours, about 12 hours, about 11-13 hours, or about 11-13.5 hours); or as exhibiting both of such properties.

[0054] The present invention relates to a composition according to any of the preceding sentences of this section, wherein said composition is further characterized by at least one of the following pharmacokinetic profile characteristics after a single dose administration: max The mean value is approximately 700ng / mL to 1250ng / mL; AUC 0~24 The mean value is approximately 12000 ng·h / mL to approximately 17500 ng·h / mL; AUC 0~t is approximately 22,000 ng·h / mL to 24,250 ng·h / mL; and AUC 0~∞ is approximately 22,500 ng·hr / mL to 26,000 ng·hr / mL.

[0055] In a further aspect, the present invention provides a pharmaceutical composition comprising an effective amount of mexiletine or a pharma- ceutically acceptable salt thereof and an effective amount of a release retardant / retarding agent, said composition further (in combination with any other aspect of this section or the present disclosure) or alternatively (for any such aspect) exhibits at least one, such as at least two, such as three or more (e.g., 1-5, 2-5, 2-4, 2-3, 1-4, 1-3, 3, 4, 5, or all) of the following pharmacokinetic profile characteristics after a single dose: (a)T max The median time is about 5 hours to about 8 hours; (b)C max The average value is approximately 700ng / mL to 1250ng / mL; (c) AUC 0~24 The mean value is approximately 12000 ng·h / mL to approximately 17500 ng·h / mL; (d) AUC 0~t the mean value being approximately 22000 ng·h / mL–24500 ng·h / mL; (e) AUC 0~∞ The mean value is approximately 22,500 ng·h / mL to 26,000 ng·h / mL; and (f)T 1 / 2 The average value is approximately 10 hours to approximately 13.5 hours.

[0056] In some embodiments, the compositions of the invention, such as those described in any of the previous parts of this section, have a C max Increases in the mean, the AUC mean, or both are further shown.

[0057] In some embodiments, the compositions of the invention exhibit one, two, three, or more of any such pharmacokinetic profile characteristics, wherein the applicable pharmacokinetic profile characteristics are significantly or detectably different from the corresponding characteristics obtained by administration of 167 mg of Namuscla three times daily.

[0058] In some embodiments, compositions of the invention, such as those described in any of the preceding sentences of this section, exhibit a dissolution profile in an appropriate dissolution medium, such as those exemplified herein or others known in the art, where about 10%-40% of the mexiletine in the composition is released within 4 hours, about 30%-70% is released within about 12 hours, and greater than about 60%, 70%, or greater than about 80% of the mexiletine in the composition is released within 24 hours.

[0059] In some aspects, the invention provides orally administerable controlled-release once-daily liquid suspensions of mexiletine or a pharma- ceutically acceptable salt thereof that allow for rapid onset of long-term therapeutic effect or efficacy, for example, about 24 hours, while maintaining drug bioavailability (e.g., at least about 70% bioavailability, at least about 80% bioavailability, such as about 60%-95%, about 65%-90%, 65%-85%, 70%-90%, about 75%-90%, 70%-85%, or 75%-85% bioavailability, etc.), for the treatment of myotonia.

[0060] In some embodiments, the present invention discloses an oral controlled release once-daily pharmaceutical composition comprising mexiletine or a pharma- ceutically acceptable salt thereof, said pharmaceutical composition exhibiting a relative bioavailability of at least about 80% based on area under the plasma concentration curve (AUC) in human subjects under fasted and fed conditions compared to commercially available Namuscla® 167 mg immediate release capsules administered three times daily.

[0061] In some embodiments, the present invention provides an oral controlled release once-daily pharmaceutical composition comprising mexiletine or a pharma- ceutical acceptable salt thereof, the pharmaceutical composition being capable of increasing C under standard fed conditions as compared to standard fasting conditions. max and increased AUC.

[0062] In some embodiments, the present invention discloses an oral controlled release once-daily pharmaceutical composition according to any one or more of the previous aspects described in this section comprising about 150 mg to about 600 mg of mexiletine or a pharma- ceutically acceptable salt thereof (e.g., about 150 mg to 550 mg, 150 mg to 500 mg, 150 mg to 450 mg, 150 mg to 400 mg, 150 mg to 350 mg, 200 mg to 550 mg, 200 mg to 500 mg, 200 mg to 450 mg, 200 mg to 400 mg, 250 mg to 600 mg, 250 mg to 550 mg, 250 mg to 500 mg, 250 mg to 450 mg, 250 mg to 400 mg, 300 mg to 500 mg, 300 mg to 450 mg, or 300 mg to 400 mg of mexiletine or a pharma- ceutically acceptable salt thereof).

[0063] The present disclosure provides several different means to obtain formulations / compositions with such properties. One exemplary embodiment relates to an oral controlled release once-daily pharmaceutical composition comprising mexiletine or a pharma- ceutically acceptable salt thereof, a pharma- ceutically acceptable ion exchange resin, and a pharma- ceutically acceptable carrier, which exhibits one or more of the properties described in the previous paragraphs of this section.

[0064] Another aspect of the present invention relates to an oral controlled release once-daily pharmaceutical composition comprising mexiletine or a pharma- ceutically acceptable salt thereof, a pharma- ceutically acceptable ion exchange resin, and a pharma- ceutically acceptable carrier, said composition further comprising at least one release retardant.

[0065] Another aspect of the present invention relates to an oral controlled release once-daily pharmaceutical composition comprising an ion exchange resin having mexiletine or a pharma- ceutically acceptable salt thereof adsorbed thereon to provide a mexiletine ion exchange resin complex, said complex being further coated with at least one release retardant to enhance control of mexiletine release from the mexiletine ion exchange resin complex.

[0066] Another aspect of the present invention relates to a method for formulating an oral controlled release once-daily pharmaceutical composition of mexiletine or a pharma- ceutically acceptable salt thereof, the method comprising: (i) preparing a complex comprising mexiletine or a pharma- ceutically acceptable salt thereof, a pharma- ceutically acceptable ion exchange resin and one or more pharma- ceutically acceptable excipients; dissolving and / or dispersing a release retardant and one or more pharma- ceutically acceptable coating excipients in a suitable solvent to prepare a coating composition; and (iii) applying the coating composition onto the complex of mexiletine and ion exchange resin to obtain a controlled release once-daily composition of mexiletine or a pharma- ceutically acceptable salt thereof.

[0067] Another aspect of the invention relates to an oral controlled release once-daily pharmaceutical composition comprising mexiletine or a pharma- ceutically acceptable salt thereof in the form of a powder or granules which may be mixed with a suspension base to produce an orally administrable controlled release aqueous suspension.

[0068] Another aspect of the present invention relates to a method for formulating an oral controlled release once-daily liquid suspension composition of mexiletine or a pharma- ceutically acceptable salt thereof, the method comprising: (i) loading mexiletine or a pharmaceutical salt thereof onto a pharma- ceutically acceptable ion exchange resin to obtain a mexiletine ion exchange resin complex; (ii) coating the mexiletine ion exchange resin complex with a suitable release retardant; preferably a hydrophilic and / or hydrophobic release retardant polymer; and (iii) suspending the coated complex in a suspension base to obtain a controlled release liquid suspension of mexiletine.

[0069] Another aspect of the invention relates to a method for formulating a controlled release once-daily dry powder for a liquid suspension of mexiletine or a pharma- ceutically acceptable salt thereof, the method comprising the steps of: (i) loading mexiletine or a pharma- ceutically acceptable salt thereof onto a pharma- ceutically acceptable ion exchange resin to obtain a mexiletine ion exchange resin complex; (ii) coating the mexiletine ion exchange resin complex with a suitable release retarding agent; preferably a hydrophilic and / or hydrophobic release retarding polymer; and (iii) suspending the coated complex in a suspension base to obtain a dry powder of a controlled release composition that is resuspended with a suitable amount of water to obtain a controlled release liquid suspension of mexiletine.

[0070] Another aspect of the invention relates to a method for formulating a controlled release once-daily dry powder for a liquid suspension of mexiletine or a pharma- ceutically acceptable salt thereof, the method comprising the steps of: (i) loading mexiletine or a pharmaceutical salt thereof onto a pharma- ceutically acceptable ion exchange resin to obtain a mexiletine ion exchange resin complex; (ii) coating the mexiletine ion exchange resin complex with a suitable release retardant; preferably a combination of hydroxypropylmethylcellulose and ethylcellulose; and (iii) suspending the coated complex in a suspension base to obtain a dry powder of a controlled release composition that is resuspended with a suitable amount of water to obtain a controlled release liquid suspension of mexiletine.

[0071] Another aspect of the invention relates to a method for formulating a controlled release once-daily dry powder for a liquid suspension of mexiletine or a pharma- ceutically acceptable salt thereof, the method comprising the steps of: (i) loading mexiletine or a pharmaceutical salt thereof onto a pharma- ceutically acceptable ion exchange resin to form a resin complex; (ii) coating the mexiletine ion exchange resin complex with a suitable release retarding agent; preferably a hydrophilic and / or hydrophobic release retarding polymer; and (iii) suspending the coated complex in a suspension base, the suspension base comprising one or more suspending agents, one or more lubricants, one or more thickening agents, one or more diluents, one or more sweeteners, one or more flavoring agents, and one or more preservatives.

[0072] Another aspect of the present invention relates to an oral controlled release once-daily pharmaceutical composition comprising mexiletine or a pharma- ceutically acceptable salt thereof, a pharma- ceutically acceptable ion exchange resin, and one or more pharma- ceutically acceptable excipients selected from the group consisting of one or more hydrophilic and / or hydrophobic release retarding polymers, one or more plasticizers, one or more vehicles, one or more suspending agents, one or more lubricants, one or more thickening agents, one or more diluents, one or more sweeteners, one or more flavoring agents, and one or more preservatives.

[0073] Another aspect of the present invention relates to an oral controlled release once-daily pharmaceutical composition comprising mexiletine or a pharma- ceutically acceptable salt thereof, a pharma- ceutically acceptable ion exchange resin, and a pharma- ceutically acceptable carrier, wherein the ratio of said mexiletine to said ion exchange resin ranges from about 1:0.25 to about 1:10.

[0074] Another aspect of the present invention relates to an oral controlled release once-daily liquid pharmaceutical composition comprising mexiletine or a pharma- ceutically acceptable salt thereof, a pharma- ceutically acceptable ion exchange resin, and a pharma- ceutically acceptable release-retarding polymer, wherein at least about 30% to about 85% of the mexiletine is released in about 8 hours to about 24 hours in a USP Type IV apparatus having a flow rate of 8 ml / min with 6 gm glass beads in 0.1N HCl medium, pH 5.0 acetate buffer medium, and pH 6.8 phosphate buffer medium, respectively, at a temperature of 37° C.±0.5° C.

[0075] Further embodiments of the present compositions and methods and the like will become apparent from the following description and examples. As can be understood from the above and following description, each feature described herein, and each combination of two or more of such features, is included within the scope of the present disclosure, provided that the features included in such combinations are not mutually inconsistent. In addition, any feature or combination of features may be specifically excluded from any embodiment of the present invention. Further aspects and advantages of the present invention are described in the following specification, particularly when considered in conjunction with the accompanying examples. [Brief description of the drawings]

[0076] The drawings / figures provided herein, and the following brief description of any associated figures provided below, are intended to illustrate certain aspects and principles of the present invention without limiting its scope.

[0077] [Figure 1] FIG. 1 is a linear mean plot of mexiletine plasma concentration (ng / mL) versus time after administration (hours) for the reference product and two test products (Test Product 1 and Test Product 2) (each exemplary composition of the invention) described in the Examples.

[0078] [Diagram 2] FIG. 2 is a linear mean plot of plasma concentrations of mexiletine (ng / mL) versus time (hours) measured in a food effect study using exemplary compositions of the invention described in the Examples. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0079] The following is a non-limiting list of exemplary aspects of the present invention, illustrating embodiments of the present invention in a summary manner to help readers quickly grasp the full scope of the present invention. As with the claims, the listed aspects described in this section of this section may refer to (depend on / from) one or more other sections. Readers will understand that such reference means that the features / characteristics or steps of such referenced aspects are incorporated into / combined with the referenced aspects. For example, an aspect of a section (e.g., a section indicated by a sentence at the end of the section as Aspect 2) will be understood to include elements, steps, or characteristics of such referenced aspects (e.g., Aspect 1 or "any one of Aspects 1-3") in addition to those of the referenced aspects (e.g., when Aspect 2 refers to Aspect 1, providing a description of a composition, method, system, device, or other that includes features of both Aspect 1 and Aspect 2).

[0080] Summary listings describing certain exemplary embodiments of the invention may also be used to aid the reader in understanding the invention. Within these, such aspects may refer to other exemplary aspects, either individually or as groups of aspects (e.g., by reference to a range within the numbered list of aspects, if such aspects are provided as a numbered list). Reference to a range of aspects should be construed as referring to all such aspects, individually, each as a sole embodiment of the invention, and in combination with each other as sole embodiments of the invention, in accordance with the provided suggestions of such aspects, unless such aspects within such referenced range are inconsistent or insignificant. In case of inconsistency, the reference to the inconsistent aspect should be excluded.

[0081] A first set of exemplary embodiments are provided herein.

[0082] In some aspects, the invention provides a pharmaceutical composition formulated for oral administration comprising a therapeutically effective amount of mexiletine or a pharma- ceutically acceptable salt thereof, and an effective amount of a release retarding agent, which releases the mexiletine or pharma- ceutically acceptable salt thereof from the composition after administration to a human patient at a rate such that a single dose of the composition administered daily is effective to treat myotonia in a statistically significant number of myotonic patients over a treatment period of at least about three months (Aspect A).

[0083] In an embodiment, the present invention provides the composition of embodiment A, comprising about 100 mg to about 600 mg of mexiletine hydrochloride (embodiment B).

[0084] In some embodiments, the present invention provides a composition according to any one or both of Aspects A and B above, comprising about 200 mg to about 600 mg of mexiletine hydrochloride (Aspect C).

[0085] In some embodiments, the present invention provides a composition of any one or more of the above embodiments A through C, comprising T max The median is about 5 hours to about 8 hours, or t 1 / 2 A composition is provided that exhibits an average value of from about 10 hours to about 13.5 hours, or both (embodiment D).

[0086] In some embodiments, the present invention provides compositions of any one or more of the above embodiments A through D, further exhibiting at least one of the following pharmacokinetic profile characteristics after a single dose: max The mean value is approximately 700ng / mL to 1250ng / mL; AUC 0~24 The mean value is approximately 12000 ng·h / mL to approximately 17500 ng·h / mL; AUC 0~t The mean value was approximately 22,000 ng·h / mL to 24,250 ng·h / mL; and the AUC 0~∞ The average value is approximately 22,500 ng·hr / mL to 26,000 ng·hr / mL (mode E).

[0087] In some embodiments, the present invention provides compositions of any one or more of the above embodiments A through E, which exhibit at least two of the following pharmacokinetic profile characteristics after a single dose: max The median value is about 5 hours to about 8 hours; C max The mean value is approximately 700ng / mL to 1250ng / mL; AUC 0~24 The mean value is approximately 12000 ng·h / mL to approximately 17500 ng·h / mL; AUC 0~t The mean value was approximately 22000 ng·h / mL to 24250 ng·h / mL; AUC 0~∞ The mean value is approximately 22,500 ng·h / mL to 26,000 ng·h / mL; and t 1 / 2 The average value is about 10 hours to about 13.5 hours (mode F).

[0088] In some embodiments, the present invention provides a composition of any one or more of Aspects A-F, comprising: max Compositions are provided that exhibit an increase in the mean, the AUC mean, or both (embodiment G).

[0089] In some embodiments, the present invention provides compositions of any one or more of the above embodiments A through G, wherein the composition exhibits an in vitro dissolution profile characterized by: (a) When measured at 37°C ± 0.5°C in 0.1N HCl medium using a USP Type IV apparatus with 6 gm glass beads and a flow rate of 8 ml / min. (1) after 0 to 2 hours, about 0% to about 30% by weight of mexiletine is released from the composition, and after 0 to 4 hours, about 10% to about 40% by weight of mexiletine is released from the composition; (2) after 4 to 12 hours, about 30% to about 70% by weight of mexiletine is released from the composition; (3) greater than about 60% by weight of mexiletine is released from the composition in a period of 6 to 14 hours; and (4) greater than about 80% by weight of mexiletine is released from the composition within about 24 hours; (b) When measured at 37° C.±0.5° C. in a pH 5.0 acetate buffer medium using a USP Type IV apparatus with 6 gm glass beads and a flow rate of 8 ml / min. (1) after 0 to 2 hours, about 0% to about 25% by weight of mexiletine is released from the composition; (2) after 0 to 4 hours, about 10% to about 40% by weight of mexiletine is released from the composition; and (3) after 4 hours to 12 hours, about 30% by weight to about 100% by weight of mexiletine is released from the composition within about 24 hours; (c) When measured at 37° C.±0.5° C. in a pH 6.8 phosphate buffer medium using a USP Type IV apparatus with 6 gm glass beads and a flow rate of 8 ml / min. (1) after 0 to 2 hours, about 0% to about 35% by weight of mexiletine is released from the composition; (2) after 0 to 4 hours, about 10% to about 50% by weight of mexiletine is released from the composition; (3) after 4 to 12 hours, about 30% to about 100% by weight of mexiletine is released from the composition; (d) When measured in a United States Pharmacopeia (USP) Type II dissolution apparatus rotating at 75 rpm at a temperature of 37°C ± 0.5°C, (1) in 500 mL 0.1 N HCl, 50% or less by weight of mexiletine is released from the composition in the first hour; and (2) 65% or more by weight of mexiletine is released from the composition in 2 hours in 700 mL pH 4.5 acetate buffer exchange medium, and then further (3) 85% or more by weight of mexiletine is released from the composition in 4 hours in 900 mL pH 6.8 phosphate buffer exchange medium; or (e) Any combination of (a) to (d), or all combinations of (a) to (d) (Mode H) .

[0090] In some embodiments, the present invention provides a composition of any one or more of Aspects A through H, wherein a single oral administration of the composition: (1) reduces T in most human patients at about 5 to about 8 hours after administration; max and (2) in most human patients, 16 hours after administration of the composition, the plasma concentration of mexiletine is max The composition is provided in a form that is at least about 33% different from (embodiment I).

[0091] In some embodiments, the present invention provides a composition of any one or more of embodiments A through I, wherein the plasma concentration in most human patients receiving a single oral dose of the composition is greater than or equal to about C for at least about four hours. max The composition remains within about 20% of the above range (embodiment J).

[0092] In some embodiments, the invention provides compositions of any one or more of Embodiments A through J above, wherein in most human patients receiving a single oral dose of the compound, the plasma concentration of mexiletine at 3 hours post-dose, 4 hours post-dose, or both, differs by no more than about 25% from the plasma concentration of mexiletine at 18 hours post-dose, 20 hours post-dose, or both (Embodiment K).

[0093] In some embodiments, the present invention provides a pharmaceutical composition formulated for oral administration comprising a therapeutically effective amount of mexiletine or a pharma- ceutically acceptable salt thereof and an effective amount of a release retarding agent, the composition exhibiting at least one of the following pharmacokinetic profile characteristics after a single dose: max The median value is about 5 hours to about 8 hours; C max The mean value is approximately 700ng / mL to 1250ng / mL; AUC 0~24 The mean value is approximately 12000 ng·h / mL to approximately 17500 ng·h / mL; AUC 0~t The mean value was approximately 22000 ng·h / mL to 24250 ng·h / mL; AUC 0~∞The mean value is approximately 22,500 ng·h / mL to 26,000 ng·h / mL; and (f)t 1 / 2 The average value is about 10 hours to about 13.5 hours (mode L).

[0094] In an embodiment, the present invention provides a composition of embodiment L, comprising: 1 / 2 The average value is about 10 hours to about 13.5 hours, or T max The composition is provided such that the median time is from about 5 hours to about 8 hours, or both (embodiment M).

[0095] In some embodiments, the present invention provides a composition of any one or both of embodiment L or embodiment M, wherein the pharmaceutical composition has a C max Compositions are provided that exhibit an increase in the mean, the AUC mean, or both (embodiment N).

[0096] In some embodiments, the present invention provides the use of a composition according to any one of embodiments A to N above, wherein the use is for a pharmaceutical preparation for treating myotonia (embodiment O).

[0097] In some embodiments, the present invention provides a method for treating myotonia in a patient in need of treatment comprising administering to the myotonic patient once daily with food for a treatment period of at least three months an effective amount of a composition described in any one of embodiments A through O above, wherein the method treats myotonia in a statistically significant number of myotonic patients (embodiment P).

[0098] In an embodiment, the present invention provides a pharmaceutical composition for oral administration, comprising: (a) a therapeutically effective amount of mexiletine or a pharma- ceutical acceptable salt thereof; (b) a pharma- ceutically acceptable ion exchange resin and at least one or more pharma- ceutically acceptable excipients; (Embodiment Q) provides a composition comprising:

[0099] In an embodiment, the invention provides the composition of embodiment Q, wherein the ratio of mexiletine or a pharma- ceutically acceptable salt thereof to the pharma- ceutically acceptable ion exchange resin in the composition is from about 1:0.5 to about 1:5 (embodiment R).

[0100] In an embodiment, the invention provides a composition of either one or both of Aspect Q or Aspect R, wherein the mexiletine or a pharma- ceutically acceptable salt thereof and the ion exchange resin form a pharma- ceutically acceptable mexiletine resin complex, and the ion exchange resin is about 30% to about 85% of the mexiletine-resin complex on a weight / weight basis (Aspect S).

[0101] In some embodiments, the present invention provides pharmaceutical compositions of any one or more of embodiments Q through S, further comprising a suitable release retarding agent selected from a hydrophilic release retarding polymer, a hydrophobic release retarding polymer, and both (embodiment T).

[0102] In some embodiments, the present invention provides the composition of any one or more of embodiments Q through T, further comprising a suspension base selected from starch, a disaccharide, and both (embodiment U).

[0103] In some embodiments, the present invention provides one or more compositions of any of Aspects Q through U above, the composition comprising about 100 mg to about 600 mg of mexiletine hydrochloride (Aspect V).

[0104] In some embodiments, the present invention provides compositions of any one or more of the above embodiments Q through V, wherein the composition exhibits an in vitro dissolution profile characterized by: (a) When measured at 37° C.±0.5° C. in 0.1N HCl medium using a USP Type IV apparatus with 6 gm glass beads and a flow rate of 8 ml / min. (1) after 0 to 2 hours, about 0% to about 30% by weight of mexiletine is released from the composition, and after 0 to 4 hours, about 10% to about 40% by weight of mexiletine is released from the composition; (2) about 30% to about 70% by weight of mexiletine is released from the composition after 4 to 12 hours; (3) greater than about 60% by weight of mexiletine is released from the composition in 6 to 14 hours; and (4) greater than about 80% by weight of mexiletine is released from the composition within about 24 hours; (b) When measured at 37° C.±0.5° C. in a pH 5.0 acetate buffer medium using a USP Type IV apparatus with 6 gm glass beads and a flow rate of 8 ml / min. (1) from about 0% to about 25% by weight of mexiletine is released from the composition after 0 to 2 hours; (2) about 10% to about 40% by weight of mexiletine is released from the composition after 0 to 4 hours; and (3) after 4 hours to 12 hours, about 30% by weight to about 100% by weight of mexiletine is released from the composition within about 24 hours; (c) When measured at 37° C.±0.5° C. in a pH 6.8 phosphate buffer medium using a USP Type IV apparatus with 6 gm glass beads and a flow rate of 8 ml / min. (1) from about 0% to about 35% by weight of mexiletine is released from the composition after 0 to 2 hours; (2) about 10% to about 50% by weight of mexiletine is released from the composition after 0 to 4 hours; (3) about 30% by weight to about 100% by weight of mexiletine is released from the composition after 4 hours to 12 hours. (d) When measured in a United States Pharmacopeia (USP) Type II dissolution apparatus rotating at 75 rpm at a temperature of 37°C ± 0.5°C, (1) 50% or less mexiletine is released by weight in 500 mL of 0.1 N HCl in the first hour, and then (2) 65% or more by weight of mexiletine is released from the composition in 2 hours in 700 mL pH 4.5 acetate buffer exchange medium, and then further (3) 85% or more by weight of mexiletine is released from the composition in 900 mL pH 6.8 phosphate buffer exchange medium in 4 hours; or (e) Any combination of (a) to (d), or all combinations of (a) to (d) (Mode W) .

[0105] In some embodiments, the present invention provides a composition of any one or more of Aspects Q through W, wherein a single oral administration of the composition: (1) reduces T max and (2) in most human patients, 18 hours after administration of the composition, the plasma concentration of mexiletine is max is at least about 33% different from (embodiment X).

[0106] In some embodiments, the present invention provides a composition of any one or more of embodiments Q through X, wherein the plasma concentration in most human patients receiving a single oral dose of the composition is greater than or equal to C for at least about 4 hours. max The composition is provided such that the difference from remains within about 20% (embodiment Y).

[0107] In some embodiments, the invention provides compositions of any one or more of Aspects Q through Y above, wherein in most human patients receiving a single oral dose of the compound, the plasma concentration of mexiletine at 3 hours post-dose, 4 hours post-dose, or both, differs by no more than about 25% from the plasma concentration of mexiletine at 18 hours post-dose, 20 hours post-dose, or both (Aspect Z).

[0108] In some embodiments, the present invention provides compositions of any one or more of the above embodiments Q through Z, which exhibit at least one of the following pharmacokinetic profile characteristics after a single dose: maxThe median value is about 5 hours to about 8 hours; C max The mean value is approximately 700ng / mL to 1250ng / mL; AUC 0~24 The mean value is approximately 12000 ng·h / mL to approximately 17500 ng·h / mL; AUC 0~t The mean value was approximately 22000 ng·h / mL to 24250 ng·h / mL; AUC 0~∞ The mean value is approximately 22,500 ng·h / mL to 26,000 ng·h / mL; and t 1 / 2 The average value is about 10 hours to about 13.5 hours (mode AA).

[0109] In some embodiments, the present invention provides a composition of any one or more of the above embodiments Q through AA, comprising: max Compositions are provided that exhibit an increase in the mean, the AUC mean, or both (embodiment AB).

[0110] In some embodiments, the present invention provides the use of a composition according to any one of embodiments Q to AB above for the preparation of a pharmaceutical agent for treating myotonia (embodiment AC).

[0111] In some embodiments, the present invention provides a method of treating myotonia in a patient in need of such treatment comprising administering to the patient once or twice daily with food an effective amount of a composition described in any one of embodiments Q through AC above at a frequency appropriate to treat one or more conditions or symptoms of myotonia in the patient (embodiment AD).

[0112] A second set of exemplary embodiments is provided herein.

[0113] In some embodiments, the present invention provides a pharmaceutical composition comprising: (a) a therapeutically effective amount of a pharma- ceutically acceptable salt of mexiletine; and (b) a pharma- ceutically acceptable ion exchange resin, wherein the pharma- ceutically acceptable salt of mexiletine forms a pharma- ceutically acceptable drug-resin complex with the ion exchange resin (Embodiment 1).

[0114] In an embodiment, the present invention provides the pharmaceutical composition of Embodiment 1, further comprising (c) an effective amount of a suitable release retarding agent comprising an effective amount of a hydrophilic release retarding polymer, a hydrophobic release retarding polymer, or both, which coats at least some of the drug-resin complexes to form coated complex particles and detectably delays the release of mexiletine from the coated complex particles (Embodiment 2).

[0115] In some embodiments, the present invention provides the composition of any one or both of Embodiments 1-2, further comprising a suspension base in which the coated composite particles are suspended to form a controlled release liquid suspension of mexiletine (Embodiment 3).

[0116] In some embodiments, the invention provides compositions comprising any one or more of Aspects 1-3, wherein the ratio of the pharma- ceutically acceptable salt of mexiletine to the pharma- ceutically acceptable cation exchange resin in the composition is about 1:0.5 to 1:5 (Aspect 4).

[0117] In an embodiment, the invention provides a composition of any one or more of embodiments 1-4, wherein the cation exchange resin comprises at least a majority of material having a pKa of about −1.5 or less (embodiment 5).

[0118] In an embodiment, the invention provides a composition according to any one or more of embodiments 1-5, wherein at least about all of the cation exchange resin comprises sulfonate groups (embodiment 6).

[0119] In an embodiment, the invention provides a composition according to any one or more of embodiments 1-6, wherein at least substantially all of the cation exchange resin comprises a polystyrene component (embodiment 7).

[0120] In some embodiments, the present invention provides a composition comprising any one or more of embodiments 1 through 7, wherein the cation exchange resin comprises about 30% to about 85% of the drug-resin complex on a weight / weight basis (embodiment 8).

[0121] In an embodiment, the invention provides a composition according to any one or more of embodiments 1-8, wherein at least substantially all of the cation exchange resin comprises sodium polystyrene sulfonate (embodiment 9).

[0122] In some embodiments, the invention provides compositions comprising any one or more of embodiments 1 through 9, wherein the mexiletine salt comprises about 15% to about 70% of the drug-resin complex on a weight / weight basis (embodiment 10).

[0123] In some embodiments, the invention provides a composition of any one or more of Embodiments 1-10, wherein the release retarding agent includes at least two different coatings, at least one coating most often including a polymer composition different from at least one other coating of the release retarding agent (Embodiment 11).

[0124] In an embodiment, the invention provides a composition of any one or more of embodiments 1-11, wherein the release retarding agent comprises a first coating comprising at least a majority of a hydrophilic polymer (embodiment 12).

[0125] In an embodiment, the invention provides the composition of any one or more of Embodiments 1-12, wherein the release retardant comprises a second coating comprising at least a majority of a hydrophobic polymer (Embodiment 13).

[0126] In an embodiment, the invention provides a composition of any one or more of Embodiments 1-13, wherein (a) the release retarding agent comprises a first coating comprising at least a majority of a hydrophilic polymer, and (b) the release retarding agent comprises a second coating comprising at least a majority of a hydrophobic polymer (Embodiment 14).

[0127] In an embodiment, the present invention provides a composition comprising any one or more of embodiments 1-14, wherein the second coating comprises a mixture of a hydrophobic polymer and a hydrophilic polymer (embodiment 15).

[0128] In an embodiment, the invention provides a composition according to any one or more of embodiments 1 through 15, wherein the hydrophilic polymer comprises, at least in majority, a hydrophilic cellulose polymer (embodiment 16).

[0129] In an embodiment, the invention provides the composition of any one or more of embodiments 1-16, wherein the hydrophilic cellulose polymer comprises, at least in majority, hydroxypropyl methylcellulose (HPMC) (embodiment 17).

[0130] In an embodiment, the invention provides the composition of any one or more of embodiments 1-17, wherein the hydrophobic polymer comprises at least a majority of a hydrophobic cellulose polymer (embodiment 18).

[0131] In an embodiment, the invention provides the composition of any one or more of Embodiments 1 through 18, wherein the hydrophobic cellulose polymer comprises, at least in majority, ethyl cellulose (Embodiment 19).

[0132] In an embodiment, the invention provides a composition comprising any one or more of the compositions of Embodiments 1-19, wherein the mixture comprises a majority of ethyl cellulose and further comprises HPMC (Embodiment 20).

[0133] In an embodiment, the invention provides a composition comprising any one or more of embodiments 1 through 20, wherein the ratio of ethylcellulose to HPMC is from about 3:1 to about 8:1, such as from 4:1 to 6:1 (e.g., about 5:1) (embodiment 21).

[0134] In some embodiments, the present invention provides a composition comprising any one or more of embodiments 1 through 21, wherein the drug-resin complex comprises about 30%-50% of the composition on a weight / weight basis (embodiment 22).

[0135] In an embodiment, the present invention provides a composition comprising any one or more of Aspects 1 to 22, wherein the suspension base comprises starch, comprising about 5% to 15% of the composition on a weight / weight basis (Aspect 23).

[0136] In some embodiments, the present invention provides a composition comprising any one or more of Aspects 1 to 23, wherein the suspension base comprises a disaccharide, the disaccharide comprising about 7.5% to 15% of the composition on a weight / weight basis (Aspect 24).

[0137] In an embodiment, the invention provides the composition of any one or more of embodiments 1-24, wherein the disaccharide comprises a mixture of sucrose and sucralose (embodiment 25).

[0138] In an embodiment, the invention provides a composition of any one or more of Aspects 1 through 25, wherein the suspension base comprises a thickening agent that comprises at least about 3% of the composition on a weight / weight basis, such as about 2.5% to 7.5% (e.g., about 5%) (Aspect 26).

[0139] In an embodiment, the invention provides the composition of any one or more of embodiments 1-26, wherein the thickener comprises, at least in majority, hydroxypropyl methylcellulose (HPC) (embodiment 27).

[0140] In some embodiments, the invention provides a composition of any one or more of embodiments 1 through 27, wherein the composition is adapted for oral administration (embodiment 28).

[0141] In some embodiments, the present invention provides the composition of any one or more of embodiments 1 through 28, wherein the composition is in the form of a capsule (embodiment 29).

[0142] In some embodiments, the present invention provides the composition of any one or more of embodiments 1 through 29, wherein the composition is in the form of a tablet (embodiment 30).

[0143] In some embodiments, the present invention provides a composition comprising any one or more of the compositions of embodiments 1 to 30, the drug-resin complex having a concentration of about 50 mg / mL to about 100 mg / mL (embodiment 31).

[0144] In some embodiments, the present invention provides a composition comprising any one or more of the compositions of embodiments 1 through 31, the composition being in a unit dosage form for a single administration to a patient (embodiment 32).

[0145] In some embodiments, the invention provides a composition comprising any one or more of the compositions of embodiments 1 through 32 in an amount expected to be effective as a once-daily treatment for myotonia (embodiment 33).

[0146] In some embodiments, the present invention provides one or more compositions of any one of embodiments 1 through 33 above, the composition comprising about 100 mg to about 600 mg of mexiletine hydrochloride (embodiment 34).

[0147] In some embodiments, the invention provides one or more compositions of any one of embodiments 1 through 34 above, the composition comprising about 100 mg to 400 mg of mexiletine hydrochloride (embodiment 35).

[0148] In an embodiment, the present invention relates to one or more compositions according to any one of embodiments 1 to 35, When measured using a USP Type IV apparatus with a flow rate of 8 ml / min with 6 gm glass beads in 0.1 N HCl medium at 37°C ± 0.5°C, After 0 to 2 hours, about 0% to about 30% by weight of mexiletine is released, After 0 to 4 hours, about 10% to about 40% by weight of mexiletine is released, After 4 to 12 hours, about 30% to about 70% by weight of mexiletine is released. Over 60% of mexiletine is released by weight in 6 to 14 hours. A composition is provided that exhibits an in vitro dissolution profile such that greater than about 80% by weight of mexiletine is released within 24 hours (embodiment 36).

[0149] In an embodiment, the present invention relates to one or more compositions according to any one of the preceding embodiments 1 to 36, When measured using a USP Type IV apparatus with a flow rate of 8 ml / min with 6 gm glass beads in a pH 5.0 acetate buffer medium at 37°C ± 0.5°C: After 0 to 2 hours, about 0% to about 25% by weight of mexiletine is released; After 0 to 4 hours, about 10% to about 40% by weight of mexiletine is released, Compositions are provided that exhibit an in vitro dissolution profile such that about 30% to about 65% or more than 65% by weight of mexiletine is released after 4 hours to 12 hours (embodiment 37).

[0150] In an embodiment, the present invention relates to one or more compositions according to any one of embodiments 1 to 37, When measured using a USP Type IV apparatus with a flow rate of 8 ml / min with 6 gm glass beads in a pH 6.8 phosphate buffer medium at 37°C ± 0.5°C: After 0 to 2 hours, about 0% to about 35% by weight of mexiletine is released; After 0 to 4 hours, about 10% to about 50% by weight of mexiletine is released, Compositions are provided that exhibit an in vitro dissolution profile such that about 30% to about 75% or more than 75% by weight of mexiletine is released after 4 hours to 12 hours (embodiment 38).

[0151] In an embodiment, the invention provides a composition comprising one or more of any of Embodiments 1-38 above, wherein 50% or less by weight of mexiletine is released from the composition in 500 mL 0.1 N HCl over the first hour, then 65% or more by weight of mexiletine is released from the composition in 700 mL pH 4.5 acetate buffer exchange medium over 2 hours, and then 85% or more by weight of mexiletine is released from the composition in 900 mL pH 6.8 phosphate buffer exchange medium over 4 hours, as measured in a United States Pharmacopeia (USP) Type II dissolution apparatus rotating at 75 rpm at a temperature of 37° C.±0.5° C. (Embodiment 39).

[0152] In some embodiments, the present invention provides a composition comprising one or more of any of the compositions of embodiments 1 through 39, wherein a single oral administration of the composition: (1) reduces T in most human patients by about 5 to about 8 hours after administration; max and (2) in most human patients, 18 hours after administration, the plasma concentration of mexiletine is max The difference from the max (Embodiment 40) provides a composition, wherein the difference from

[0153] In some embodiments, the present invention provides a composition of any one or more of embodiments 1 through 40, wherein in most human patients receiving a single oral dose of the composition, the plasma concentration is greater than or equal to C for at least about 4 hours. max The composition has a variation of within about 20% from (embodiment 41).

[0154] In some embodiments, the present invention provides a composition of any one or more of embodiments 1-41, wherein in most human patients receiving a single oral dose of the composition, the plasma concentration is greater than or equal to C for at least about 4 hours. max The composition has a variation of within about 15% from (embodiment 42).

[0155] In some embodiments, the present invention provides a composition of any one or more of embodiments 1-42, wherein in most human patients receiving a single oral dose of the composition, the plasma concentration is greater than or equal to C for at least about 4 hours. max The composition has a variation of within about 10% from (embodiment 43).

[0156] In some embodiments, the present invention provides a composition of any one or more of embodiments 1 through 43, wherein in most human patients receiving a single oral dose of the composition, the plasma concentration is greater than or equal to C for at least about 5 hours. max The composition has a variation of within about 20% from (embodiment 44).

[0157] In some embodiments, the present invention provides a composition of any one or more of embodiments 1 through 44, wherein in most human patients receiving a single oral dose of the composition, the plasma concentration is greater than or equal to C for at least about 5 hours. max The composition has a variation of within about 15% from (embodiment 45).

[0158] In some embodiments, the present invention provides a composition of any one or more of embodiments 1 through 45, wherein in most human patients receiving a single oral dose of the composition, the plasma concentration is greater than or equal to C for at least about 5 hours. max The composition has a variation of within about 10% from (embodiment 46).

[0159] In some embodiments, the present invention provides a composition of any one or more of embodiments 1 through 46, wherein in most human patients receiving a single oral dose of the composition, the plasma concentration is greater than or equal to C for at least about 6 hours. max The composition has a variation of within about 20% from (embodiment 47).

[0160] In some embodiments, the present invention provides a composition of any one or more of embodiments 1 through 47, wherein in most human patients receiving a single oral dose of the composition, the plasma concentration is greater than or equal to C for at least about 6 hours. maxThe composition has a variation of within about 15% from (embodiment 48).

[0161] In some embodiments, the present invention provides a composition of any one or more of embodiments 1 through 48, wherein in most human patients receiving a single oral dose of the composition, the plasma concentration is greater than or equal to C for at least about 6 hours. max The composition has a variation of within about 10% from (embodiment 49).

[0162] In some embodiments, the invention provides compositions comprising any one or more of Embodiments 1 through 49 above, wherein in most human patients receiving a single oral dose of the compound, the plasma concentration of mexiletine at either 3 hours post-administration, 4 hours post-administration, or both, differs by no more than about 25% from the plasma concentration of mexiletine at 18 hours post-administration, 20 hours post-administration, or both (Embodiment 50).

[0163] In some embodiments, the present invention relates to a composition of any one or more of the above embodiments 1 through 50, wherein the composition exhibits at least one of the following pharmacokinetic profile characteristics: (g) a single-dose median Tmax of about 5 hours to about 8 hours; (h) Single Dose C max an average value of about 700 ng / mL to 1250 ng / mL, such as about 700 ng / mL to 1200 ng / mL or 725 ng / mL to 1200 ng / mL, for example, 763.2237 ng / mL to about 1162.5969 ng / mL; (i) Single-dose AUC 0~24 the mean value is about 12500 ng·h / mL, such as 16250 ng·h / mL (e.g., 16323.9271 ng·h / mL), 12750 ng·h / mL (e.g., 12826.7066 ng·h / mL) to about 16000 ng·h / mL; (j) Single-dose AUC 0~tthe mean value is between about 21000 ng·h / mL and 25000 ng·h / mL, such as between about 22000 ng·h / mL and 24000 ng·h / mL (e.g., between about 22301.7312 ng·h / mL and about 23909.8110 ng·h / mL); (k) Single-dose AUC 0~∞ a mean value between 22500 ng·h / mL and 26000 ng·h / mL, such as between about 23000 ng·h / mL and 25000 ng·h / mL (e.g., between about 23345.7516 ng·h / mL and about 25363.6969 ng·h / mL); and (l) Single dose 1 / 2 The average value is about 10 hours to about 13.5 hours (Aspect 51).

[0164] In some embodiments, the present invention provides a composition comprising any one or more of the compositions of embodiments 1 through 51, comprising a single dose of t 1 / 2 The composition has an average value of about 10 hours to about 13.5 hours (embodiment 52).

[0165] In some embodiments, the present invention provides a composition comprising any one or more of the compositions of embodiments 1 to 52, comprising a single dose of T max The composition has a median duration of about 5 hours to about 8 hours (embodiment 53).

[0166] In some embodiments, the present invention provides a composition comprising any one or more of the compositions of embodiments 1 to 53, comprising a single dose of T max The composition has a median duration of about 6 hours or more (embodiment 54).

[0167] In some embodiments, the present invention provides a composition of any one or more of embodiments 1 to 54, comprising a single dose of C max The composition is provided wherein the average value is about 700 ng / mL or greater (e.g., about 750 ng / mL or greater, such as about 763.2237 ng / mL or greater) (embodiment 55).

[0168] In some embodiments, the present invention provides a composition comprising any one or more of the above embodiments 1 through 55, comprising a single-dose AUC 0~24A composition is provided in which the average value is about 12000 ng·hr / mL to 13500 ng·hr / mL (e.g., about 12500 ng·hr / mL to 13000 ng·hr / mL, such as about 12826.7066 ng·hr / mL) (embodiment 56).

[0169] In some embodiments, the present invention provides a composition comprising any one or more of the above embodiments 1 through 55, comprising a single-dose AUC 0~t A composition is provided in which the average value is about 21500 ng·hr / mL to 24000 ng·hr / mL (e.g., about 22000 ng·hr / mL to 23000 ng·hr / mL, such as about 22301.7312 ng·hr / mL) (embodiment 57).

[0170] In some embodiments, the present invention provides a composition comprising any one or more of the above embodiments 1 through 55, comprising a single-dose AUC 0~∞ A composition is provided in which the average value is about 22,500 ng·hr / mL to 24,000 ng·hr / mL (e.g., about 23,000 ng·hr / mL to 23,500 ng·hr / mL, such as about 23,345.7516 ng·hr / mL) (embodiment 58).

[0171] In some embodiments, the present invention provides a composition comprising any one or more of the compositions of embodiments 1 through 58, comprising a single dose of t 1 / 2 The composition is provided wherein the average value is about 12 hours or greater (embodiment 59).

[0172] In some embodiments, the present invention provides a composition comprising any one or more of the compositions of embodiments 1 to 59, comprising a C max Compositions are provided that exhibit a detectable or significant increase in the mean, the AUC mean, or both (embodiment 60).

[0173] In some embodiments, the present invention provides a composition comprising any one or more of the compositions of embodiments 1 through 60, comprising an AUC 0~∞ The composition has a fed / fasted ratio average of:

[0174] In an embodiment, the present invention provides a composition of any one or more of the above embodiments 1 through 61, comprising a C of about 1.25 or greater. max The composition has a mean fed / fasted ratio of:

[0175] In an embodiment, the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of mexiletine or a pharma- ceutical acceptable salt thereof and a release retarding agent, the composition having a therapeutically effective amount of mexiletine or a pharma- ceutical acceptable salt thereof, the release retarding agent being capable of releasing a therapeutically effective amount of mexiletine or a pharma- ceutical ... After 0 to 2 hours, about 0% to about 30% by weight of mexiletine is released, After 0 to 4 hours, about 10% to about 40% by weight of mexiletine is released, After 4 to 12 hours, about 30% to about 70% by weight of mexiletine is released. After 6 to 14 hours, more than 60% by weight of mexiletine is released. A composition is provided that exhibits an in vitro dissolution profile such that greater than about 80% by weight of mexiletine is released by 24 hours (embodiment 63).

[0176] In an embodiment, the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of mexiletine or a pharma- ceutical acceptable salt thereof and a release retarding agent, the composition having a release rate of 8 ml / min, as measured using a USP Type IV apparatus with 6 gm glass beads in a pH 5.0 acetate buffer medium at 37° C.±0.5° C. After 0 to 2 hours, about 0% to about 25% by weight of mexiletine is released; After 0 to 4 hours, about 10% to about 40% by weight of mexiletine is released, Compositions are provided that exhibit an in vitro dissolution profile such that about 30% to about 65% or more than 65% by weight of mexiletine is released after 4 hours to 12 hours (embodiment 64).

[0177] In an embodiment, the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of mexiletine or a pharma- ceutical acceptable salt thereof and a release retarding agent, the composition having a release rate of 8 ml / min, as measured using a USP Type IV apparatus with 6 gm glass beads in a pH 6.8 phosphate buffer medium at 37° C.±0.5° C. After 0 to 2 hours, about 0% to about 35% by weight of mexiletine is released; After 0 to 4 hours, about 10% to about 50% by weight of mexiletine is released, Compositions are provided that exhibit an in vitro dissolution profile such that about 30% to about 75% or more than 75% by weight of mexiletine is released after 4 hours to 12 hours (embodiment 65).

[0178] In an embodiment, the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of mexiletine or a pharma- ceutically acceptable salt thereof and a release retarding agent, wherein, when measured in a United States Pharmacopeia (USP) Type II dissolution apparatus rotating at 75 rpm at a temperature of 37° C.±0.5° C., 50% or less by weight of the mexiletine is released from the composition in 500 mL 0.1 N HCl over the first hour, then 65% or more by weight of the mexiletine is released from the composition in 2 hours in 700 mL pH 4.5 acetate buffer exchange medium, and then 85% or more by weight of the mexiletine is released from the composition in 4 hours in 900 mL pH 6.8 phosphate buffer exchange medium (Embodiment 66).

[0179] In an embodiment, the invention provides a composition according to any one or more of the above embodiments 1 through 66, wherein the retarder comprises a pharma- ceutically acceptable ion exchange resin (Embodiment 67).

[0180] In an embodiment, the invention provides the composition of any one or more of the above embodiments 1 through 68, wherein the ion exchange resin is a cation exchange resin (embodiment 68).

[0181] In an embodiment, the invention provides the composition of any one or more of embodiments 1 through 68, wherein the cation exchange resin comprises at least a majority of material having a pKa of about −1.5 or less (embodiment 69).

[0182] In an embodiment, the invention provides the composition of any one or more of Embodiments 1 through 69, wherein at least about all of the cation exchange resin comprises sulfonate groups (Embodiment 70).

[0183] In an embodiment, the invention provides the composition of any one or more of embodiments 1 through 70, wherein at least substantially all of the cation exchange resin comprises a polystyrene component (embodiment 71).

[0184] In some embodiments, the invention provides a composition comprising any one or more of embodiments 1 through 71, wherein the cation exchange resin comprises about 30% to about 85% of the drug-resin complex on a weight / weight basis (embodiment 72).

[0185] In an embodiment, the invention provides the composition of any one or more of Embodiments 1 through 72, wherein at least substantially all of the cation exchange resin comprises sodium polystyrene sulfonate (Embodiment 73).

[0186] In an embodiment, the invention provides a composition of any one or more of Aspects 1 through 73, wherein the ion exchange resin is present in an amount such that the mexiletine and ion exchange resin are present in a ratio of about 1:0.5 to about 1:5 (Aspect 74).

[0187] In some embodiments, the invention provides compositions according to any one or more of embodiments 1 through 74, wherein the mexiletine is present as a pharma- ceutically acceptable salt of mexiletine (embodiment 75).

[0188] In some embodiments, the invention provides compositions comprising any one or more of embodiments 1 through 75, wherein the pharma- ceutically acceptable salt of mexiletine and the ion exchange resin form a pharma- ceutically acceptable drug-resin complex (embodiment 76).

[0189] In an embodiment, the invention provides a composition of any one or more of Embodiments 1 through 76, wherein the retarding agent comprises a hydrophilic release retarding polymer, a hydrophobic release retarding polymer, or both, which produces a coated composite particle comprising a drug-resin complex and provides a detectable delayed release of mexiletine from the coated composite particle (Embodiment 77).

[0190] In some embodiments, the invention provides compositions of any one or more of embodiments 1 through 77, wherein the composition comprises a pharmaceutical excipient in an amount effective to detectably alter one or more properties of the composition other than the pharmaceutical activity of the composition (embodiment 78).

[0191] In some embodiments, the invention provides a composition of any one or more of embodiments 1 to 78, wherein the property associated with the pharmaceutical excipient comprises taste of the formulation, stability of the formulation, viscosity of the formulation, or a combination of any or all thereof (embodiment 79).

[0192] In some embodiments, the invention provides the composition of any one or more of embodiments 1 through 79, further comprising a suspension base in which the coated composite particles are suspended to form a controlled release liquid suspension of mexiletine (embodiment 80).

[0193] In some embodiments, the invention provides compositions comprising any one or more of embodiments 1 through 80, wherein the mexiletine comprises about 15% to about 70% of the drug-resin complex of the composition on a weight / weight basis (embodiment 81).

[0194] In some embodiments, the invention provides a composition of any one or more of embodiments 1 through 81, wherein the release retarding agent includes at least two different coatings, at least one coating most often including a polymer composition different from at least one other coating of the release retarding agent (embodiment 82).

[0195] In an embodiment, the invention provides a composition of any one or more of embodiments 1 through 82, wherein the release retardant comprises a first coating comprising at least a majority of a hydrophilic polymer (embodiment 83).

[0196] In an embodiment, the invention provides the composition of any one or more of embodiments 1 through 83, wherein the release retardant comprises a second coating comprising at least a majority of a hydrophobic polymer (embodiment 84).

[0197] In an embodiment, the invention provides a composition of any one or more of Embodiments 1 to 84, wherein (a) the release retarding agent comprises a first coating comprising at least a majority of a hydrophilic polymer, and (b) the release retarding agent comprises a second coating comprising at least a majority of a hydrophobic polymer (Embodiment 85).

[0198] In an embodiment, the invention provides a composition comprising any one or more of embodiments 1 through 85, wherein the second coating comprises a mixture of a hydrophobic polymer and a hydrophilic polymer (embodiment 86).

[0199] In an embodiment, the invention provides the composition of any one or more of embodiments 1 through 86, wherein the hydrophilic polymer comprises, at least in majority, a hydrophilic cellulose polymer (embodiment 87).

[0200] In an embodiment, the invention provides the composition of any one or more of embodiments 1 through 87, wherein the hydrophilic cellulose polymer comprises, at least in majority, hydroxypropyl methylcellulose (HPMC) (embodiment 88).

[0201] In an embodiment, the invention provides the composition of any one or more of embodiments 1 through 88, wherein the hydrophobic polymer comprises at least a majority of a hydrophobic cellulose polymer (embodiment 89).

[0202] In an embodiment, the invention provides the composition of any one or more of embodiments 1 through 89, wherein the hydrophobic cellulose polymer comprises, at least in majority, ethyl cellulose (embodiment 90).

[0203] In an embodiment, the invention provides the composition of any one or more of Embodiments 1 through 90, wherein the second coating comprises a mixture comprising a majority of ethyl cellulose and further comprising HPMC (Embodiment 91).

[0204] In an embodiment, the invention provides a composition comprising any one or more of embodiments 1 through 91, wherein the ratio of ethylcellulose to HPMC is from about 3:1 to about 8:1, such as from 4:1 to 6:1 (e.g., about 5:1) (embodiment 92).

[0205] In some embodiments, the present invention provides a composition comprising any one or more of embodiments 1 through 92, wherein the drug-resin complex comprises about 30%-50% of the composition on a weight / weight basis (embodiment 93).

[0206] In an embodiment, the present invention provides a composition comprising any one or more of embodiments 1 to 93, wherein the suspension base comprises starch, comprising about 5% to 15% of the composition on a weight / weight basis (embodiment 94).

[0207] In some embodiments, the invention provides a composition comprising any one or more of embodiments 1 to 93, wherein the suspension base comprises a disaccharide, the disaccharide comprising about 7.5% to 15% of the composition on a weight / weight basis (embodiment 95).

[0208] In an embodiment, the invention provides the composition of any one or more of embodiments 1 to 95, wherein the disaccharide comprises a mixture of sucrose and sucralose (embodiment 96).

[0209] In an embodiment, the invention provides a composition according to any one or more of embodiments 1 to 96, wherein the suspension base comprises a thickening agent that comprises at least about 3% of the composition on a weight / weight basis, such as about 2.5% to 7.5% (e.g., about 5%) (embodiment 97).

[0210] In an embodiment, the invention provides the composition of any one or more of embodiments 1 through 97, wherein the thickener comprises, at least in majority, hydroxypropyl methylcellulose (HPC) (embodiment 98).

[0211] In some embodiments, the invention provides a composition of any one or more of embodiments 1 through 98, wherein the composition is adapted for oral administration (embodiment 99).

[0212] In some embodiments, the present invention provides the composition of any one or more of embodiments 1 through 99, wherein the composition is in the form of a capsule (embodiment 100).

[0213] In some embodiments, the present invention provides a composition comprising any one or more of embodiments 1 through 100, the composition being in the form of a tablet (embodiment 101).

[0214] In some embodiments, the present invention provides a composition comprising any one or more of embodiments 1 through 101, the drug-resin complex having a concentration of about 50 mg / mL to about 100 mg / mL (embodiment 102).

[0215] In some embodiments, the present invention provides a composition comprising any one or more of the compositions of embodiments 1 through 102, the composition being in a unit dosage form for a single administration to a patient (embodiment 103).

[0216] In some embodiments, the invention provides a composition comprising any one or more of the compositions of embodiments 1 to 103 in an amount expected to be effective as a once-daily treatment for myotonia (embodiment 104).

[0217] In some embodiments, the invention provides one or more compositions of any one of embodiments 1 through 104 above, the composition comprising from about 100 mg to about 600 mg of mexiletine hydrochloride (embodiment 105).

[0218] In some embodiments, the invention provides one or more compositions of any one of embodiments 1 through 105 above, the composition comprising about 100 mg to 400 mg of mexiletine hydrochloride (embodiment 106).

[0219] In some embodiments, the invention provides one or more compositions of any of Embodiments 1 through 106 above, wherein the composition is stable under standard US FDA accelerated stability testing conditions (40° C. / 75% RH) for a period of at least 2 months, such as at least 3 months or at least 6 months, or under regular (long-term) stability testing conditions for a period of at least 12 months, such as at least 18 months or at least 24 months (Embodiment 107).

[0220] In some embodiments, the present invention provides a composition comprising one or more of any one of embodiments 1 through 107, wherein a single administration of an effective dose of the composition to a human recipient results in: (1) a T max and (2) in most human patients, 18 hours after administration, the plasma concentration of mexiletine is max The difference from the max The composition is provided in a form having a difference of at least about 40% from (embodiment 108).

[0221] In some embodiments, the present invention provides a composition of any one or more of embodiments 1 through 108, wherein in most human patients receiving a single oral dose of the composition, the plasma concentration is greater than or equal to C for at least about 4 hours. max The composition has a variation of within about 20% from (embodiment 109).

[0222] In some embodiments, the present invention provides a composition of any one or more of embodiments 1 through 109, wherein in most human patients receiving a single oral dose of the composition, the plasma concentration is greater than or equal to C for at least about 4 hours. max The composition is provided such that the deviation from the formula (110) remains within about 15%.

[0223] In some embodiments, the present invention provides a composition of any one or more of embodiments 1 through 110, wherein in most human patients receiving a single oral dose of the composition, the plasma concentration is greater than or equal to C for at least about 4 hours. max The composition is provided such that the difference is within about 10% from (embodiment 111).

[0224] In some embodiments, the present invention provides a composition of any one or more of embodiments 1 through 11, wherein in most human patients receiving a single oral dose of the composition, the plasma concentration is greater than or equal to C for at least about 5 hours. max The composition is provided such that the difference is within about 20% from (embodiment 112).

[0225] In some embodiments, the present invention provides a composition of any one or more of embodiments 1 through 112, wherein in most human patients receiving a single oral dose of the composition, the plasma concentration is greater than or equal to C for at least about 5 hours. max The composition has a variation of within about 15% from (embodiment 113).

[0226] In some embodiments, the present invention provides a composition of any one or more of embodiments 1 through 113, wherein in most human patients receiving a single oral dose of the composition, the plasma concentration is greater than or equal to C for at least about 5 hours.max The composition has a variation of within about 10% from (embodiment 114).

[0227] In some embodiments, the present invention provides a composition of any one or more of embodiments 1 through 114, wherein in most human patients receiving a single oral dose of the composition, the plasma concentration is greater than or equal to C for at least about 6 hours. max The composition is provided such that the difference is within about 20% from (embodiment 115).

[0228] In some embodiments, the present invention provides a composition of any one or more of embodiments 1 through 115, wherein in most human patients receiving a single oral dose of the composition, the plasma concentration is greater than or equal to C for at least about 6 hours. max The composition is provided such that the deviation from the formula (I) remains within about 15% (embodiment 116).

[0229] In some embodiments, the present invention provides a composition of any one or more of embodiments 1 through 116, wherein in most human patients receiving a single oral dose of the composition, the plasma concentration is greater than or equal to C for at least about 6 hours. max The composition has a variation of within about 10% from (embodiment 117).

[0230] In some embodiments, the invention provides compositions of any one or more of Embodiments 1 through 117, wherein in most human patients receiving a single oral dose of the compound, the plasma concentration of mexiletine at either 3 hours post-administration, 4 hours post-administration, or both, differs by no more than about 25% from the plasma concentration of mexiletine at 18 hours post-administration (Embodiment 118).

[0231] In some embodiments, the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of mexiletine or a pharma- ceutical acceptable salt thereof in an oral delivery formulation, and an effective amount of a release retarding agent, the oral delivery formulation being capable of providing, upon a single oral administration of the composition, (1) a T maxand (2) in most human patients, 18 hours after administration, the plasma concentration of mexiletine is max The difference from max In one embodiment, the composition exhibits a delayed release profile that differs from the initial release profile by at least about 40% (embodiment 119).

[0232] In some embodiments, the present invention provides a composition of any one or more of embodiments 1 through 119, wherein in most human patients receiving a single oral dose of the composition, the plasma concentration is greater than or equal to C for at least about 4 hours. max The composition is provided such that the deviation from the formula (120) remains within about 20%.

[0233] In some embodiments, the present invention provides a composition of any one or more of embodiments 1 through 120, wherein in most human patients receiving a single oral dose of the composition, the plasma concentration is greater than or equal to C for at least about 4 hours. max The composition is provided such that the difference is within about 15% from (embodiment 121).

[0234] In some embodiments, the present invention provides a composition of any one or more of embodiments 1 through 121, wherein in most human patients receiving a single oral dose of the composition, the plasma concentration is greater than or equal to C for at least about 4 hours. max The composition has a variation of within about 10% from (embodiment 122).

[0235] In some embodiments, the present invention provides a composition of any one or more of embodiments 1 through 122, wherein in most human patients receiving a single oral dose of the composition, the plasma concentration is greater than or equal to C for at least about 5 hours. max The composition has a variation of within about 20% from (embodiment 123).

[0236] In some embodiments, the present invention provides a composition of any one or more of embodiments 1 through 123, wherein in most human patients receiving a single oral dose of the composition, the plasma concentration is greater than or equal to C for at least about 5 hours. max The composition has a variation of within about 15% from (embodiment 124).

[0237] In some embodiments, the present invention provides a composition of any one or more of embodiments 1 through 124, wherein in most human patients receiving a single oral dose of the composition, the plasma concentration is greater than or equal to C for at least about 5 hours. max The composition has a variation of within about 10% from (embodiment 125).

[0238] In some embodiments, the present invention provides a composition of any one or more of embodiments 1 through 125, wherein in most human patients receiving a single oral dose of the composition, the plasma concentration is greater than or equal to C for at least about 6 hours. max The composition has a variation of within about 20% from (embodiment 126).

[0239] In an embodiment, the present invention relates to the composition of embodiment 126, wherein in most human patients receiving a single oral dose of the composition, the plasma concentration is greater than or equal to C for at least about 6 hours. max The composition has a variation of within about 15% from (embodiment 127).

[0240] In an embodiment, the present invention relates to the composition of embodiment 127, wherein in most human patients receiving a single oral dose of the composition, the plasma concentration is greater than or equal to C for at least about 6 hours. max The composition has a variation of within about 10% from (embodiment 128).

[0241] In some embodiments, the invention provides compositions of any one or more of embodiments 120 through 128, wherein in most human patients receiving a single oral dose of the compound, the plasma concentration of mexiletine at either 3 hours post-administration, 4 hours post-administration, or both, differs by no more than about 25% from the plasma concentration of mexiletine at 18 hours post-administration (embodiment 129).

[0242] In some embodiments, the present invention relates to a composition of any one or more of embodiments 120 through 129, the composition incorporating one or more of the features of the composition of any one or more of embodiments 1 through 62 (embodiment 130).

[0243] In some embodiments, the present invention provides pharmaceutical compositions comprising mexiletine or a pharma- ceutically acceptable salt thereof and a release retarding agent, the composition exhibiting at least one of the following pharmacokinetic profile characteristics: (a) the median single-dose Tmax is about 5 hours to about 8 hours; (b) Single Dose C max an average value of about 700 ng / mL to 1250 ng / mL, such as about 700 ng / mL to 1200 ng / mL or 725 ng / mL to 1200 ng / mL, for example, 763.2237 ng / mL to about 1100 to 1200 ng / mL, for example, about 1125 ng / mL to 1175 ng / mL, such as about 1162.5969 ng / mL; (c) Single-dose AUC 0~24 the mean value is between about 12500 ng·h / mL and 13000 ng·h / mL, such as between 12750 ng·h / mL (e.g., 12826.7066 ng·h / mL) and about (16000-17000) ng·h / mL, such as between about 16500 ng·h / mL (e.g., 16323.9271 ng·h / mL); (d) Single-dose AUC 0~t the mean value is between about 21000 ng·h / mL and 25000 ng·h / mL, such as between about 22000 ng·h / mL and 24250 ng·h / mL (e.g., between about 22301.7312 ng·h / mL and about 23909.8110 ng·h / mL); (e) Single-dose AUC 0~∞ a mean value between 22500 ng·h / mL and 26000 ng·h / mL, such as between about 23000 ng·h / mL and 25500 ng·h / mL (e.g., between about 23345.7516 ng·h / mL and about 25363.6969 ng·h / mL); and (f) Single dose 1 / 2 The average value is about 10 hours to about 13.5 hours (embodiment 131).

[0244] In an embodiment, the present invention provides the composition of embodiment 131, comprising a single dose t 1 / 2 The composition has an average value of about 10 hours to about 13.5 hours (embodiment 132).

[0245] In an embodiment, the present invention provides a composition according to embodiment 131 or embodiment 132, comprising a single dose T max The composition has a median duration of about 5 hours to about 8 hours (embodiment 133).

[0246] In an embodiment, the present invention provides the composition of embodiment 133, comprising a single dose T max The composition has a median duration of about 6 hours or more (embodiment 134).

[0247] In some embodiments, the present invention provides a composition of any one or more of embodiments 131 to 134, comprising a single dose of C max The composition is provided having an average value of about 700 ng / mL or greater (e.g., about 750 ng / mL or greater, such as about 763.2237 ng / mL or greater) (embodiment 135).

[0248] In some embodiments, the present invention provides a composition comprising any one or more of embodiments 131-135, comprising a single-dose AUC 0~24 A composition is provided (embodiment 136), wherein the average value is about 12000 ng·hr / mL to 13500 ng·hr / mL (e.g., about 12500 ng·hr / mL to 13000 ng·hr / mL, such as about 12826.7066 ng·hr / mL).

[0249] In some embodiments, the present invention provides a composition comprising any one or more of the compositions of embodiments 131 through 136, comprising a single-dose AUC 0~t A composition is provided in which the average value is about 21,500 ng·hr / mL to 23,500 ng·hr / mL (e.g., about 22,000 ng·hr / mL to 22,750 ng·hr / mL, such as about 22,301.7312 ng·hr / mL) (embodiment 137).

[0250] In some embodiments, the present invention provides a composition comprising any one or more of the compositions of embodiments 131 through 137, comprising a single-dose AUC 0~∞ A composition is provided in which the average value is about 22,500 ng·hr / mL to 24,500 ng·hr / mL (e.g., about 23,000 ng·hr / mL to 23,750 ng·hr / mL, such as about 23,345.7516 ng·hr / mL) (embodiment 138).

[0251] In some embodiments, the present invention provides a composition comprising any one or more of the compositions of embodiments 131 through 138, comprising a single dose of t 1 / 2 The composition is provided wherein the average value is about 12 hours or greater (embodiment 139).

[0252] In some embodiments, the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of mexiletine or a pharma- ceutical acceptable salt thereof and a release retarding agent, the composition comprising mexiletine or a pharma- ceutical ... max Compositions are provided that exhibit a detectable or significant increase in the mean, the AUC mean, or both (embodiment 140).

[0253] In an embodiment, the present invention provides the composition of embodiment 140, further comprising: 0~∞ The composition has a fed / fasted ratio average of about 1.13 or greater (embodiment 141).

[0254] In an embodiment, the present invention provides the composition of embodiment 141, comprising: max The composition has a fed / fasted ratio average of about 1.25 or greater (embodiment 142).

[0255] In some embodiments, the present invention provides a composition comprising any one or more of the compositions of Embodiments 1 through 62 above, the composition exhibiting a pharmacokinetic profile characteristic of Embodiment 131 (Embodiment 143).

[0256] In an embodiment, the present invention provides a pharma- ceutically acceptable composition comprising a therapeutically effective amount of mexiletine and a retarding agent, said composition exhibiting plasma levels of mexiletine at three or more time points that are statistically similar to plasma levels of mexiletine achieved by a corresponding single dose of Test Product 1 (T1) at three or more time points between 3 hours and 24 hours after administration under the same conditions (Embodiment 144).

[0257] In an embodiment, the present invention provides a pharma- ceutically acceptable composition comprising a therapeutically effective amount of mexiletine and a retarding agent, said composition exhibiting plasma levels of mexiletine at five or more time points that are statistically similar to plasma levels of mexiletine achieved by a corresponding single dose of Test Product 1 (T1) at five or more time points between 3 hours and 24 hours after administration under the same conditions (Embodiment 145).

[0258] In an embodiment, the present invention provides a pharma- ceutically acceptable composition comprising a therapeutically effective amount of mexiletine and a retarding agent, said composition exhibiting plasma levels of mexiletine at seven or more time points that are statistically similar to plasma levels of mexiletine achieved by a corresponding single dose of Test Product 1 (T1) at seven or more time points between 3 hours and 24 hours after administration under the same conditions (Embodiment 146).

[0259] In an embodiment, the present invention provides a pharma- ceutically acceptable composition comprising a therapeutically effective amount of mexiletine and a retarding agent, said composition exhibiting plasma levels of mexiletine at three or more time points similar to the plasma levels of mexiletine achieved by a corresponding single dose of Test Product 2 (T2) at three or more time points between 3 hours and 24 hours after administration under the same conditions (Embodiment 147).

[0260] In an embodiment, the present invention provides a pharma- ceutically acceptable composition comprising a therapeutically effective amount of mexiletine and a retarding agent, said composition exhibiting plasma levels of mexiletine at five or more time points similar to the plasma levels of mexiletine achieved by a corresponding single dose of Test Product 2 (T2) at five or more time points between 3 hours and 24 hours after administration under the same conditions (Embodiment 148).

[0261] In an embodiment, the present invention provides a pharma- ceutically acceptable composition comprising a therapeutically effective amount of mexiletine and a retarding agent, said composition exhibiting plasma levels of mexiletine at 7 or more time points similar to the plasma levels of mexiletine achieved by a corresponding single dose of Test Product 2 (T2) at 7 or more time points between 3 hours and 24 hours after administration under the same conditions (Embodiment 149).

[0262] In some embodiments, the present invention provides a pharmaceutical composition comprising: (a) a therapeutically effective amount of a pharma- ceutical acceptable salt of mexiletine; and max About 5 to 8 hours, t 1 / 2 and a means for delaying release of the mexiletine such that the release period is from about 10 hours to about 13.5 hours (embodiment 150).

[0263] In an embodiment, the invention provides the composition of embodiment 150, further comprising a means for delivering the composition to a patient by oral administration (embodiment 151).

[0264] In an embodiment, the invention provides the composition of embodiment 151, further comprising a means for suspending the mexiletine in a liquid formulation (embodiment 152).

[0265] In some embodiments, the invention provides a composition comprising any one or more of the compositions of embodiments 150 to 152, wherein the composition exhibits a pharmacokinetic profile characteristic of any one or more of embodiments 131 to 149 (embodiment 153).

[0266] In some embodiments, the invention provides a composition comprising any one or more of embodiments 150 to 152 above, wherein the composition exhibits the dissolution characteristics of any one or more of embodiments 63 to 117 (embodiment 154).

[0267] In some embodiments, the present invention provides an article made by a process comprising: (1) providing a pharma- ceutically acceptable form of mexiletine or a pharma- ceutically acceptable salt thereof; (2) combining the mexiletine with an ion exchange resin to form a pharma- ceutically acceptable ion exchange resin; (3) dissolving and / or dispersing a release retardant and one or more pharma- ceutically acceptable coating additives in a suitable solvent to prepare a coating composition; and (4) applying the coating composition onto the complex of mexiletine and ion exchange resin to obtain a pharmaceutical controlled-release once-daily composition of mexiletine or a pharmaceutical salt thereof (Embodiment 155).

[0268] In an embodiment, the invention provides the product of embodiment 155, wherein the pharma- ceutically acceptable ion exchange resin comprises two layers of a hydrophilic and a hydrophobic release-retarding polymer (embodiment 156).

[0269] In an embodiment, the invention provides the product of embodiment 156, wherein the mexiletine or pharma- ceutically acceptable salt thereof present comprises mexiletine hydrochloride (embodiment 157).

[0270] In some embodiments, the invention provides a product produced by the method described in any one of the Examples described herein (embodiment 158).

[0271] In some embodiments, the invention provides a product made by a process that includes most, substantially all, or all of the process steps described in the Examples herein (embodiment 159).

[0272] In an embodiment, the present invention provides the composition of any one of the above embodiments 1 to 62, wherein the ion exchange resin particles are loaded with a pharmaceutical drug prior to incorporation into the polymer system to form a drug-resin complex, which is further coated with a release-retarding polymer to form a controlled release drug-resin complex (Embodiment 160).

[0273] In some embodiments, the invention provides a method of treating myotonia in a patient in need of such treatment, the method comprising administering to the patient an effective amount of a composition described in any one or more of embodiments 1 to 160 (embodiment 161).

[0274] In an embodiment, the invention provides the method of embodiment 161, wherein the method comprises administering to the patient a dose of the composition once daily during part or all of the treatment period, twice daily during part or all of the treatment period, or both (embodiment 162).

[0275] In some embodiments, the invention provides the method of embodiment 162, wherein the method comprises administering mostly one dosage of the composition per day (embodiment 163).

[0276] In some embodiments, the present invention provides the method of embodiment 163, wherein said method is as effective as administering Namuscla three times a day in a significant number of patients (embodiment 164).

[0277] In some embodiments, the present invention provides the method of embodiment 164, wherein said method is as effective as administering Namuscla three times a day in most patients (embodiment 165).

[0278] In an embodiment, the present invention provides the method of embodiment 161 or embodiment 162, wherein the method is associated with less adverse gastrointestinal outcomes associated with the use of Namuscla (embodiment 166).

[0279] In some embodiments, the invention provides one or more of the methods of any one of embodiments 161 to 163, wherein a significantly greater number of patients receiving the treatment continue the treatment for an extended period of time (e.g., at least about 1 month, at least about 3 months, at least about 6 months, at least about 1 year) (embodiment 167).

[0280] In an embodiment, the invention provides the method of any one of embodiments 161 to 164, wherein the method comprises the patient consuming the product after a meal (embodiment 168).

[0281] In some embodiments, the present invention provides one or more of the methods according to any one of embodiments 161 to 168, wherein the treating is performed by any one or more of the means according to any one of embodiments 150 to 154.

[0282] In an embodiment, the present invention provides a method for making a pharma- ceutically acceptable mexiletine composition, the method comprising the steps of: (1) providing a pharma- ceutically acceptable form of mexiletine or a pharma- ceutically acceptable salt thereof; (2) combining the mexiletine with an ion exchange resin to produce a pharma- ceutically acceptable ion exchange resin; (3) dissolving and / or dispersing a release retardant and one or more pharma- ceutically acceptable coating additives in a suitable solvent to prepare a coating composition; and (4) applying the coating composition onto the mexiletine and ion exchange resin complex to obtain a pharmaceutical controlled-release once-daily composition of mexiletine or a pharmaceutical salt thereof (Embodiment 170).

[0283] In some embodiments, the invention provides a method for producing one or more of the compositions of any one of embodiments 1 to 62, wherein the ion exchange resin particles are loaded with a pharmaceutical drug prior to incorporation into a polymer system to produce a drug-resin complex (embodiment 171).

[0284] In an embodiment, the present invention provides the method of any one of embodiments 170 to 171, wherein the drug-resin complex is further coated with a release-retarding polymer to form a controlled release drug-resin complex (embodiment 172).

[0285] Detailed Description of the Invention Various aspects will now be described in more detail. For convenience, both combinations of elements / steps and individual elements / steps are described in this section of the disclosure. Notwithstanding the text that includes a focus on a particular element / step, any aspect, aspect, embodiment, or other description of the specific step or element may be applied to the general description of the compositions / methods of the invention, or any other described element / step thereof, set forth in any portion of this disclosure.

[0286] As used herein, the word "exemplary" means "serving as an example, instance, or illustration." The following detailed description is merely exemplary in nature and is not intended to limit the application and uses. Any embodiment described herein as "exemplary" is not necessarily to be construed as preferred or advantageous over other embodiments.

[0287] Composition / composition properties In some embodiments, the present invention discloses controlled release pharmaceutical compositions and methods for their manufacture. In some embodiments, the compositions of the present invention are formulated for oral administration. In some embodiments, the compositions are in the form of or include tablets, capsules, etc. In some embodiments, a composition adapted for oral administration comprises a therapeutically effective amount of mexiletine or a pharma- ceutically acceptable salt thereof and a release retarding agent, wherein the release retarding agent effectively controls the release of the mexiletine or pharma- ceutically acceptable salt thereof from the composition after administration to a human patient, such that a single dose of the composition administered daily releases the mexiletine or pharma- ceutically acceptable salt thereof from the composition at a rate that is effective to treat a statistically significant number of myotonia patients over a treatment period of at least about one month, such as at least about three months (e.g., at least about six months, twelve months, eighteen months, twenty-four months, thirty months, or thirty-six months, or more). In some embodiments, the present invention provides methods of using such compositions to treat conditions such as myotonia, comprising administering an effective amount of a composition of the present disclosure to a patient once daily for a period of time such as at least one month, or about 3, 6, 9, 12, 18, 24, 30, or 36 months or more, and not comprising administering the composition to the patient more than once daily. In some embodiments, the methods and compositions are as effective as Nasmuscla (e.g., 167 mg dose three times a day) as described in the EMA, 2018 publication cited herein and in the Background Art, if not detectably or significantly more effective than a control drug such as a known commercial product. In some embodiments, such compositions can be distinguished from Nasmuscla, which is effective throughout the treatment period when administered only once a day. In some embodiments, the number of patients for whom administration of the compositions of the present invention only once a day is effective is significantly greater than the number of patients treatable with Nasmuscla administered once a day.

[0288] In some embodiments, each dose of the composition described in the preceding paragraph contains from about 100 mg to about 600 mg of mexiletine hydrochloride, such as from about 200 mg to about 600 mg of mexiletine hydrochloride (e.g., about 225 to 600 mg, about 250 to 600 mg, about 275 to 600 mg, about 300 to 600 mg, about 350 to 600 mg, about 400 to 600 mg, or about 450 to 600 mg, such as about 100 to 550 mg, about 100 to 500 mg, about 100 to 450 mg, about 100 to 400 mg, about 100 to 300 mg, or about 100 to 250 mg). In some embodiments, each dose of the composition comprises at least about 200 mg, 250 mg, or about 300 mg up to about 600 mg, 550 mg, 500 mg, 450 mg, 400 mg, or about 350 mg.

[0289] In an embodiment, the present invention provides a composition according to any of the preceding paragraphs of this section, comprising T max the median is about 5 hours to about 8 hours (e.g., about 5.5 hours to 7.5 hours, such as about 6 hours to 7 hours, about 5.75 hours to 6.75 hours, about 5.75 hours to 6.25 hours, or about 6 hours); 1 / 2 or about 11 to 13.5 hours (e.g., about 10.5 to 13 hours, about 11 to 12.5 hours, about 10.5 to 12.5 hours, about 11 to 12 hours, about 10.5 to 12 hours, about 11 hours, about 12 hours, about 11 to 13 hours, or about 11 to 13.5 hours); or may be further characterized by both of the above characteristics. The present invention further provides a composition according to any of the preceding sentences of this section, further characterized in that the composition exhibits at least one of the following pharmacokinetic profile characteristics following a single dose administration: (a) C max The mean value is approximately 700ng / mL to 1250ng / mL; AUC 0~24 The mean value is approximately 15,500 ng·h / mL to approximately 17,250 ng·h / mL; AUC 0~t is approximately 22,000 ng·h / mL to 24,250 ng·h / mL; and AUC 0~∞in about 22500 ng·hr / mL to 26000 ng·hr / mL. In a further aspect, the present invention provides a pharmaceutical composition comprising an effective amount of mexiletine or a pharma- ceutically acceptable salt thereof, and an effective amount of a release retarder / retardant, said composition further (in combination with any other aspect of this section or of the present disclosure) or alternatively (for any such aspect) exhibits at least one, such as at least two, such as three or more (e.g., 1-5, 2-5, 2-4, 2-3, 1-4, 1-3, 3, 4, 5, or all) of the following pharmacokinetic profile characteristics after a single dose: (g)T max The median time is about 5 hours to about 8 hours; (h)C max The average value is approximately 700ng / mL to 1250ng / mL; (i) AUC 0~24 The mean value is approximately 12000 ng·h / mL to approximately 17500 ng·h / mL; (j) AUC 0~t the mean value being approximately 22000 ng·h / mL–24500 ng·h / mL; (k) AUC 0~∞ The average value is approximately 22,500 ng·h / mL to 26,000 ng·h / mL; and (l)T 1 / 2 The average value is approximately 10 hours to approximately 13.5 hours.

[0290] In some embodiments, the compositions of the invention, such as those described in any of the previous parts of this section, have a C max Increases in the mean, the AUC mean, or both are further shown.

[0291] In some embodiments, the compositions provided herein comprise one or more pharma- ceutically acceptable compounds of mexiletine in addition to one or more other compounds potentially useful in the treatment of a mexiletine-treatable condition, such as myotonia (e.g., in some embodiments, the compositions provided herein comprise an effective amount of a mexiletine compound or a suitable salt thereof, and an effective amount of one or more other myotonia-treating APIs). In some embodiments, such one or more pharma-ceutically acceptable compounds are loaded onto one or more ion exchange resins. In some embodiments, the compositions comprise a detectable or significant amount of an uncoated drug-resin complex. In some embodiments, the compositions comprise a detectable or significant amount of a coated drug-resin complex. In some embodiments, the compositions comprise a detectable or significant amount of both an uncoated drug-resin complex and a coated drug-resin complex.

[0292] Mexiletine Compounds In some embodiments, the compositions provided herein include a pharma- ceutically acceptable compound, such as, for example, mexiletine. In some embodiments, such a compound can be provided in any pharma- ceutically acceptable form suitable for mammalian administration, such as, for example, a pharma- ceutically acceptable salt, solvate, hydrate, enantiomer, derivative, polymorph, active metabolite, or prodrug of such a compound.

[0293] Unless inconsistent, any reference herein to mexiletine or mexiletine compounds will be understood to implicitly and concomitantly hold under any and all suitable salts thereof (e.g., any reference herein to a composition comprising mexiletine should be understood to implicitly disclose a corresponding composition comprising an equivalent amount of a suitable mexiletine salt, such as mexiletine hydrochloride), and any disclosure of mexiletine or a salt of a mexiletine compound, if applicable, will be understood to provide an implicit and concomitant disclosure of corresponding methods, compositions, etc. comprising mexiletine or another suitable mexiletine that is not in any such salt form.

[0294] In some embodiments, the compositions provided herein include mexiletine, e.g., a mexiletine compound. In some embodiments, the mexiletine compound can be any specified or identifiable or conceivable pharma- ceutically acceptable mexiletine compound suitable for mammalian administration, such as, for example, mexiletine or a pharma- ceutically acceptable salt, pharma-ceutically acceptable solvate, pharma-ceutically acceptable hydrate, pharma-ceutically acceptable enantiomer, pharma-ceutically acceptable geometric isomer, pharma-ceutically acceptable stereoisomer, pharma-ceutically acceptable diastereomer, pharma-ceutically acceptable N-oxide, pharma-ceutically acceptable derivative, pharma-ceutically acceptable polymorph, and pharma-ceutically acceptable prodrug thereof. In some embodiments, the compositions can include a mixture of any one or more of mexiletine or a pharma-ceutically acceptable salt, solvate, hydrate, enantiomer, derivative, polymorph, or prodrug of mexiletine.

[0295] In some embodiments, the compositions herein can include a mexiletine compound that is a salt of mexiletine, such as, for example, mexiletine hydrochloride, or a mexiletine compound salt disclosed, for example, in U.S. Patent Application Publication No. 2011 / 0028552 or, for example, in U.S. Patent Application Publication No. 2012 / 0196933. In some embodiments, the compositions herein can include a mexiletine compound that is, for example, a solvated form (such as a hydrate) of mexiletine, an unsolvated form of mexiletine, or both. In some embodiments, the invention encompasses both such forms, such as those described by Andrews, et. al., in, “Derisking the Polymorph Landscape: The Complex Polymorphism of Mexiletine Hydrochloride,” Cryst. Growth Des. 2021, 21, 12, 7150-7167. In some embodiments, the compositions herein may include, for example, any pharma- ceutically acceptable geometric isomer, stereoisomer, enantiomer, diastereomer, or N-oxide of mexiletine. Mexiletine or mexiletine compounds can exist in two or more stereoisomers (e.g., diastereomers and enantiomers). In some embodiments, the mexiletine compounds can cover all known stereoisomers of mexiletine and mixtures thereof. In some embodiments, specific stereoisomers of mexiletine provided herein can be separated from one another by methods known in the art, or, for example, a given isomer can be obtained, for example, by stereospecific or asymmetric synthesis. In some embodiments, it may be particularly advantageous to use a particular isomer of mexiletine, such as, for example, a form that exhibits a detectably significantly higher level of bioactivity, bioavailability, or both.Exemplary forms of such mexiletine compounds are disclosed, for example, in Tekewe, et. al., "Development and validation of HPLC method for the resolution of drug intermediates: DL-3-Phenyllactic acid, DL-O-acetyl-3-phenyllactic acid and (+ / -)-mexiletine acetamide enantiomers," Talanta 75 (2008) 239-245, and the many references cited therein (see, for example, references 1-15 cited therein). In some embodiments, the mexiletine compounds disclosed herein can be, for example, any one or more of such cited compounds or such compounds disclosed in the cited references. In some embodiments, the compositions herein can include a mexiletine compound that is a derivative of mexiletine, such as, for example, a pyrroline derivative of mexiletine, such as those disclosed in Frederickson, et. al., "Fragment-Based Discovery of Mexiletine Derivatives as Orally Bioavailable Inhibitors of Urokinase-Type Plasminogen Activator," J. Med. Chem., 2008, 51, 2, 183-186, or those disclosed by Chau, et. al., in, "Synthesis of six mexiletine derivatives with isoindolines attached as potential antioxidants and their evaluation as cardioprotective agents," MedChemComm, 2015, 6, 634-639.In some embodiments, the mexiletine compound herein can be a polymorph of mexiletine, such as, for example, a polymorph of mexiletine hydrochloride disclosed by Andrews, et. al., supra, or, for example, Kiss and Repasi, "Investigation of polymorphism of mexiletine hydrochloride by Fourier transform infrared and differential scanning calorimetric techniques," Analyst, 1993, 118, 661-664. In some embodiments, the mexiletine compound can be a prodrug of mexiletine, such as, for example, those disclosed in WO 2012 / 085586, U.S. Patent Application Publication No. 2011 / 028552, or, for example, U.S. Patent Application Publication No. 2012 / 0196933. Use of the term "mexiletine compound" herein should be construed to represent any such mexiletine compound disclosed in this section or other mexiletine compounds known in the art. In certain aspects, the compositions herein include a mexiletine compound that can be characterized as a salt of mexiletine, e.g., mexiletine hydrochloride.

[0296] Release retardant The compositions of the present invention have various release profile characteristics as described above (e.g., the compositions have T max The median is about 5 hours to about 8 hours, or t 1 / 2The release retardant may comprise any suitable number of release retarding compositions present in any suitable amount. Numerous types of release retardants, and equivalents thereof known in the art, are provided herein. To illustrate such embodiments, a significant disclosure is provided herein of compositions that include an ion exchange resin component as part of a release retarding component / component, either alone or in combination with other release retardants / components (e.g., one or more release retarding coating polymers). While such formulations are only one aspect of the invention, such detailed disclosure is not intended to devalue the use of other release retardants of skill in the art to obtain compositions having the properties described herein, which the inventors believe to be suitable as therapeutic agents according to the various aspects of the invention provided throughout this disclosure.

[0297] Sustained / Controlled Release Properties and Ingredients An important aspect of the properties of the compositions for the present invention is the controlled release of the drug, e.g., mexiletine compound, contained therein. Such controlled release (e.g., sustained release) provides many advantages of the present invention over existing technology, mitigating the requirement for more consistent or continuous therapeutic administration to overcome the rapid dissolution and rapid decline in plasma concentrations of mexiletine administered in immediate release form.

[0298] Pharmaceutical compositions that include one or more drugs, e.g., a mexiletine compound, are released slowly and in a controlled manner over time and can be described as having a "controlled release." According to certain embodiments, the term "controlled release" refers to releasing a drug, e.g., a mexiletine compound, at a rate that is slower than an immediate release. In some embodiments, controlled release means releasing a drug, e.g., a mexiletine compound, following a single administration over a course of about 1 hour, about 2 hours, about 4 hours, about 6 hours, about 8 hours, about 10 hours, about 12 hours, about 14 hours, about 16 hours, about 18 hours, about 20 hours, about 22 hours, or about 24 hours or more, such as, for example, about 2 hours to about 22 hours, about 6 hours to about 18 hours, or about 10 hours to about 14 hours. In some embodiments, the mexiletine compound of the compositions provided herein can be released over a period of 24 hours or greater.

[0299] The long-acting sustained release properties of the pharmaceutical compositions of the present invention can aid in therapeutic dosing regimens of such compositions, where the compositions are administered three or less times per day, for example, once about every 8 hours, once about every 12 hours, once about every 16 hours, once about every 20 hours, or, for example, once about every 24 hours, for example, once about every 8 to about 24 hours, once about every 8 to about 20 hours, once about every 8 to about 16 hours, once about every 8 to about 12 hours, or once about every 10 to about 24 hours, once about every 14 to about 24 hours, once about every 18 to about 24 hours, or once about every 22 to about 24 hours. In some embodiments, the composition is administered no more than twice a day, e.g., no more than once every about 12 to about 24 hours, e.g., once every about 16 to about 24 hours or once every about 20 to about 24 hours, or about once every about 12 to about 20 hours, about 12 to about 16 hours, or about once every about 16 to about 20 hours, for example. In some embodiments, the composition is administered no more than once a day, e.g., once every 24 hours.

[0300] In some embodiments, compositions provided herein are provided as controlled release dosage forms, the compositions including one or more drugs, e.g., one or more mexiletine compounds. In some embodiments, compositions provided herein are provided in sustained release form. In some embodiments, compositions provided herein are administered no more than once per about 12, 14, 16, 18, 20, 22, or 24 hour period. In some embodiments, compositions provided herein are administered once a day, e.g., once per 24 hour period. In some embodiments, compositions provided herein provide a mexiletine compound that is in sustained release form.

[0301] In certain embodiments, the present invention provides controlled release pharmaceutical compositions comprising a mexiletine compound. In some embodiments, the present invention provides controlled release once-daily pharmaceutical compositions comprising a mexiletine compound. In some embodiments, the mexiletine compound is a salt of mexiletine. In some embodiments, the mexiletine compound is complexed with an ion exchange resin.

[0302] In some embodiments, the present invention provides controlled release once-daily compositions comprising a mexiletine compound that provide a detectable or significantly faster, e.g., faster, or faster onset of therapeutic effect in treating myotonia than currently marketed products (e.g., NaMuscla®). In some embodiments, such therapeutic effect is observed within a period of time that is at least about 1% faster, ≧about 2%, ≧about 3%, ≧about 4%, ≧about 5%, ≧about 6%, ≧about 7%, ≧about 8%, ≧about 9%, ≧about 10%, ≧about 15%, ≧about 20%, ≧about 25%, ≧about 30%, ≧about 35%, ≧about 40%, ≧about 45%, or, for example, ≧about 50% shorter than currently marketed products (e.g., NaMuscla®).

[0303] In some embodiments, the controlled release compositions provided herein provide clinically relevant efficacy in treating myotonia for a detectable or significantly longer period of time as compared to currently marketed products (e.g., NaMuscla®). In some embodiments, a single administration of the compositions herein provides a detectable or significantly longer period of time of clinically relevant efficacy in treating myotonia as compared to currently marketed products (e.g., NaMuscla®). In some embodiments, a single administration of the compositions herein provides a detectable or significantly longer period of time of clinically relevant efficacy in treating myotonia as compared to currently marketed products (e.g., NaMuscla®). 0%, ≥ about 55%, ≥ about 60%, ≥ about 65%, ≥ about 70%, ≥ about 75%, ≥ about 80%, ≥ about 85%, ≥ about 90%, ≥ about 95%, ≥ about 100%, ≥ about 150%, ≥ about 200%, ≥ about 250%, ≥ about 300%, ≥ about 350%, ≥ about 400%, ≥ about 450%, or ≥ about 500% to provide clinically relevant efficacy in treating myotonia over a long period of time.

[0304] In some embodiments, the compositions provided herein maintain clinically relevant levels of drug efficacy for a detectably or significantly longer period of time compared to currently marketed products (e.g., NaMuscla®). ...) at least about 1%, ≥ about 2%, ≥ about 3%, ≥ about 4%, ≥ about 5%, ≥ about 6%, ≥ about 7%, ≥ about 8%, ≥ about 9%, ≥ about 10%, ≥ about 15%, ≥ about 20%, ≥ about 25%, ≥ about 30%, ≥ about 35%, ≥ about 40%, ≥ about 45%. , ≧about 50%, ≧about 55%, ≧about 60%, ≧about 65%, ≧about 70%, ≧about 75%, ≧about 80%, ≧about 85%, ≧about 90%, ≧about 95%, ≧about 100%, ≧about 150%, ≧about 200%, ≧about 250%, ≧about 300%, ≧about 350%, ≧about 400%, ≧about 450%, or ≧about 500% maintain clinically relevant levels of drug efficacy for a longer period of time.

[0305] As used herein, a "therapeutically effective amount" refers to an amount of a compound or pharmaceutical composition that induces a desired (usually significant) biological or medical response in a tissue, system, animal, or human, as typically sought by a researcher, physician, or other clinician. In some embodiments, a therapeutically effective amount is demonstrated by at least one or at least two well-controlled clinical trials and sufficient clinical trials in human subjects / patients (e.g., as would be sufficient to be considered for regulatory approval). As used herein, a "clinically relevant efficacy" refers to demonstrating a detectable or significant desired effect or biomedical or medical response (usually significant) in or on a targeted tissue, system, animal, or human, as typically sought by a researcher, physician, or other clinician. As used herein, a "clinically relevant level" of a drug is a level sufficient to obtain a detectable or significant desired effect or biomedical or medical response (usually significant) in or on a targeted tissue, system, animal, or human.

[0306] Ion Exchange Resins In some embodiments, the compositions provided herein include a drug loaded onto an ion exchange resin, e.g., an ion exchange resin particle. In some embodiments, the ion exchange resin particle is loaded with a pharmaceutical drug prior to incorporation into the polymer system to produce a drug-resin complex. In some embodiments, the drug-resin complex is left uncoated. In some embodiments, the drug-resin complex is further coated with one or more release-retarding polymers to produce a controlled release drug-resin complex.

[0307] Ion exchange resins are water insoluble polymers in the form of very small particles and beads. The properties of ion exchange resins can vary depending on the intended application, and in some embodiments, they generally consist of an insoluble porous polymer lattice or matrix with ionic functional groups attached. In some embodiments, a drug disclosed herein, e.g., a mexiletine compound, is bound to the ion exchange resin through an acid-base reaction. In certain embodiments, the composition includes a cation exchange resin. In certain embodiments, the composition includes an anion exchange resin. In some embodiments, the composition can include a combination of a cation exchange resin and an anion exchange resin. In some embodiments, the ion exchange resin is selected based on the drug to be bound to the resin. In some embodiments, the ion exchange resin is selected based on the acidic or basic nature of the drug. In some embodiments, a basic drug can be bound to a cation exchange resin and an acidic drug can be bound to an anion exchange resin. In some embodiments, the composition includes a mexiletine compound, which is bound to, e.g., a cationic ion exchange resin.

[0308] In some embodiments, any pharma- ceutically suitable, e.g., biologically safe (wherein "biologically safe" means that it does not cause a detectable or significant adverse or detrimental effect on the health of the patient receiving it, such as, e.g., a detectable or significant adverse effect on the function of one or more tissues or systems of the patient) ion exchange resin can be used in preparing the mexiletine-ion exchange resin complex of a composition, e.g., mexiletine-ion exchange resin complex, of the invention, provided that it is pharma- ceutically acceptable and has an appropriate particle size or bead diameter.

[0309] In certain embodiments, the compositions herein comprise ion exchange resin particles having a particle size of at least about 20 μm, e.g., ≧about 20 μm, ≧about 22 μm, ≧about 24 μm, ≧about 26 μm, ≧about 28 μm, ≧about 30 μm, ≧about 32 μm, ≧about 34 μm, ≧about 36 μm, ≧about 38 μm, or, e.g., ≧about 40 μm. In some embodiments, the compositions herein comprise ion exchange resin particles having a particle size of ≧40 μm, such as, for example, ≧about 42 μm, ≧about 44 μm, ≧about 46 μm, ≧about 48 μm, ≧about 50 μm, ≧about 52 μm, ≧about 54 μm, ≧about 56 μm, ≧about 58 μm, ≧about 60 μm, or, for example, ≧about 70 μm, ≧about 80 μm, ≧about 90 μm, ≧about 100 μm, ≧about 120 μm, ≧about 140 μm, ≧about 160 μm, ≧about 180 μm, ≧about 200 μm, ≧about 220 μm, ≧about 240 μm, ≧about 260 μm, ≧about 280 μm, or even ≧about 300 μm.

[0310] All commercially available ion exchange resins are intended to be within the scope of the present invention. In some embodiments, ion exchange resins useful in the practice of the present invention include, but are not limited to, anionic resins such as DUOLITE® AP143 / 1083 (cholestyramine resin USP) and cationic resins such as AMBERLITE® IRP-64 (porous copolymer of methacrylic acid crosslinked with divinylbenzene), AMBERLITE® IRP-69 (sodium polystyrene sulfonate USP) and AMBERLITE® IRP-88. In certain embodiments, the composition comprises AMBERLITE® IRP 69 resin. AMBERLITE® IRP 69 (sodium polystyrene sulfonate) is commercially available as the sodium salt. However, it is within the scope of the present invention to convert the sodium salt to other salt forms, including, but not limited to, K and Li. Thus, in certain embodiments, AMBERLITE® IRP 69 resin provided as the potassium salt, AMBERLITE® IRP 69 resin provided as the potassium salt, the lithium salt, or both.

[0311] Drug-resin complex In some embodiments, the drug-resin complex is formed by placing an ion exchange resin, e.g., an ion exchange resin selected based on one or more properties of the drug to be complexed, in an aqueous solution of a selected form of the drug. In some embodiments, the combination is mixed or otherwise agitated. In some embodiments, the formed drug-resin complex is collected and washed. In some embodiments, the complex is washed with demineralized water or pure water. In some embodiments, the washing ensures removal of roughly all, substantially all, or all of the unbound drug (e.g., drug that is not bound to the ion exchange resin particles). In some embodiments, the complex is then dried. In certain embodiments, the drug is a mexiletine compound, e.g., a salt of mexiletine. In some embodiments, the ion exchange resin is a cation exchange resin. In some embodiments, the cation exchange resin is, e.g., AMBERLITE® IRP 69 resin or a resin that is at least about the same, at least substantially the same, essentially the same, or shares the same properties as AMBERLITE® IRP 69 resin.

[0312] According to certain embodiments, the ion exchange resin is maximally loaded with drug, e.g., the ion exchange resin is loaded with the maximum amount of drug that the resin can hold. In some aspects, the ion exchange resin is loaded with about 10% to about 99%, e.g., about 20% to about 99%, about 30% to about 99%, e.g., about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, or about 95%, about 97.5%, or about 99%, of its maximum drug binding capacity. , about 40% to about 99%, about 50% to about 99%, about 60% to about 99%, about 70% to about 99%, or about 80% to about 99%, or about 90% to about 99%, for example, about 10% to about 90%, about 10% to about 80%, about 10% to about 70%, about 10% to about 60%, about 10% to about 50%, about 10% to about 40%, about 10% to about 30%, or, for example, about 10% to about 20%, or the like, which is its maximum binding capacity. In some embodiments, such amounts are selected based on the desired dose of drug to be delivered. In some embodiments, such amounts as disclosed herein can be provided for a drug-resin complex, where the drug is, for example, a mexiletine compound and the resin is a cation exchange resin, such as AMBERLITE® IRP 69 resin or a resin at least about the same, at least substantially the same, essentially the same, or sharing the same properties as AMBERLITE® IRP 69 resin.

[0313] In some embodiments, the compositions herein detectably or significantly reduce, or at least generally, at least substantially, or essentially eliminate, the bitter taste of mexiletine using complexation of the mexiletine compound with a cation exchange resin.

[0314] In some embodiments, loading of a drug, e.g., a mexiletine compound, onto a resin, e.g., AMBERLITE® IRP 69 resin or a resin at least about the same, at least substantially the same, essentially the same, or sharing the same properties as AMBERLITE® IRP 69 resin, can be accomplished by known techniques. In some embodiments, batch loading can be used, where the drug solution is mixed with the resin in a suitable vessel for the time required to obtain the maximum load. In alternative embodiments, a solution of the drug can be passed through a column of resin until loading is complete.

[0315] In some embodiments, the drug-resin complex that is further subjected to the coating process is dried prior to coating.

[0316] Drug-resin complex coating In some embodiments, a pharmaceutical composition includes a drug-resin complex, e.g., a mexiletine-resin complex, at least a portion of which is coated with a release-retarding coating, e.g., a release-retarding polymer coating. In some embodiments, a pharmaceutical composition including a drug-resin complex coated with a release-retarding polymer coating, e.g., a mexiletine compound-resin complex coated with a release-retarding polymer coating, provides a controlled release of a drug, e.g., a mexiletine compound, e.g., a pharma- ceutically acceptable salt of mexiletine, for a period of at least about 24 hours, e.g., for a period of 24 hours or more, e.g., for a period of at least about 10 hours, ≥ about 12 hours, ≥ about 14 hours, ≥ about 12 hours, ≥ about 16 hours, ≥ about 18 hours, ≥ about 20 hours, ≥ about 22 hours, or ≥ about 24 hours.

[0317] In some embodiments, the compositions include a means for delaying the release of the mexiletine compound. In some embodiments, such means can be any means by which sustained release, controlled release, or both are performed in the art, such as, for example, by encapsulation, coating, modification of the type, chemistry, or degree of binding of the drug to a resin, or any other mechanism known in the art. In some embodiments, the means for delaying the release of the mexiletine compound in the compositions herein is a coating means. In some embodiments, the coating means can be any coating means, such as, for example, a single coating, multiple coatings, or different coating systems. In some embodiments, the compositions herein include a means for delaying the release of the mexiletine compound, which can be characterized, for example, by a coating means comprising a polymeric coating system.

[0318] According to certain embodiments, the compositions provided by the present invention include an uncoated drug-resin complex. In certain embodiments, the compositions provided by the present invention include a coated drug-resin complex. In yet further embodiments, the compositions include both an uncoated drug-resin complex and a coated drug-resin complex. In some embodiments, the drug-resin complex coating can provide the composition with sustained release properties, e.g., sustained drug release properties. In some embodiments, the amount of uncoated complex and the amount of coated complex in the composition can contribute to the drug release profile of the composition, and thus the ratio of uncoated to coated drug-resin complex in the composition can be selected based on the target drug release profile.

[0319] In certain embodiments, the compositions herein comprise a first plurality of uncoated drug-resin particles and a second plurality of drug-resin particles coated with a coating comprising at least one or more release retardants. In some embodiments, the drug-resin complex may comprise a single coating of a release retardant. In some embodiments, the drug-resin complex may comprise two or more coatings of a release retardant. In some embodiments, the drug-resin complex may comprise two coatings of a release retardant. In some embodiments herein, unless inconsistent, references to "coated" drug-resin particles, or, for example, to a "coating" of a drug-resin particle, may be interpreted to mean drug-resin particles comprising a single coating or multiple coatings, each coating providing a detectable or significant amount of one or more release retardants.

[0320] In some embodiments, a drug loaded ion exchange resin particle, e.g., a mexiletine compound-resin particle complex is established and the loaded resin particle is coated. In some embodiments, the coating material can include any of a number of natural or synthetic film formers used alone, mixed with each other, and mixed with plasticizers, pigments, and other materials to modify the properties of the coating. In some embodiments, the release retarding agent comprises a pharma- ceutically acceptable polymer, ethyl cellulose (or ethylcellulose), methylcellulose, hydroxypropylmethylcellulose (HPMC), hydroxyethylcellulose (HEC), an acrylic acid ester, such as Eudragit RL 100, Eudragit RLPO, Eudragit RL 30 D, Eudragit RSPO, Eudragit RS 30D, Eudragit NE 30D, Eudragit NE 40D, cellulose acetate phthalate, HEC phthalate, HPMC phthalate, or other cellulosic polymers, or a mixture of polymers.

[0321] In some embodiments, the release retardant of the coated mexiletine compound ion exchange resin complex particles is in the range of about 5% (wt / wt) to about 30% (wt / wt) of the total weight of the coated complex composition, e.g., about 10% (wt / wt) to about 30% (wt / wt), about 15% (wt / wt) to about 30% (wt / wt), about 20% (wt / wt) to about 30% (wt / wt), or about 25% (wt / wt) to about 30% (wt / wt), or, for example, about 5% (wt / wt) to about 25% (wt / wt), about 5% (wt / wt) to about 20% (wt / wt), about 5% (wt / wt) to about 15% (wt / wt), or about 5% (wt / wt) to about 10% (wt / wt) of the total weight of the composition. In some embodiments, the release retarder comprises hydroxypropyl methylcellulose, ethyl cellulose, or a combination thereof in a relative ratio range of about 30:70 to about 0:100, preferably about 25:75 to about 95:05, by weight of the total release retarder polymer in the composition, as described elsewhere herein.

[0322] In some embodiments, a polymer system, e.g., a release-retarding polymer system, totally encapsulates the mexiletine compound ion exchange resin complex particles when such particles are added thereto. In some embodiments, the polymer system comprises one or more compounds described in this section. In some embodiments, the polymer system comprises a plasticizer, such as dibutyl sebacate, vegetable oil, diethyl sebacate, diethyl phthalate, tricetin, or propylene glycol.

[0323] In some embodiments, once a drug-resin complex is formed, e.g., a mexiletine compound-resin complex is formed, the complex can be incorporated into a polymer system. In some embodiments, such a polymer system can be any polymer system that includes one or more release retardants or compounds that detectably or significantly delay the release of the drug-resin particles, including a coating. In some embodiments, by adding the drug-resin complex to a polymer system (e.g., a polymer coating), the polymer coating at least partially, e.g., at least approximately or at least substantially, or, e.g., completely encapsulates each drug-resin (e.g., mexiletine-ion exchange resin) complex particle. In some embodiments, the polymer coating at least partially, e.g., at least approximately or at least substantially, or, e.g., completely encapsulates at least 50%, ≧about 60%, ≧about 70%, ≧about 80%, ≧about 90%, ≧about 95%, ≧about 97.5%, ≧about 99%, or, e.g., all, of the drug-resin (e.g., mexiletine-ion exchange resin) complex particles.

[0324] Dosage form In some embodiments, the compositions provided by the present invention are provided in any suitable dosage form capable of delivering sustained release drug. In some embodiments, such dosage forms can be administered, e.g., swallowed, transdermally, transmucosally, or by other methods, e.g., known in the art. In some embodiments, the delivery form can be an oral delivery form. In some embodiments, such oral dosage forms can be, e.g., solid dosage forms, e.g., tablets, lozenges, or capsules containing a solid composition, or liquid dosage forms, e.g., liquids provided alone or within an enclosed delivery mechanism, e.g., a capsule. In some embodiments, the liquid oral dosage form can be, e.g., in the form of a liquid. In some embodiments, the liquid oral dosage form can be, e.g., in the form of a suspension. In some embodiments, the liquid dosage form can be a liquid suspension provided within a capsule.

[0325] In some embodiments, the compositions provided herein are provided in a liquid oral dosage form, such as, for example, an aqueous solution, a non-aqueous solution, an emulsion, a suspension, or a solution or suspension reconstituted, for example, from granules or a powder. In some embodiments, any of the dosage forms described herein can include, for example, one or more suitable solvents, preservatives, emulsifying agents, suspending agents, diluents, sweeteners, colorants, flavoring agents, or pharmaceutical excipients or carriers described herein.

[0326] According to certain aspects, the coated complexes can be suspended in a substantially liquid carrier medium to produce a liquid suspension composition. In one embodiment, the controlled release, e.g., sustained release, compositions can be readily prepared as liquid suspensions for oral delivery at the time of product use. In one embodiment, the present invention provides mexiletine controlled release formulations that can be reconstituted into aqueous controlled release liquid suspension formulations for oral administration.

[0327] In some embodiments, the compositions provided herein can be provided as dispersible tablets intended to be dispersed in water to suspend the controlled-release mexiletine compound ion-exchange complex and then administered by swallowing.

[0328] In some embodiments, compositions provided herein are provided as dry powders or granules containing one or more mexiletine compounds, such as, for example, a salt of mexiletine. In some embodiments, such dry powders, granules, or any other dosage forms described herein, can be formulated into various strengths by proportionally adjusting the active mexiletine compound as well as pharma- ceutically acceptable amounts of excipients.

[0329] In certain specific embodiments, the present invention provides oral controlled release once-daily compositions comprising a mexiletine compound, a pharma- ceutically acceptable ion exchange resin, and a pharma- ceutically acceptable carrier. In some embodiments, such compositions comprise a mexiletine compound complexed with a pharma- ceutically acceptable ion exchange resin. In some embodiments, at least a portion of such mexiletine compound-resin complex is coated with at least one coating comprising at least one release retarding polymer. In some embodiments, at least a portion of such mexiletine compound-resin complex is coated with at least two coatings each comprising at least one release retarding polymer. In some embodiments, at least about all, at least substantially all, or all of the mexiletine compound-resin complex is coated with at least one coating comprising at least one release retarding polymer. In certain embodiments, a composition in which at least about all, at least substantially all, or all of the mexiletine compound-resin complex is coated with at least one coating comprising at least one release retarding polymer comprises at least a portion of a mexiletine compound-resin complex comprising at least two coatings each comprising at least one release retarding polymer. In some embodiments, the complex of any such composition comprises a complex of a mexiletine compound and an ion exchange resin in powder, tablet, granule, or bead form. In some embodiments, such powder, tablet, or granule form is supplied in unit dose pack form, for example, in a sachet or bottle, or as a bulk multi-dose pack.

[0330] In some embodiments, the compositions provided herein can be provided in unit doses. In some embodiments, the compositions provided herein can be provided in a package containing multiple doses of unit dosage forms. For example, in some embodiments, the present invention provides the same amount of drug as an individually packaged liquid drug suspension or dispersible tablet composition or in the form of a dry powder or granules in a preferred dosage form. The dry powder or granule material can be distributed in unit dose packs or multi-dose packs in the form of sachets or bottles (PET, HDPE and glass), blisters that can be reconstituted in a suitable medium at the time of use.

[0331] In some embodiments, the coated drug-resin particles, e.g., mexiletine compound-resin particles, can be used in any suitable dosage form, e.g., suspensions, chewable compositions, orally disintegrating compositions, capsules, tablets, etc. In some embodiments, the compositions of the invention can be administered once daily in single unit compositions. In some embodiments, the compositions of the invention can be administered once daily in multiple unit compositions. In some embodiments, the single unit compositions or multiple unit compositions provide the same or detectably or significantly greater or superior (e.g., improving) therapeutic effect than multiple administrations of an immediate release dosage form.

[0332] In one embodiment, a multiple unit tablet system for modified drug release (MUPS) composition can be prepared by loading mexiletine hydrochloride into a microcrystalline cellulose tablet with the use of povidone and talc. In some embodiments, the tablet can be coated with hydroxymethylpropylcellulose. In some embodiments, the coated tablet can be coated twice with ethylcellulose and hydroxymethylpropylcellulose.

[0333] In some embodiments, the present invention provides one or more advantages over prior art compositions and methods. For example, the mexiletine compound-containing ion-exchange complex can be formulated into a number of different, easy-to-swallow dosage forms, including, but not limited to, liquid suspensions, granules, or dry powders for reconstitution.

[0334] Further, in some embodiments, the coated or granulated mexiletine compound ion exchange resin complex or the uncoated and coated mexiletine compound ion exchange resin complex can be filled into a suitably sized capsule with or without a lubricant, or compressed into a tablet with suitable pharmaceutical excipients. In some embodiments, the capsules provided herein can be swallowed directly by the patient, or the contents of the capsule can be added to water or sprinkled on food immediately prior to eating.

[0335] amount / dose In one embodiment, the compositions provided herein are provided for administering an effective amount of a mexiletine compound. In some embodiments, the effective amount is, for example, about 50 mg to about 1400 mg, about 50 mg to about 1300 mg, about 50 mg to about 1200 mg, about 50 mg to about 1100 mg, about 50 mg to about 1000 mg, about 50 mg to about 900 mg, about 50 mg to about 800 mg, about 50 mg to about 700 mg, or about 50 mg to about 600 mg, for example, about 60 mg to about 1400 mg, about 70 mg to about 1400 mg, about 80 mg to about 1400 mg, about 90 mg to about 1400 mg. g, about 100 mg to about 1400 mg, about 200 mg to about 1400 mg, about 300 mg to about 1400 mg, about 400 mg to about 1400 mg, about 500 mg to about 1400 mg, or, for example, about 100 mg to about 1300, about 100 mg to about 1200 mg, about 100 mg to about 1000 mg, about 100 mg to about 900 mg, about 100 mg to about 800 mg, about 100 mg to about 700 mg, or about 600 mg to about 1400 mg, such as, for example, about 100 mg to about 600 mg.

[0336] In certain aspects, the compositions herein provide for administering an effective amount of a mexiletine compound for the treatment of myotonia in patients with dystrophic or non-dystrophic myotonic disease, myotonic dystrophy type 1 patients, myotonic dystrophy type 2 patients, or any combination of any or all thereof, wherein the effective dosage amount can be, for example, about 150 mg administered once per day, about 200 mg administered once per day, about 300 mg administered once per day, about 400 mg administered once per day, about 500 mg administered once per day, or about 600 mg administered once per day.

[0337] In some embodiments, the compositions herein can be administered once daily (e.g., in a single unit or multiple unit compositions) in an amount that provides a therapeutic effect equivalent to multiple administrations of an immediate release dosage form.

[0338] In some embodiments, the invention provides controlled release once-daily pharmaceutical compositions of a mexiletine compound for administration once every 8 to 24 hour period (interval), e.g., once every 8 hour period, once every 10 hour period, once every 12 hour period, once every 14 hour period, once every 16 hour period, once every 18 hour period, once every 20 hour period, once every 22 hour period, or, for example, once every 24 hour period.

[0339] Dissolution profile characteristics The release profile of the mexiletine ion exchange resin complex may be assessed by in vitro dissolution using techniques known to those of skill in the art.

[0340] In some embodiments, following administration of a single dose of an oral mexiletine compound controlled, e.g., sustained release, in the form of a liquid suspension, a therapeutically effective amount of mexiletine is achieved within about 60 minutes, e.g., within about 50 minutes, about 40 minutes, or within about 30 minutes, such as within about 25 minutes, about 20 minutes, or within about 15 minutes of administration, and the formulation provides a controlled release profile for at least about 12 hours, about 14 hours, about 16 hours, about 18 hours, about 20 hours, about 22 hours, or up to, e.g., about 24 hours.

[0341] In some embodiments, pharmaceutical compositions comprising a mexiletine compound ion exchange resin complex of the present invention may exhibit an in vitro dissolution profile, when measured using a USP Type IV apparatus having a flow rate of about 8 ml / min with 6 gm glass beads in 0.1 N HCl medium at 37° C.±0.5° C., such that from about 0% (wt / wt) to about 70% (wt / wt) of the mexiletine compound is released after 0 to 2 hours, such as, for example, from about 0% (wt / wt) to about 60% (wt / wt), from about 0% (wt / wt) to 50% (wt / wt), from about 0% (wt / wt) to 40% (wt / wt), from about 0% (wt / wt) to 30% (wt / wt), or from about 0% (wt / wt) to 20% (wt / wt) of the mexiletine compound is released, such as, for example, from about 0% (wt / wt) to about 35% (wt / wt) of the mexiletine compound is released after 0 to 2 hours.

[0342] In some embodiments, a pharmaceutical composition comprising a mexiletine compound ion exchange resin complex of the present invention may exhibit an in vitro dissolution profile, when measured using a USP Type IV apparatus having a flow rate of about 8 ml / min with 6 gm glass beads in 0.1 N HCl medium at 37° C.±0.5° C., such that from about 10% (wt / wt) to about 85% (wt / wt), e.g., from about 10% (wt / wt) to about 80% (wt / wt), from about 10% (wt / wt) to about 70% (wt / wt), from about 10% (wt / wt) to about 60% (wt / wt) of the mexiletine is released after 0 to 4 hours, or, e.g., from about 0% (wt / wt) to about 50% (wt / wt), or, e.g., from about 10% (wt / wt) to about 65% (wt / wt), or from about 10% (wt / wt) to about 50% (wt / wt) of the mexiletine is released after 0 to 4 hours.

[0343] In some embodiments, a pharmaceutical composition comprising a mexiletine compound ion exchange resin complex of the present invention may release, for example, about 30% (wt / wt) to about 90% (wt / wt), about 30% (wt / wt) to about 80% (wt / wt), about 30% (wt / wt) to about 70% (wt / wt) of the mexiletine compound after 4 to 12 hours, e.g., about 30% (wt / wt) to about 90% (wt / wt), about 30% (wt / wt) to about 80% (wt / wt), about 30% (wt / wt) to about 70% (wt / wt) of the mexiletine compound after 4 to 12 hours, when measured using a USP Type IV apparatus having a flow rate of about 8 ml / min with 6 gm glass beads in 0.1 N HCl medium at 37° C.±0.5° C. The composition may exhibit an in vitro dissolution profile such that about 30% (wt / wt) to about 100% (wt / wt) is released, such as about 30% (wt / wt) to about 60% (wt / wt), or about 40% (wt / wt) to about 100% (wt / wt), about 50% (wt / wt) to about 100% (wt / wt), about 60% (wt / wt) to about 100% (wt / wt), about 70% (wt / wt) to about 100% (wt / wt), or about 80% (wt / wt) to about 100% (wt / wt).

[0344] In some embodiments, pharmaceutical compositions comprising a mexiletine compound ion exchange resin complex of the present invention may exhibit an in vitro dissolution profile, when measured using a USP Type IV apparatus having a flow rate of about 8 ml / min with 6 gm glass beads in a pH 5.0 acetate buffer medium at 37° C.±0.5° C., such that from about 0% (wt / wt) to about 30% (wt / wt) of mexiletine is released after 0 to 2 hours, from about 10% (wt / wt) to about 70% (wt / wt) of mexiletine is released after 0 to 4 hours, from about 30% (wt / wt) to about 100% (wt / wt) of mexiletine is released after 4 to 12 hours, or any combination thereof.

[0345] In some embodiments, pharmaceutical compositions comprising a mexiletine compound ion exchange resin complex of the present invention may exhibit an in vitro dissolution profile such that after 0 to 1 hour, about 50% (wt / wt) or more of the mexiletine is released, after about 2 hours, about 80% (wt / wt) or more of the mexiletine is released, and after about 4 hours, about 90% (wt / wt) or more of the mexiletine is released, when measured using a USP Type IV apparatus having a flow rate of about 8 ml / min with 6 gm glass beads in a pH 6.8 phosphate buffer medium at 37° C.±0.5° C.

[0346] In some embodiments, the release rate of the mexiletine compound is controlled by the thickness of the release retardant; thus, in some embodiments, the coating thickness can be altered to vary the release rate to obtain optimal dissolution and bioavailability profiles.

[0347] In some embodiments, pharmaceutical compositions comprising a mexiletine compound ion exchange resin complex of the present invention may exhibit an in vitro dissolution profile such that from about 10% (wt / wt) to about 65% (wt / wt) of the mexiletine compound is released after 0 to 4 hours, and from about 30% (wt / wt) to about 90% (wt / wt) of the mexiletine compound is released after 4 to 12 hours, when measured using a USP Type IV apparatus having a flow rate of about 8 ml / min with 6 gm glass beads in a pH 6.8 phosphate buffer medium at 37° C.±0.5° C.

[0348] In some embodiments, the pharmaceutical compositions of the present invention may exhibit an in vitro dissolution profile, when measured using a USP Type IV apparatus having a flow rate of about 8 ml / min with 6 gm glass beads in 0.1 N HCl medium at 37° C.±0.5° C., such that between 0 and 2 hours, about 0% (wt / wt) to about 30% (wt / wt) of the mexiletine compound is released; between 0 and 4 hours, about 10% (wt / wt) to about 40% (wt / wt) of the mexiletine compound is released; between 4 and 12 hours, about 30% (wt / wt) to about 70% (wt / wt) of the mexiletine is released; between 6 and 14 hours, greater than about 60% (wt / wt) of the mexiletine is released; and by 24 hours, greater than about 80% (wt / wt) of the mexiletine is released.

[0349] In some embodiments, the pharmaceutical compositions of the present invention may exhibit an in vitro dissolution profile, when measured using a USP Type IV apparatus having a flow rate of about 8 ml / min with 6 gm glass beads in a pH 5.0 acetate buffer medium at 37° C.±0.5° C., such that between 0 and 2 hours, about 0% (wt / wt) to about 25% (wt / wt) of the mexiletine compound is released; between 0 and 4 hours, about 10% (wt / wt) to about 40% (wt / wt) of the mexiletine compound is released; and between 4 and 12 hours, about 30% (wt / wt) to about 65% (wt / wt) or greater than about 65% (wt / wt) of the mexiletine compound is released.

[0350] In another embodiment, the pharmaceutical compositions of the present invention may exhibit an in vitro dissolution profile such that between 0 and 2 hours, about 0% (wt / wt) to about 35% (wt / wt) of the mexiletine compound is released; between 0 and 4 hours, about 10% (wt / wt) to about 50% (wt / wt) of the mexiletine compound is released; and between 4 and 12 hours, about 30% (wt / wt) to about 75% (wt / wt) or greater than about 75% (wt / wt) of the mexiletine compound is released, when measured using a USP Type IV apparatus having a flow rate of about 8 ml / min with 6 gm glass beads in a pH 6.8 phosphate buffer medium at 37° C.±0.5° C.

[0351] In another embodiment, the pharmaceutical compositions of the present invention may exhibit an in vitro dissolution profile, when measured in a United States Pharmacopeia (USP) Type II dissolution apparatus rotating at 75 rpm at a temperature of 37° C.±0.5° C., such that in 500 mL 0.1 N HCl, the composition releases 50% (wt / wt) or less of the mexiletine compound in the first hour, then in 700 mL pH 4.5 acetate buffer exchange medium, the composition releases 65% (wt / wt) or more of the mexiletine compound in 2 hours, and then further in 900 mL pH 6.8 phosphate buffer exchange medium, the composition releases 85% (wt / wt) or more of the mexiletine compound in 4 hours.

[0352] Pharmacokinetic properties The compositions of the present invention can be characterized, inter alia, by their pharmacokinetic (PK) profile based on one or more PK properties / parameters exhibited by the compositions of the present invention when administered to a subject. In some embodiments, the release profile of the pharmaceutical compositions of the present invention can be characterized as a peak plasma concentration (C max ), area under the curve (AUC), and time to maximum plasma concentration (Tmax) can be evaluated in vivo (for relative bioavailability determinations). In some embodiments, any specific value provided in this section should be construed to indicate any value within such range, to either end of such range, to any order of magnitude, and ranges, for example, from less than about 20% of such value to more than about 20% of such value, including subranges thereof.

[0353] In some embodiments, the relative bioavailability can be measured as the concentration in blood (serum or plasma) versus time area under the curve (AUC) determined for the test composition divided by the area under the curve (AUC) in hair obtained with the reference composition. Preferably, this test / reference ratio is determined for each subject. In some embodiments, the ratio is averaged across all subjects in the study.

[0354] In certain embodiments, the present invention provides an oral controlled release pharmaceutical composition comprising a mexiletine compound and at least one release retarding agent, wherein a single dose of the pharmaceutical composition administered once daily is sufficient to achieve a T max The composition provided herein has a median value of about 6 hours or more, such as, for example, about 4 hours to about 10 hours, for example, about 4 hours to about 9 hours, about 4 hours to about 8 hours, about 4 hours to about 7 hours, or about 4 hours to about 6 hours, such as, for example, about 5 hours to about 7 hours, such as, for example, about 5 hours to about 10 hours, about 6 hours to about 10 hours, about 7 hours to about 10 hours, or about 8 hours to about 10 hours, such as, for example, ≧4 hours, ≧5 hours, ≧6 hours, ≧7 hours, or ≧8 hours.

[0355] In certain embodiments, the present invention provides an oral controlled release pharmaceutical composition comprising a mexiletine compound and at least one release retarding agent, wherein a single dose of the pharmaceutical composition administered once daily has a concentration of about 700 ng / mL to about 1250 ng / mL, e.g., about 700 ng / mL to about 1150 ng / mL, about 700 ng / mL to about 1050 ng / mL, about 700 ng / mL to about 950 ng / mL, or about 700 ng / mL to about 850 ng / mL, e.g., about 800 ng / mL. C of about 763.2237 ng / mL or more, such as about 800 ng / mL to about 1250 ng / mL, about 900 ng / mL to about 1250 ng / mL, about 1000 ng / mL to about 1250 ng / mL, or about 1100 ng / mL to about 1250 ng / mL, for example, ≧700 ng / mL, ≧800 ng / mL, ≧900 ng / mL, ≧1000 ng / mL, 1100 ng / mL, or ≧1200 ng / mL. max The compositions are provided showing average values.

[0356] In an embodiment, the present invention provides an oral controlled release pharmaceutical composition comprising a mexiletine compound and at least one release retarding agent, wherein a single dose of the pharmaceutical composition administered once daily has a release rate of, e.g., about 15,500 ng·hr / mL to about 17,250 ng·hr / mL, e.g., about 15,500 ng·hr / mL to about 17,000 ng·hr / mL, about 15,500 ng·hr / mL to about 17,250 ng·hr / mL, or about 15,500 ng·hr / mL to about 160 AUC of about 12826.7066 ng·hr / mL or more, such as about 15500 ng·hr / mL to about 17250 ng·hr / mL, about 16000 ng·hr / mL to about 17250 ng·hr / mL, about 16000 ng·hr / mL to about 17250 ng·hr / mL, about 16500 ng·hr / mL to 17250 ng·hr / mL, or 17000 ng·hr / mL to about 17250 ng·hr / mL. 0~24 The compositions are provided showing average values.

[0357] In an embodiment, the present invention provides an oral controlled release pharmaceutical composition comprising a mexiletine compound and at least one release retarding agent, wherein a single dose of the pharmaceutical composition administered once daily is, for example, about 22000 ng·hr / mL to 24250 ng·hr / mL, e.g., about 22000 ng·hr / mL to about 24000 ng·hr / mL, about 22000 ng·hr / mL to about 23500 ng·hr / mL, about 22000 ng·hr / mL to about 23000 ng·hr / mL, or about 22000 ng·hr / mL to about 22500 ng·hr / mL, e.g., about 22500 ng·hr / mL. an AUC of about 22301.7312 ng·hr / mL or more, such as about 22500 ng·hr / mL to about 24250 ng·hr / mL, about 23000 ng·hr / mL to about 24250 ng·hr / mL, about 23500 ng·hr / mL to about 24250 ng·hr / mL, or about 24000 ng·hr / mL to about 24250 ng·hr / mL, for example, ≧22000 ng·hr / mL, ≧22500 ng·hr / mL, ≧23000 ng·hr / mL, ≧23500 ng·hr / mL, or ≧24000 ng·hr / mL 0~t The compositions are provided showing average values.

[0358] In some embodiments, the present invention provides an oral controlled release pharmaceutical composition comprising a mexiletine compound and at least one release retarding agent, wherein a single dose of the pharmaceutical composition administered once daily is, for example, about 22500 ng·hr / mL to 26000 ng·hr / mL, e.g., about 22500 ng·hr / mL to about 25500 ng·hr / mL, about 22500 ng·hr / mL to about 25000 ng·hr / mL, about 22500 ng·hr / mL to about 24500 ng·hr / mL, about 22500 ng·hr / mL to about 24000 ng·hr / mL, or about 22500 ng·hr / mL to about 23500 ng·hr / mL, e.g. an AUC of about 23345.7516 ng·hr / mL or more, such as about 23000 ng·hr / mL to about 25500 ng·hr / mL, for example, about 23000 ng·hr / mL to about 26000 ng·hr / mL, about 23500 to about 26000 ng·hr / mL, about 24000 ng·hr / mL to about 26000 ng·hr / mL, about 24500 ng·hr / mL to about 26000 ng·hr / mL, or 25000 ng·hr / mL to about 26000 ng·hr / mL, for example, ≧22500 ng·hr / mL, ≧23500 ng·hr / mL, ≧24500 ng·hr / mL, or ≧25500 ng·hr / mL 0~∞ The compositions are provided showing average values.

[0359] In an embodiment, the present invention provides an oral controlled release pharmaceutical composition comprising a mexiletine compound and at least one release retarding agent, wherein a single dose of the pharmaceutical composition administered once daily is t 1 / 2 The composition provided herein has an average value of about 12 hours or more, such as, for example, about 10 hours to about 13.5 hours, about 10 hours to about 13 hours, about 10 hours to about 12.5 hours, about 10 hours to about 12 hours, about 10 hours to about 11.5 hours, or about 10 hours to about 11 hours, for example, about 11.5 hours to about 13 hours, such as, for example, about 10.5 hours to about 13.5 hours, about 11 hours to about 13.5 hours, about 11.5 hours to about 13.5 hours, about 12 hours to about 13.5 hours, about 12.5 hours to about 13.5 hours, or about 13 hours to about 13.5 hours, for example, ≧10 hours, ≧10.5 hours, ≧11 hours, ≧11.5 hours, ≧12 hours, ≧12.5 hours, or ≧13 hours.

[0360] In some embodiments, the present invention provides an oral controlled release pharmaceutical composition comprising a mexiletine compound and at least one release retarding agent, wherein a single dose of the pharmaceutical composition administered once daily exhibits a mean Kel of about 0.05 or greater, e.g., about 0.05 to about 0.09, about 0.05 to about 0.08, about 0.05 to about 0.07, or about 0.05 to about 0.06, such as about 0.06 to about 0.08, e.g., about 0.06 to about 0.09, about 0.07 to about 0.09, or about 0.06 to about 0.09, such as ≧0.05, ≧0.06, ≧0.07, ≧0.08, or ≧0.09.

[0361] In an embodiment, the invention provides a controlled release once-daily pharmaceutical composition of a mexiletine compound complexed with a pharma- ceutically acceptable ion exchange resin, said pharmaceutical composition exhibiting a steady state concentration of mexiletine compound in an amount of from about 0.4 μg / mL to about 2.0 μg / mL, from about 0.4 μg / mL to about 1.5 μg / mL, or from about 0.4 μg / mL to about 1.0 μg / mL, such as from about 1.5 μg / mL to about 2.0 μg / mL, e.g., from about 0.8 μg / mL to about 2.5 μg / mL, from about 1.2 μg / mL to about 2.5 μg / mL, from about 1.6 μg / mL to about 2.5 μg / mL, or from about 2.0 μg / mL to about 2.5 μg / mL.

[0362] In some aspects, the present invention provides an oral controlled release pharmaceutical composition comprising a mexiletine compound and at least one release retarding agent, said pharmaceutical composition exhibiting a bioavailability relative to NaMuscla® based on area under the plasma concentration curve (AUC) over 24 hours following a once daily dose in human subjects of 167 mg or more of commercially available NaMuscla® capsules administered three times daily under fasted and fed conditions.

[0363] In an embodiment, the present invention provides an oral controlled release pharmaceutical composition comprising a mexiletine compound and at least one release retarding agent, the pharmaceutical composition having, for example, an AUC 0~24In one embodiment, the composition exhibits a relative bioavailability of about 140%, such as about 130%, about 135%, about 145%, or about 150%, relative to

[0364] In an embodiment, the present invention provides an oral controlled release pharmaceutical composition comprising a mexiletine compound and at least one release retarding agent, the pharmaceutical composition comprising: max The present invention provides a composition that exhibits a relative bioavailability of about 130% relative to

[0365] In an embodiment, the present invention provides an oral controlled release pharmaceutical composition comprising a mexiletine compound and at least one release retarding agent, the pharmaceutical composition having, for example, an AUC 0~24 In one embodiment, the composition exhibits a relative bioavailability of about 105%, such as about 90%, about 95%, about 100%, about 110%, or about 115% relative to

[0366] In an embodiment, the present invention provides an oral controlled release pharmaceutical composition comprising a mexiletine compound and at least one release retardant, the pharmaceutical composition comprising, for example, max In one embodiment, the composition exhibits a relative bioavailability of about 85%, such as about 75%, about 80%, about 90%, or about 95%.

[0367] In an embodiment, the present invention provides an oral controlled release pharmaceutical composition comprising a mexiletine compound and at least one release retardant, the pharmaceutical composition having a C 2 H 2 O 4 concentration in a fed state compared to a fasted state. max and increased AUC.

[0368] In an embodiment, the present invention provides an oral controlled release pharmaceutical composition comprising a mexiletine compound and at least one release retarding agent, the pharmaceutical composition having a C of about 40%, e.g., about 30%, about 35%, about 45%, or about 50%, of mexiletine hydrochloride when administered with food. maxand an increase in AUC of about 15%, such as about 5%, about 10%, about 20%, or about 25%.

[0369] In some embodiments, the mexiletine ion exchange resin complexes described herein may be coated with one or more release retarding agents and / or mixed with one or more different polymer coatings to form a single composition, and may be administered in a range of about 0.4 μg / ml to about 2.5 μg / ml, more preferably, for example, about 0.4 μg / ml to about 2.0 μg / ml, about 0.4 μg / ml to about 1.5 μg / ml, or about 0.4 μg / ml to about 1.0 μg / ml. The mexiletine compound may have one or more types of release profiles by maintaining a plasma concentration of the mexiletine compound in the range of about 0.5 μg / ml to 2 μg / ml, such as about 0.8 μg / ml to about 2.5 μg / ml, about 1.2 μg / ml to about 2.5 μg / ml, about 1.6 μg / ml to about 2.5 μg / ml, or about 2.0 μg / ml to about 2.5 μg / ml, such as about 1.5 μg / ml to about 2.0 μg / ml.

[0370] stability In some embodiments, the present invention provides pharmaceutical compositions that are free of any one impurity or the total amount / total number of impurities that have been deemed unsafe by one or more recognized regulatory agencies. In some embodiments, the present invention provides pharmaceutical compositions that are free of any one decomposition product or the total amount / total number of decomposition products that have been deemed unsafe by one or more recognized regulatory agencies. (For example, KOE-5692 (i.e., 2,3-dihydro-3,9-dimethyl-1,4-benzoxazepine) is a cyclic imine impurity (decomposition product) of mexiletine drug products.)

[0371] In certain embodiments, the present invention provides controlled release liquid suspensions with improved delivery characteristics. In some embodiments, the compositions of the present invention remain stable for extended periods of time when formulated in a multi-dose configuration. In some embodiments, the compositions of the present invention are stable under ambient, 30°C / 75% RH or 25°C / 60% RH or 40°C / 75% RH stability conditions for a period of at least about 1 month, ≥ about 2 months, ≥ about 3 months, ≥ about 4 months, ≥ about 5 months, or, for example, after at least about 6 months. In some embodiments, the compositions provided herein are at least substantially free of impurities, essentially free of impurities, or free of impurities after at least about 1 month, ≥ about 2 months, ≥ about 3 months, ≥ about 4 months, ≥ about 5 months, or, for example, after at least about 6 months. In some embodiments, the compositions provided herein are at least substantially free, essentially free, or free of impurities after at least about 1 month, ≧about 2 months, ≧about 3 months, ≧about 4 months, ≧about 5 months, or, e.g., at least about 6 months, as measured by a HPLC method, such as the HPLC methods briefly described herein.

[0372] In some embodiments, an analytical method using HPLC is used to detect one or more impurities in the compositions provided herein. In some embodiments, an Inertsil ODS 3v, 250×4.6 mm 5μ column is used, operating at a column temperature of 30° C. and a UV wavelength of 262 nm. Mobile phase A is, for example, a buffer, while mobile phase B is, for example, a mixture of acetonitrile and methanol. Sample diluent is, for example, a mixture of sodium acetate buffer and methanol containing 1.5% calcium chloride solution, with an injection volume of 10 μL. The mobile phase gradient (e.g., mobile phase gradient program for blank, placebo, and sample) is shown in Table 2 below. [Table 1]

[0373] In some embodiments, the compositions provided by the present invention have high stability as demonstrated by the data disclosed herein. In some embodiments, stability testing of the compositions provided by the present invention, when stored under recommended storage conditions, has not observed significant mexiletine compound degradation. In some embodiments, stability testing of the compositions provided by the present invention, when stored under recommended storage conditions for commercially relevant periods, has not observed significant mexiletine compound degradation.

[0374] Additional drug excipients In some embodiments, pharmaceutical compositions comprising the drug-resin complex can further comprise one or more pharma- ceutically and physiologically acceptable excipients. In some embodiments, for example, the pharma- ceutically acceptable excipients can be any of a number of art-recognized excipients, such as fillers, binders, bulking agents, diluents, disintegrants, glidants, colorants, anti-adherents, dispersants, lubricants, coating agents, preservatives, antioxidants, flavors, sweeteners, adsorbents, solvents, co-solvents, buffers, chelating agents, viscosity modifiers, surfactants, humectants, emulsifiers, and the like. In some embodiments, such pharmaceutical additives can be any pharma- ceutically acceptable pharmaceutical additives that aid in the manufacture of the dosage form, aid in the performance of the dosage form, or both, but do not impart significant pharmaceutical activity (e.g., are not active pharmaceutical ingredients (APIs). In some embodiments, pharmaceutical compositions comprising a drug-resin complex can include one or more pharma- ceutically acceptable and physiologically suitable carriers. In some embodiments, one or more components of the composition can provide, for example, a single component can provide, for example, detectable or significant dispersing activity, viscosity modifying activity, or a plurality of detectable or significant suspending activity in addition to, for example, one or more of emulsifying activity.

[0375] In some embodiments, formulations are established according to the target route of administration. Any of the well-known acceptable formulation techniques, composition carriers, and composition pharmaceutical additives may be used as appropriate and understood in the art. Exemplary ingredients suitable for the pharmaceutical compositions described herein can be found, for example, in Remington: The Science and Practice of Pharmacy, Nineteenth Ed (Easton, Pa.: Mack Publishing Company, 1995); Hoover, John E., Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975; Liberman, HA and Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, NY, 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Ed. (Lippincott Williams & Wilkinsl 999), which are incorporated herein by reference in their entirety.

[0376] In some embodiments, the compositions provided herein include one or more preservatives in an amount suitable to detectably or significantly inhibit microbial activity or in an amount sufficient to inhibit microbial activity (e.g., at an appropriate antimicrobial concentration). Suitable preservatives include mercury-containing substances such as merphen, thiomersal, and others; stabilized chlorine dioxide; and quaternary ammonium compounds such as benzalkonium chloride, cetyltrimethylammonium bromide, and cetylpyridinium chloride, and others, as well as other pharma- ceutically acceptable and physiologically suitable preservatives known in the art.

[0377] In certain aspects, the compositions herein include one or more dispersing agents, viscosity modifiers, or emulsifiers. Disintegrants and / or viscosity modifiers or emulsifiers can include, for example, substances that control the diffusion and homogenization or granulation or blending process of the drug through the liquid medium. In some embodiments, these agents can promote the effectiveness of the coating or eroding matrix. In some embodiments, exemplary diffusion facilitators / dispersing agents include, for example, hydrophilic polymers, electrolytes, Tween® 60 or 80 (e.g., polysorbate 60 or polysorbate 80), PEG, polyvinylpyrrolidone (PVP; commercially known as Plasdone®), and hydrocarbon-based dispersing agents such as, for example, hydroxypropylcellulose (e.g., HPC, HPC-SL, and HPC-L), hydroxypropylmethylcellulose (e.g., HPMC K100, HPMC K4M, HPMC K15M, and HPMC K100M), sodium carboxymethylcellulose, methylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate stearate (HPMCAS), amorphous cellulose, magnesium aluminum silicate, triethanolamine, polyvinyl alcohol (PVA), vinylpyrrolidone / vinyl acetate copolymer (S630), 4-(1,1,3,3-Tetramethylbutyl)phenol polymers (also known as tyloxapol), poloxamers (e.g., Pluronics F68®, F88®, and F108®, which are block copolymers of ethylene oxide and propylene oxide), poloxamines (e.g., Tetronic 908®, also known as Poloxamine 908®, a tetrafunctional block copolymer derived from the sequential addition reaction of propylene oxide and ethylene oxide to ethylenediamine (BASF Corporation, Parsippany, NJ)), polyvinylpyrrolidone K12, polyvinylpyrrolidone K17, polyvinylpyrrolidone K25, polyvinylpyrrolidone K30, polyvinylpyrrolidone / vinyl acetate copolymer (S-630), polyethylene glycol (e.g., polyethylene glycol having a molecular weight of about 300 g / mol to about 6000 g / mol, or about 3350 g / mol to about 4000 g / mol, or about 7000 g / mol to about 5400 g / mol), alginates such as sodium alginate, gums (e.g., gum tragacanth and gum arabic, guar gum, xanthan including xanthan gum), sugars, polyethoxylated sorbitan monolaurate, polyethoxylated sorbitan monolaurate, povidone, carbomer, polyvinyl alcohol (PVA), chitosan, and combinations thereof. Plasticizers such as cellulose or triethylcellulose can also be used as dispersing agents. For example, dispersing agents that are particularly useful in liposomal and self-emulsifying dispersions are dimyristoyl phosphatidylcholine, natural phosphatidylcholine from eggs, natural phosphatidylglycerol from eggs, cholesterol, and isopropyl imyristate.

[0378] In some embodiments, the compositions herein can include, for example, one or more flavoring or sweetening agents. In some embodiments, flavorings and / or sweeteners useful in the formulations described herein include, for example, acacia syrup, acesulfame K, alitame, anise, apple, aspartame, banana, bavarois, berry, blackcurrant, butterscotch, calcium citrate, camphor, caramel, cherry, cherry cream, chocolate, cinnamon, bubble gum, citrus, citrus punch, citrus cream, cotton candy, cocoa, cola, cool cherry, cool citrus, cyclamate, cyclamate, dextrose, eucalyptus, eugenol, fructose, fruit punch, ginger, glycyrrhetinic acid, licorice syrup, grape, grapefruit, honey, isomalt, lemon, lime, lemon cream, monoammonium glycyrrhizinate (MagnaSweet®), maltol, mannitol, maple, marshmallow, menthol, mint cream, mixed berry, neohesperidin DC, neo tame, orange, pear, pear, peppermint, peppermint cream, Prosweet® powder, raspberry, root beer, rum, saccharin, safrole, sorbitol, spearmint, spearmint cream, strawberry, strawberry cream, stevia, sucralose, sucrose, sodium saccharin, saccharin, aspartame, acesulfame potassium, mannitol, talc, sylitol, sucralose, sorbitol, Swiss cream, taga Toss, tangerine, thaumatin, tutti-frutti, vanilla, walnut, watermelon, wild cherry, wintergreen, xylitol, or any combination of these flavor ingredients, such as anise-menthol, cherry-anise, cinnamon-orange, cherry-cinnamon, chocolate-mint, honey-lemon, lemon-lime, lemon-mint, menthol-eucalyptus, orange-cream, vanilla-mint, and combinations or mixtures thereof.

[0379] In some embodiments, the compositions provided herein may include one or more suspending agents. In some embodiments, the suspending agents may include, for example, polyvinylpyrrolidone, e.g., polyvinylpyrrolidone K12, polyvinylpyrrolidone K17, polyvinylpyrrolidone K25, or polyvinylpyrrolidone K30, vinylpyrrolidone / vinyl acetate copolymer (S630), polyethylene glycol, e.g., the polyethylene glycol may have a molecular weight of about 300 to about 6000, or about 3350 to about 4000, or about 7000 to about 5400, sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, hydroxymethylcellulose acetate stearate, polyvinylpyrrolidone ... Resorbate 80, hydroxyethylcellulose, sodium alginate, gums such as tragacanth and gum arabic, guar gum, xanthan including xanthan gum, sugars, cellulose polymers such as sodium carboxymethylcellulose, methylcellulose, sodium carboxymethylcellulose, hydroxypropylmethylcellulose, hydroxyethylcellulose, polysorbate 80, sodium alginate, polyethoxylated sorbitan monolaurate, polyethoxylated sorbitan monolaurate, povidone, and the like.

[0380] In some embodiments, compositions provided herein can include one or more lubricants or slipping agents. In some embodiments, a lubricant or slipping agent is a compound that detectably or significantly prevents, reduces, or inhibits adhesion or friction of a material. Exemplary lubricants may include, for example, stearic acid, calcium hydroxide, talc, sodium stearyl fumarate, hydrocarbons such as mineral oil or hydrogenated vegetable oils such as hydrogenated soybean oil (Sterotex®), higher fatty acids and their alkali metal and alkaline earth metal salts such as aluminum, calcium, magnesium, zinc salts, sodium stearate, glycerol, talc, wax, Stearowet®, boric acid, sodium benzoate, sodium acetate, sodium chloride, leucine, polyethylene glycol (e.g., PEG-4000) or methoxypolyethylene glycol such as Carbowax™, sodium oleate, sodium benzoate, glyceryl behenate, polyethylene glycol, magnesium or sodium lauryl sulfate, colloidal silica such as Syloid™, Cab-O-Sil®, starch such as corn starch, silicone oil, surfactants, and the like.

[0381] In some embodiments, the pharmaceutical compositions provided by the present invention may include a carrier. In some embodiments, the carrier may be a liquid carrier. In some embodiments, the carrier may be an oil-based carrier. In some embodiments, the carrier may be a solid carrier. In some embodiments, the carrier in which the drug-resin complex of the present invention is suspended may optionally include one or more pharma- ceutically acceptable excipients known in the art. In some embodiments, exemplary components may include, for example, one or more sweeteners, a preservative such as methylparaben, propylparaben, or a combination thereof; and, for example, one or more emulsifiers such as polysorbate 80 or polysorbate 60 (e.g., Tween 80 or Tween 60). In some embodiments, the carrier can include one or more thickening agents, such as guar gum or xanthan gum; one or more humectants, such as propylene glycol or glycerin; one or more fragrances; one or more colorants; one or more suspending agents; one or more anti-agglomerating agents; one or more viscosity enhancing agents; one or more lubricants; one or more opacifying agents; or a combination of any or all of these.

[0382] Relative amounts and relationships between components In some embodiments, the amount of drug, e.g., mexiletine compound, loaded onto the resin may be, for example, from about 20% (wt / wt) to about 350% (wt / wt), from about 30% (wt / wt) to about 300% (wt / wt), from about 40% (wt / wt) to about 250% (wt / wt), or from about 50% (wt / wt) to about 20% (wt / wt) of the loaded mexiletine resin particles. 0% by weight (weight / weight), or, for example, about 50% by weight (weight / weight) to about 100% by weight (weight / weight), for example, about 50% by weight (weight / weight) to about 400% by weight (weight / weight), about 100% by weight (weight / weight) to about 400% by weight (weight / weight), about 150% by weight (weight / weight) to about 400% by weight (weight / weight), about 200% by weight (weight / weight) to about 400% by weight (weight / weight). For example, about 10 wt% (wt / wt) to about 350 wt% (wt / wt), about 10 wt% (wt / wt) to about 300 wt% (wt / wt), about 10 wt% (wt / wt) to about 400 wt% (wt / wt), about 250 wt% (wt / wt) to about 400 wt% (wt / wt), about 300 wt% (wt / wt) to about 400 wt% (wt / wt), or about 350 wt% (wt / wt) to about 400 wt% (wt / wt). The composition may be in the range of about 10 wt% (wt / wt) to about 400 wt% (wt / wt), such as about 10 wt% (wt / wt) to about 250 wt% (wt / wt), about 10 wt% (wt / wt) to about 200 wt% (wt / wt), about 10 wt% (wt / wt) to about 150 wt% (wt / wt), about 10 wt% (wt / wt) to 100 wt% (wt / wt), about 10 wt% (wt / wt) to about 50 wt% (wt / wt).

[0383] In some embodiments, ion exchange resins useful in the practice of the invention may be, for example, from about 10 wt% (wt / wt) to about 90 wt% (wt / wt), from about 10 wt% (wt / wt) to about 80 wt% (wt / wt), from about 10 wt% (wt / wt) to about 70 wt% (wt / wt), from about 10 wt% (wt / wt) to about 60 wt% (wt / wt), from about 10 wt% (wt / wt) to about 50 wt% (wt / wt), from about 10 wt% (wt / wt) to about 40 wt% (wt / wt), from about 10 wt% (wt / wt) to about 30 wt% (wt / wt), from about 10 wt% (wt / wt) to about 20 wt% (wt / wt), or, for example, about 20 wt% (wt / wt). The mexiletine ion exchange resin complex of the present invention may comprise from about 10% (wt / wt) to about 95% (wt / wt), such as from about 30% (wt / wt) to about 95% (wt / wt), from about 40% (wt / wt) to about 95% (wt / wt), from about 50% (wt / wt) to about 95% (wt / wt), from about 60% (wt / wt) to about 95% (wt / wt), from about 70% (wt / wt) to about 95% (wt / wt), from about 80% (wt / wt) to about 95% (wt / wt), or, for example, from about 90% (wt / wt) to about 95% (wt / wt).

[0384] In some embodiments, the drug loading onto the resin prior to coating is, for example, about 30% (wt / wt) to about 100% (wt / wt), about 40% (wt / wt) to about 100% (wt / wt), about 50% (wt / wt) to about 100% (wt / wt), about 60% (wt / wt) to about 100% (wt / wt), about 70% (wt / wt) to about 10% (wt / wt), about 80% (wt / wt) to about 100% (wt / wt), about 90% (wt / wt) to about 100% (wt / wt), or, for example, about 100% (wt / wt). As described elsewhere herein, in some embodiments, one of skill in the art can selectively increase or decrease the amount of drug loaded onto the resin particles to alter the drug release profile depending on the target selection. In some embodiments, selectively altering the amount of drug loaded onto the resin particles provides a desired in vivo plasma concentration profile.

[0385] In some embodiments, the composition may be in a ratio of about, such as, for example, about 1:0.5 to about 1:4, about 1:0.75 to about 1:3, or about 1:1, such as, for example, 1:0.25 to about 1:5, for example, about 1:0.25 to about 1:9, about 1:0.25 to about 1:8, about 1:0.25 to about 1:7, about 1:0.25 to about 1:6, about 1:0.25 to about 1:5, about 1:0.25 to about 1:4, about 1:0.25 to about 1:3, about 1:0.25 to about 1:2, or about 1:0.25 to about 1 In some embodiments, the ratio of drug, e.g., a mexiletine compound, e.g., a salt of mexiletine, to ion exchange resin may range from about 1:0.25 to about 1:10, such as about 1:0.5 to about 1:10, about 1:0.75 to about 1:10, about 1:1 to about 1:10, about 1:2 to about 1:10, about 1:3 to about 1:10, about 1:4 to about 1:10, about 1:5 to about 1:10, about 1:6 to about 1:10, about 1:7 to about 1:10, about 1:8 to about 1:10, or about 1:9 to about 1:10.

[0386] In some embodiments, the release retardant of the coated mexiletine ion exchange resin complex particles is, for example, about 10% (wt / wt) to about 25% (wt / wt), such as, for example, about 10% (wt / wt) to about 30% (wt / wt), about 15% (wt / wt) to about 30% (wt / wt), about 20% (wt / wt) to about 30% (wt / wt), or, for example, about 25% of the total weight of the composition including the coated complex. The coated composite may be present in an amount ranging from about 5% (wt / wt) to about 30% (wt / wt) of the total weight of the composition including the coated composite, such as, for example, an amount of from about 5% (wt / wt) to about 25% (wt / wt), from about 5% (wt / wt) to about 20% (wt / wt), from about 5% (wt / wt) to about 15% (wt / wt), or from about 5% (wt / wt) to about 10% (wt / wt).

[0387] In some embodiments, the compositions include one or more release retardants, such as, for example, hydroxypropyl methylcellulose, ethyl cellulose, or a combination thereof, where the ratio of hydroxypropyl methylcellulose to ethyl cellulose is from 30:70 (1:2.3) to about 0:100, such as, for example, 25:75 (1:3) to about 95:05 (1:0.05).

[0388] In some embodiments, the amount of sodium polystyrene sulfonate (Amberlite IRP69) is from about 20% (wt / wt) to about 85% (wt / wt), such as from about 40% (wt / wt) to about 85% (wt / wt), about 50% (wt / wt), such as, for example, about 35% (wt / wt) to about 80% (wt / wt), about 40% (wt / wt) to about 70% (wt / wt), about 45% (wt / wt) to about 60% (wt / wt), about 45% (wt / wt) to about 55% (wt / wt), or about 50% (wt / wt) of the total composition.

[0043] The composition is present in an amount ranging from about 30% (wt / wt) to about 80% (wt / wt), about 40% (wt / wt) to about 80% (wt / wt), about 50% (wt / wt) to about 80% (wt / wt), about 60% (wt / wt) to about 80% (wt / wt), or about 70% (wt / wt) to about 80% (wt / wt).

[0389] In some embodiments, the amount of the release-retarding first coating agent, e.g., coating 1 agent, e.g., hydroxypropyl methylcellulose (e.g., 3 mPa to 4000 mPa hydroxypropyl methylcellulose), is present in an amount ranging from about 1.7% (wt / wt) to about 1.9% (wt / wt), such as about 1.75% (wt / wt) to about 1.9% (wt / wt), about 1.8% (wt / wt) to about 1.9% (wt / wt), such as about 1.85% (wt / wt) to about 1.9% (wt / wt), e.g., about 1.7% (wt / wt) to about 1.85% (wt / wt), about 1.7% (wt / wt) to about 1.8% (wt / wt), about 1.7% (wt / wt) to about 1.75% (wt / wt), e.g., about 1.8% (wt / wt) of the total composition.

[0390] In some embodiments, the amount of the release-retarding second coating agent, e.g., coating 2, includes, for example, hydroxypropyl methylcellulose (e.g., 3 mPa to 4000 mPa hydroxypropyl methylcellulose) present in the range of about 0.4% (wt / wt) to about 2.6% (wt / wt), ethylcellulose (e.g., 3 mPa to 330 mPa ethylcellulose) present in the range of about 3.3% (wt / wt) to about 7.8% (wt / wt), and triethyl citrate present in the range of about 0.2% (wt / wt) to about 0.6% (wt / wt). In some embodiments, such second coating comprises hydroxypropyl methylcellulose in an amount of about, e.g., about 0.4% (wt / wt) to about 2.5% (wt / wt), about 0.4% (wt / wt) to about 2% (wt / wt), about 0.4% (wt / wt) to about 1.5% (wt / wt), about 0.4% (wt / wt) to about 1% (wt / wt), such as, for example, 0.4% (wt / wt) to 2.6% (wt / wt), such as, for example, about 0.5% (wt / wt) to about 2.6% (wt / wt), about 1% (wt / wt) to about 2.6% (wt / wt), about 1.5% (wt / wt) to about 2.6% (wt / wt), or about 2% (wt / wt) to about 2.6% (wt / wt), such as, for example, about 1% (wt / wt) to about 2% (wt / wt) of the total composition.In some embodiments, such second coating comprises from about 3.3% (wt / wt) to about 7.8% (wt / wt) of the total composition, e.g., from about 3.3% (wt / wt) to about 7.5% (wt / wt), from about 3.3% (wt / wt) to about 7% (wt / wt), from about 3.3% (wt / wt) to about 6.5% (wt / wt), from about 3.3% (wt / wt) to about 6% (wt / wt), from about 3.3% (wt / wt) to about 5.5% (wt / wt), from about 3.3% (wt / wt) to about 5% (wt / wt), from about 3.3% (wt / wt) to about 4.5% (wt / wt), from about 3.3% (wt / wt) to about 4% (wt / wt), or from about 3.3% (wt / wt) to about 3.5% (wt / wt). The ethyl cellulose is contained in an amount of about 3.5% (wt / wt) to about 7.8% (wt / wt), about 4% (wt / wt) to about 7.8% (wt / wt), about 4.5% (wt / wt) to about 7.8% (wt / wt), about 5% (wt / wt) to about 7.8% (wt / wt), about 5.5% (wt / wt) to about 7.8% (wt / wt), about 6% (wt / wt) to about 7.8% (wt / wt), about 6.5% (wt / wt) to about 7.8% (wt / wt), about 7% (wt / wt) to about 7.8% (wt / wt), or about 7.5% (wt / wt) to about 7.8% (wt / wt), for example, about 4% (wt / wt) to about 7% (wt / wt).In some embodiments, the second coating may comprise from about 0.2% (wt / wt) to about 0.6% (wt / wt) of the total composition, e.g., from about 0.2% (wt / wt) to about 0.55% (wt / wt), from about 0.2% (wt / wt) to about 0.5% (wt / wt), from about 0.2% (wt / wt) to about 0.45% (wt / wt), from about 0.2% (wt / wt) to about 0.4% (wt / wt), from about 0.2% (wt / wt) to about 0.35% (wt / wt), from about 0.2% (wt / wt) to about 0.3% (wt / wt), or from about 0.2% (wt / wt) to about 0.25% (wt / wt). For example, triethyl citrate is contained in an amount of about 0.25% (wt / wt) to about 0.6% (wt / wt), about 0.3% (wt / wt) to about 0.6% (wt / wt), about 0.35% (wt / wt) to about 0.6% (wt / wt), about 0.4% (wt / wt) to about 0.6% (wt / wt), about 0.45% (wt / wt) to about 0.6% (wt / wt), about 0.5% (wt / wt) to about 0.6% (wt / wt), or about 0.55% (wt / wt) to about 0.6% (wt / wt), for example, about 0.3% (wt / wt) to about 0.5% (wt / wt).

[0391] In some embodiments, the dispersible tablet composition has a dispersible fraction of about 60% (wt / wt) to about 70% (wt / wt), such as, for example, 60% (wt / wt) to about 68% (wt / wt), about 60% (wt / wt) to about 66% (wt / wt), about 60% (wt / wt) to about 64% (wt / wt), about 60% (wt / wt) to about 62% (wt / wt), such as, for example, about 62% (wt / wt) to about 68% (wt / wt), or, for example, 62% (wt / wt). The sustained release coated mexiletine compound, e.g., mexiletine hydrochloride, e.g., mexiletine HCl resinate, is present in an amount of from about 62% (wt / wt) to about 70% (wt / wt), such as from about 64% (wt / wt) to about 70% (wt / wt), from about 66% (wt / wt) to about 70% (wt / wt), or from about 68% (wt / wt) to about 70% (wt / wt).

[0392] In some embodiments, the composition comprises from about 3% (wt / wt) to about 6% (wt / wt) of the composition, e.g., from about 3% (wt / wt) to about 5.5% (wt / wt), from about 3% (wt / wt) to about 5% (wt / wt), from about 3% (wt / wt) to about 4.5% (wt / wt), from about 3% (wt / wt) to about 4% (wt / wt), or from about 3% (wt / wt) to about 3.5% (wt / wt), e.g., about 4% (wt / wt) of the composition. ) to about 5% (wt / wt), for example, about 3.5% (wt / wt) to about 6% (wt / wt), about 4% (wt / wt) to about 6% (wt / wt), about 4.5% (wt / wt) to about 6% (wt / wt), about 5% (wt / wt) to about 6% (wt / wt), or about 5.5% (wt / wt) to about 6% (wt / wt).

[0393] In some embodiments, the composition comprises crystalline cellulose present in an amount of about 10% (wt / wt) to about 15% (wt / wt), e.g., about 10% (wt / wt) to about 14% (wt / wt), about 10% (wt / wt) to about 13% (wt / wt), about 10% (wt / wt) to about 12% (wt / wt), about 10% (wt / wt) to about 11% (wt / wt), or, for example, about 12% (wt / wt) to about 15% (wt / wt), about 12% (wt / wt) to about 15% (wt / wt), about 13% (wt / wt) to about 15% (wt / wt), about 14% (wt / wt) to about 15% (wt / wt).

[0394] In some embodiments, the composition comprises colloidal silicon dioxide in an amount of about 0.5% (wt / wt) to about 2% (wt / wt) of the total composition, e.g., about 0.5% (wt / wt) to about 1.5% (wt / wt), or about 0.5% (wt / wt) to 1% (wt / wt), e.g., about 1% (wt / wt) to about 2% (wt / wt), or about 1.5% (wt / wt) to about 2% (wt / wt), e.g., about 0.8% (wt / wt) to about 1.2% (wt / wt).

[0395] In some embodiments, the composition comprises sucralose in an amount of about 1% (wt / wt) to about 5% (wt / wt), such as about 1% (wt / wt) to about 4% (wt / wt), about 1% (wt / wt) to about 3% (wt / wt), or about 1% (wt / wt) to about 2% (wt / wt), such as about 2% (wt / wt) to about 3% (wt / wt), for example, about 2% (wt / wt) to about 5% (wt / wt), about 3% (wt / wt) to about 5% (wt / wt), or about 4% (wt / wt) to about 5% (wt / wt) of the total composition.

[0396] In some embodiments, the composition comprises a flavoring, e.g., a strawberry flavor / flavoring (flavor / flavoring), in an amount of from about 1% (wt / wt) to about 5% (wt / wt), such as from about 1% (wt / wt) to about 4% (wt / wt), from about 1% (wt / wt) to about 3% (wt / wt), or from about 1% (wt / wt) to about 2% (wt / wt), such as from about 2% (wt / wt) to about 3% (wt / wt), from about 2% (wt / wt) to about 5% (wt / wt), from about 3% (wt / wt) to about 5% (wt / wt), or from about 4% (wt / wt) to about 5% (wt / wt) of the total composition.

[0397] In some embodiments, the composition may be present in an amount of from about 10% (wt / wt) to about 15% (wt / wt), e.g., from about 10% (wt / wt) to about 14% (wt / wt), from about 10% (wt / wt) to about 13% (wt / wt), from about 10% (wt / wt) to about 12% (wt / wt), from about 10% (wt / wt) to about 11% (wt / wt), or, e.g., from about 12% (wt / wt) to about 15% (wt / wt), or about 13% (wt / wt) to about 15% (wt / wt), such as about 11% (wt / wt) to about 15% (wt / wt), about 12% (wt / wt) to about 15% (wt / wt), about 13% (wt / wt) to about 15% (wt / wt), about 14% (wt / wt) to about 15% (wt / wt), or, for example, about 12% (wt / wt) to about 13% (wt / wt).

[0398] In some embodiments, the composition comprises magnesium stearate in an amount of about 0.2% (wt / wt) to about 5% (wt / wt), such as, for example, about 0.2% (wt / wt) to about 4% (wt / wt), about 0.2% (wt / wt) to about 3% (wt / wt), or about 0.2% (wt / wt) to about 2% (wt / wt), for example, about 0.4% (wt / wt) to about 5% (wt / wt), about 0.6% (wt / wt) to about 5% (wt / wt), or about 0.8% (wt / wt) to about 5% (wt / wt), or for example, 0.8% (wt / wt) to 1.2% (wt / wt) of the total composition.

[0399] Excluded / Excluded Elements In one embodiment, the invention provides a controlled release pharmaceutical composition comprising a drug, e.g., a mexiletine compound, administered no more than once per 12 hour, 14 hour, 16 hour, 18 hour, 20 hour, 22 hour, or 24 hour period, said composition not comprising at least one ingredient present in NaMuscla®, e.g., not comprising one or more, two or more, three or more, four or more, or e.g., five or more ingredients present in NaMuscla®. "NaMuscla®" or "approved immediate release mexiletine composition" herein or elsewhere herein refers to a medicinal product approved with the European Medicines Agency product number EMA / 831802 / 2018 that received such first granted first marketing authorization effective throughout the European Union on July 21, 2016; this product has been designated an orphan medicinal product EU / 3 / 14 / 1353 on November 19, 2014; is a product that is featured in Europe as NaMuscla® as of the filing date of this application, or any combination thereof.

[0400] In one embodiment, the invention provides a controlled release pharmaceutical composition comprising a drug, e.g., a mexiletine compound, administered no more than once per about 12 hour, 14 hour, 16 hour, 18 hour, 20 hour, 22 hour, or 24 hour period, said composition not including at least one component in Mexitil, e.g., not including one or more, two or more, three or more, four or more, or e.g., five or more components present in Mexitil. "Mexitil" or "approved marketed mexiletine hydrochloride product" herein or elsewhere herein refers to a drug product approved by the FDA under NDA #018873 and the trade name Mexitil® and marketed under such trademark in the United States by Boehringer Ingelheim Pharmaceuticals, Inc., e.g., as of December 31, 1985, December 31, 2020, or December 31, 2021, prior to the filing of this disclosure; refers to the drug product originally approved on December 30, 1985, or another product marketed under the same NDA.

[0401] Exemplary target composition (e.g., product) profile characteristics are shown in Table 1 (below). In some embodiments, the compositions provided herein include one or more, two or more, three or more, four or more, or all five such characteristics shown in Table 1. In some embodiments, Table 1 shows one or more exemplary sustained release characteristics of the compositions provided by the invention, one or more exemplary pharmacokinetic characteristics of the compositions provided by the invention, or a combination thereof. [Table 2]

[0402] In one embodiment, the invention provides pharmaceutical compositions comprising a mexiletine compound complexed with a pharma- ceutically acceptable ion exchange resin, the compositions being characterized as controlled release mexiletine compound compositions, sustained release mexiletine compound compositions, or both. For example, immediate release mexiletine compositions, such as NaMuscla®, typically provide a therapeutic effect lasting for about 6 to 8 hours, e.g., for about 6 hours or less, 7 hours or less, or for example, typically for about 8 hours or less. Thus, in some embodiments, sustained release or controlled release mexiletine compound compositions described herein are characterized as having therapeutically effective plasma levels of mexiletine for at least about 10 hours to at least about 24 hours, e.g., ≥ about 12 hours, ≥ about 14 hours, ≥ about 16 hours, ≥ about 18 hours, ≥ about 20 hours, ≥ about 22 hours, or for at least about 10 hours to at least about 24 hours, e.g., ≥ about 24 hours. In some embodiments, the release profile of the compositions provided herein allows for the compositions to be administered no more than about twice a day, or only about once a day, e.g., once or twice a day. In some embodiments, the compositions herein are administered no more than once a day.

[0403] How to use In some embodiments, the present invention provides a method of modulating a sodium channel. In some embodiments, the present invention blocks state-dependent (inactivated sodium channels). In some embodiments, the present invention provides a method of modulating a sodium channel, the sodium channel exhibiting detectably or significantly slower recovery times when compared to lidocaine modulating the sodium channel. In some embodiments, the present invention provides a method of modulating a sodium channel by enhancing fast inactivation of the sodium channel, resulting in use-dependent sodium channel block. In some embodiments, the present invention provides a method of preparation that modulates a sodium channel by any one of the aforementioned effects, but does not exhibit any significant, e.g., detectable or significant, effect on chloride channels. In some embodiments, the methods provided herein can include the use of any one or more compositions described herein. In some embodiments, the methods provided herein can include the use of any one or more compositions described herein that are produced by any one or more methods described herein.

[0404] Adverse events As previously discussed, the compositions described herein can detectably or significantly reduce, limit, or, e.g., eliminate, undesirable side effects associated with multiple administrations of mexiletine immediate release compositions, including undesirable cardiac and gastrointestinal related side effects (e.g., those reported in association with the use of NaMuscla®, e.g., those reported in one or more NaMuscla® regulatory documents, product labeling, or one or more appropriate comparative studies).

[0405] In some embodiments, the compositions described herein detectably or significantly reduce one or more side effects associated with administration of multiple doses of a mexiletine immediate release composition, such as detectably or significantly reducing one or more cardiac-related effects, detectably or significantly reducing one or more gastrointestinal-related effects, or both.

[0406] In some embodiments, the compositions described herein may exhibit detectably lower adverse events, or significantly less adverse events, specifically related to cardiac and gastrointestinal adverse events, when compared to current commercially available treatments administered three times daily (e.g., treatment with NaMuscla®).

[0407] compliance In some embodiments, the compositions described herein detectably or significantly improve patient compliance as compared to mexiletine compositions that require administration more than once or more than twice a day, or, for example, per 12, 18, or 24 hours.

[0408] In some embodiments, the compositions described herein detectably or significantly improve patient compliance at an individual level, a population level, or both. In some embodiments, at a population level, for example within a population of myotonia patients, the compositions described herein demonstrate detectably or significantly greater medication compliance due to a single administration of a mexiletine compound associated with a reduction in one or more adverse cardiac events, associated with a reduction in one or more gastrointestinal-related adverse events, or a combination thereof.

[0409] Manufacturing method In one aspect, the present invention provides a method for preparing a controlled release once-daily dispersible tablet comprising a mexiletine compound in the form of a mexiletine compound-resin complex and a pharma- ceutically acceptable ion exchange resin, and at least one release controlling coating layer enveloping at least a portion of each complex, at least a portion of the total complex present in the composition, or both, for controlling the release of the mexiletine compound.

[0410] In one embodiment, the present invention provides a method for making the compositions described herein. In some embodiments, the present invention provides a method (e.g., process) in which ion exchange resin particles are loaded with a pharmaceutical drug prior to incorporation into a polymer system to produce a drug resin that is further coated with a release retarding polymer to produce a controlled release drug resin complex.

[0411] In some aspects, the invention provides products made by any of the methods described herein, including, for example, the methods of manufacture described herein. EXAMPLES

[0412] Examples of Applications, Embodiments, or Principles The following detailed examples of applications, embodiments, or principles ("Examples") are provided to aid the reader in further understanding of aspects of the present invention or principles related to the practice of aspects of the present invention. Any specific materials, methods, steps, and conditions used / described in the following examples, and any results thereof, are intended merely to further illustrate aspects of the present invention. These examples reflect exemplary embodiments of the present invention, and the specific methods, findings, principles, and general effects of such examples may be combined with any other part of this disclosure. However, the reader should understand that the present invention is not limited by these examples or any part thereof.

[0413] Example 1: Method for preparing uncoated mexiletine ion exchange resin complex The following non-limiting examples demonstrate preferred compositions of the present invention, which are prepared on a weight to volume (w / v) basis.

[0414] Mexiletine ion exchange resin complex was prepared by first dissolving mexiletine hydrochloride in pure water under stirring. Sodium polystyrene sulfonate (Amberlite IRP 69) was then dispersed in the solution with continuous stirring for 18-20 hours. After stirring, the dispersion was then allowed to settle and the supernatant was decanted. After decanting the supernatant, sufficient water was added with continuous stirring for an appropriate time to produce a slurry. The slurry was filtered through 325 mesh, air dried in a fluid bed dryer for 30 minutes, and then dried at an inlet temperature of 60°C until an LOD NMT of 4.0% was obtained to finally produce the mexiletine ion exchange resin complex.

[0415] The mexiletine ion exchange resin ratios and the percentage of mexiletine loading on the ion exchange resin for Composition A, Composition B, Composition C, and Composition D are shown in Table 2 (below). [Table 3]

[0416] Exemplary uncoated mexiletine ion exchange resin complexes were dissolution tested using a USP Type IV dissolution apparatus at 8 mL / min, 6 g beads, 0.1 N HCl, at 37° C.±0.5° C. The data is presented in Table 3 (below). Baseline conditions for dissolution testing include those known in the art. [Table 4]

[0417] As shown in Table 3 (above), Compositions B and D demonstrated dissolution profiles with drug resin ratio compositions that averaged 1:1 and 1:15, respectively. As further shown in Table 3 (above), Compositions A and D demonstrated dissolution profiles where, on average, about 81% and 84%, respectively, of all respective compositions were dissolved after 12 hours under the test conditions. These results illustrate that compositions according to the present invention can exhibit dissolution profiles where a significant amount of mexiletine remains undissolved after several hours (after 6 hours, at least about 15% remaining, such as 10%-50% remaining, such as about 5%-40% remaining; after 8 hours, at least 1% remaining, such as 1%-30%, and in most cases at least 10% remaining; after 12 hours, in most cases at least 1% remaining, such as 2%-20%).

[0418] Assays were performed for Composition A, Composition B, Composition C, and Composition D. The data is shown in Table 4 (below). The basic conditions for the assay included tests performed by HPLC with a UV / PDA detector. [Table 5]

[0419] A second dissolution test was performed on the exemplary uncoated mexiletine ion exchange resin complex, USP Type IV, 8 mL / min, 6 g beads, and pH 5.0 acetate buffer medium at 37° C.±0.5° C. The data is shown in Table 5 (below).

[0420] [Table 6]

[0421] As shown in Table 5 (above), Composition B demonstrated a dissolution profile where, on average, about 88% of the total composition was dissolved after 8 hours at a pH of 5.0 under test conditions. These results illustrate that compositions according to the present invention can exhibit dissolution profiles where a significant amount of mexiletine remains undissolved after several hours (at least about 20% remaining after 6 hours, at least about 12% remaining after 8 hours; at least about 4% remaining after 12 hours).

[0422] A third dissolution test was performed on an exemplary uncoated mexiletine ion exchange resin complex, USP Type IV, 8 mL / min, 6 g beads, and pH 6.8 phosphate buffer medium at 37° C.±0.5° C. The data is shown in Table 6 (below). [Table 7]

[0423] As shown in Table 6 (above), Composition B demonstrated a dissolution profile where, on average, about 96% of the total composition was dissolved after 4 hours at a pH of 6.8 under test conditions. These results illustrate that compositions according to the present invention can exhibit dissolution profiles where a significant amount of mexiletine remains undissolved after several hours (at least about 20% remaining after 2 hours, at least about 10% remaining after 3 hours; at least about 4% remaining after 4 hours).

[0424] Example 2: A method for sustained release coating of mexiletine ion exchange resin complex using a fluid bed processor. This example demonstrates a method for sustained release coating of an exemplary mexiletine ion exchange resin complex using a fluid bed processor.

[0425] Step 1: Hydroxypropyl methylcellulose was dissolved in sufficient amount of water and / or isopropyl alcohol with continuous stirring.

[0426] Step 2: The mexiletine ion exchange resin was loaded into a fluid bed processor and the coating solution was applied until the desired weight was obtained.

[0427] Step 3: Further, hydroxypropyl methylcellulose was dispersed in isopropyl alcohol under stirring, and methylene dichloride was added and stirred continuously until a clear solution was obtained.

[0428] Step 4: Ethyl cellulose and triethyl citrate were added to the above solution and stirred until a clear solution was formed.

[0429] Step 5: The coated mexiletine ion exchange resin complex obtained from step 2 was again coated with the coating solution of step 4 in a fluid bed processor until the desired coating weight was obtained. Finally, the coated mexiletine ion exchange resin complex was dried to an LOD of 4.0% or less and sieved through a suitable sieve or screen.

[0430] Coating concentrations that provide sustained release mexiletine ion exchange resin complex are shown in Table 7 (below). [Table 8]

[0431] Dissolution testing was performed on the coated drug-resin complex in USP Type IV dissolution, 8 mL / min, 6 g beads, 0.1 N HCl, 37° C.±0.5° C. The data is shown in Table 8 (below). [Table 9]

[0432] As shown in Table 8 (above), Compositions E and F exhibit dissolution profiles in which, on average, about 83% and 92% of the total composition is dissolved after 8 hours under the test conditions. As further shown in Table 8, Compositions G and H exhibit dissolution profiles in which, on average, about 79% and 73% of the total composition is dissolved after 8 hours under the test conditions. Furthermore, as shown in Table 8, Composition I exhibits a dissolution profile in which, on average, about 57% of the total composition is dissolved after 8 hours under the test conditions. In particular, as shown in Table 8, Composition I exhibits a dissolution profile in which, on average, about 65% of the total composition is dissolved after 12 hours under the test conditions. These results illustrate that compositions according to the invention can exhibit dissolution profiles in which a significant amount of mexiletine remains undissolved after several hours (after 6 hours, at least about 35% remaining, such as about 16% to about 50% remaining; after 8 hours, at least 25% remaining, such as 10% to 40%, and in most cases at least about 30%; after 12 hours, in most cases at least about 15%, such as 5% to 35%).

[0433] A second dissolution test was performed on the coated drug-resin complex in USP Type IV dissolution, 8 mL / min, 6 g beads, pH 5.0 acetate buffer medium, 37° C.±0.5° C. The data is shown in Table 9 (below). [Table 10]

[0434] As shown in Table 9 (above), Compositions F and H demonstrate dissolution profiles where, on average, about 67% and 49% of the total composition is dissolved after 8 hours at a pH of 5.0 under test conditions. As further shown in Table 9, Compositions F and H demonstrate dissolution profiles where, on average, about 77% and 59% of the total composition is dissolved after 12 hours at a pH of 5.0 under test conditions. These results illustrate that compositions according to the present invention can exhibit dissolution profiles where a significant amount of mexiletine remains undissolved after several hours (after 6 hours, at least about 45% remaining, such as about 40% to about 58% remaining; after 8 hours, at least 40% remaining, such as 30% to 50% remaining; after 12 hours, in most cases at least about 35%, such as 35% to 45%).

[0435] A third dissolution test was performed on the coated drug-resin complex in USP Type IV dissolution, 8 mL / min, 6 g beads, pH 6.8 phosphate buffer medium, 37° C.±0.5° C. The data is shown in Table 10 (below). [Table 11]

[0436] As shown in Table 10 (above), Compositions F and H demonstrate dissolution profiles where, on average, about 80% and 64% of the total composition is dissolved after 8 hours at a pH of 6.8 under test conditions. As further shown in Table 10, Compositions F and H demonstrate dissolution profiles where, on average, about 88% and 73% of the total composition is dissolved after 12 hours at a pH of 6.8 under test conditions. These results illustrate that compositions according to the present invention can exhibit dissolution profiles where a significant amount of mexiletine remains undissolved after several hours (after 6 hours, at least about 35% remaining, such as about 30% to about 45% remaining; after 8 hours, at least 30% remaining, such as 20% to 35% remaining; after 12 hours, in most cases at least about 20%, such as 15% to 25% remaining).

[0437] Example 3: Method for making dry powder for oral suspension This example demonstrates how to make a dry powder for oral suspension.

[0438] Step-1: Sucrose (part quantity) was mixed with suspending agents and viscosity modifiers (spray dried blend of hydroxypropyl cellulose or microcrystalline cellulose and sodium carboxymethylcellulose or guar gum or xanthan gum or sodium carboxymethylcellulose or povidone) and sieved through a 40 mesh sieve.

[0439] Step 2: Sift together methylparaben, propylparaben and a portion of sucrose through a 40 mesh sieve.

[0440] Step 3: Simultaneous sieving is done by sieving colloidal silicon dioxide or microcrystalline cellulose or starch or talc or sucralose or aspartame with a portion of sucrose through a 40 mesh sieve.

[0441] Step 4: The flavor is further co-sieved with a portion of sucrose through a 40 mesh sieve.

[0442] Step 5: The contents of step 1 were mixed with step 4.

[0443] Step 6: The coated mexiletine ion exchange resin complex was added to step 5 and blended.

[0444] Step 7: The contents of step 6 are filled into sachets (unit dose or multi-dose) or bottles (unit dose or multi-dose).

[0445] Example 4: Method of making prepared oral suspension: This example demonstrates how to make the oral suspension prepared.

[0446] The co-mixture of crystalline cellulose and sodium carboxymethylcellulose as suspending agent was added to the water under stirring, then sucrose was added under stirring, and then preservative, flavor, sweetener were added thereto. The coated drug-resin complex obtained in Example 2 was added thereto and stirred. The final content was filled into sachets or bottles (unit dose or multiple doses).

[0447] The components (TI) of Suspension Composition 1 and their respective % (w / w) are shown in Table 11 (below). [Table 12]

[0448] Dissolution testing was performed on Suspension Composition 1 (TI) at USP Type IV dissolution, 8 mL / min, 6 g beads, and 0.1 N HCl at 37° C.±0.5° C. The data is shown in Table 12 (below). [Table 13]

[0449] As shown in Table 12 (above), Suspension Composition 1 (T1) demonstrates a dissolution profile where, on average, about 59% of the total suspension composition is dissolved after 8 hours under the test conditions. As further shown in Table 12 (above), the suspension compositions demonstrate a dissolution profile where, on average, about 81% of the total suspension composition is dissolved after 24 hours under the test conditions. These results illustrate that compositions according to the present invention can exhibit dissolution profiles where a significant amount of mexiletine remains undissolved after several hours (at least about 50% remaining after 6 hours, at least about 30% remaining after 16 hours; at least about 20% remaining after 24 hours).

[0450] As a result of this study, and as further illustrated above, the present invention provides various forms of compositions and methods of making that may be advantageous to the treatment population.

[0451] Example 5: Stability Study This example demonstrates several stability studies.

[0452] Stability study for Suspension Composition 1 (T1): Samples were held for stability study for periods of 1 month, 3 months and 6 months. Afterwards, assay % and decomposition product studies were conducted to evaluate the stability of the samples. Details of the stability study are given below for 40°C / 75%RH and 30°C / 75%RH.

[0453] Stability studies were performed at 40° C. / 75% RH using aluminum pouches. The data is shown in Table 13 (below). Baseline conditions for stability studies include those well known in the art. [Table 14]

[0454] The above results clearly demonstrate that the formulations of the present invention are stable under these conditions for a significant period of time. From the data, one of ordinary skill in the art would be able to see a minimal loss of less than about 5%, such as less than about 1%.

[0455] A second stability study was performed at 30°C / 75% RH using aluminum pouches, the data of which are shown in Table 14 (below). [Table 15]

[0456] The above results clearly demonstrate that the formulations of the present invention are stable under these conditions for a significant period of time. From the data, one of ordinary skill in the art would be able to see a minimal loss of less than about 5%, such as less than about 1%.

[0457] A third stability study was performed at 40°C / 75% RH in glass vials, and the data is shown in Table 15 (below). [Table 16]

[0458] The above results clearly demonstrate that the formulations of the present invention are stable under these conditions for a significant period of time. From the data, one of ordinary skill in the art would be able to see a minimal loss of less than about 5%, such as less than about 1%.

[0459] A fourth stability study was conducted at 30°C / 75% RH in glass vials, and the data is shown in Table 16 (below). [Table 17]

[0460] The above results clearly demonstrate that the formulations of the present invention are stable under these conditions for a significant period of time. From the data, one of ordinary skill in the art would be able to see a minimal loss of less than about 5%, such as less than about 1%.

[0461] The components of Suspension Composition 2 (T2) and their respective % (wt / wt) are shown in Table 17 (below). [Table 18]

[0462] Example 6: Dissolution Test This example demonstrates several dissolution tests.

[0463] Dissolution testing was performed on Suspension Composition 2 (T2) at USP Type IV dissolution, 8 mL / min, 6 g beads, 37° C.±0.5° C. The data are shown in Table 18 (below). [Table 19]

[0464] As shown in Table 18 (above), Suspension Composition 2 (T2) demonstrates a dissolution profile under test conditions in 0.1N HCl where an average of about 51% of the total suspension composition is dissolved after 8 hours. As further shown in Table 18 (above), Suspension Composition 2 (T2) demonstrates a dissolution profile under test conditions at pH 5.0 where an average of about 53% of the total suspension composition is dissolved after 8 hours. As further shown in Table 18 (above), Suspension Composition 2 (T2) demonstrates a dissolution profile under test conditions at pH 6.8 where an average of about 68% of the total suspension composition is dissolved after 8 hours. These results illustrate that compositions according to the invention can exhibit dissolution profiles in which a significant amount of mexiletine remains undissolved after several hours (after 6 hours, at least about 50% remaining, such as about 40% to about 65% remaining; after 8 hours, at least 45% remaining, such as 40% to 50%; after 12 hours, in most cases at least about 30%, such as 25% to 40% remaining).

[0465] Dissolution testing for Composition 1 and Composition 2 (T1 and T2) was performed using USP Type II (paddle) in 500 mL of 0.1 N HCl for the first (1) hour, then in 700 mL pH 4.5 acetate buffer switching medium for (1) hour, then in 900 mL pH 6.8 phosphate buffer switching medium for (2) hours. The data is shown in Table 19 (below). [Table 20]

[0466] As shown in Table 19 (above), Suspension Composition 1 (T1) demonstrates a dissolution profile under test conditions in 0.1N HCl where, on average, about 38% of the total suspension composition is dissolved after 1 hour. As further shown in Table 19 (above), Suspension Composition 1 (T1) demonstrates a dissolution profile under test conditions at pH 4.5 where, on average, about 88% of the total suspension composition is dissolved. As further shown in Table 19 (above), Suspension Composition 1 (T1) demonstrates a dissolution profile under test conditions at pH 6.8 where, on average, about 99% of the total suspension composition is dissolved. As also shown in Table 19, Suspension Composition 2 (T2) demonstrates a slightly more favorable dissolution profile where, on average, about 30%, about 81%, and about 98% of the total suspension composition is dissolved after the three stepwise applied test conditions. These results illustrate that compositions according to the invention can exhibit dissolution profiles in which a significant amount of mexiletine remains undissolved after several hours (at least about 65% remaining, such as about 62% to about 70% remaining after the first hour; at least 15% remaining, such as 10% to 20% remaining after an additional hour at pH 4.5; in most cases at least about 1.5%, such as 1% to 2% remaining after the final 2 hours at pH 6.8).

[0467] Example 7: Suspension test for composition T2 This example demonstrates suspension testing for composition T2.

[0468] Stability study for Suspension Composition 2 (T2): Samples were held for stability study for periods of 1 month and 3 months. Then, assay % by HPLC method and decomposition product test were performed to evaluate the stability of the samples. Details of the stability study are shown below for 40°C / 75%RH.

[0469] A stability test was carried out on Composition 2 (T2) at 40°C / 75% RH conditions, and the data are shown in Table 20 (below).

[0470] [Table 21]

[0471] The above results clearly demonstrate that the formulations of the present invention are stable under these conditions for a significant period of time. From the data, one of ordinary skill in the art would be able to see a minimal loss of less than about 5%, such as less than about 1%.

[0472] Example 8: Suspension composition T3 and dissolution testing This example demonstrates the components of Suspension Composition 3 (T3) as well as the dissolution testing performed on Suspension Composition T3.

[0473] The components of Suspension Composition 3 (T3) are shown in Table 21 (below). [Table 22]

[0474] Dissolution testing for Suspension Composition 3 (T3) was performed in 0.1 N HCl with 6 g glass beads at 37° C.±0.5° C. in a USP Type IV apparatus at a flow rate of 8 mL / min. The data is shown in Table 22 (below). [Table 23]

[0475] As shown in Table 22 (above), Suspension Composition 3 (T3) demonstrates a dissolution profile where, on average, about 70% of the total suspension composition is dissolved after 8 hours under the test conditions. As further shown in Table 22 (above), Suspension Composition 3 (T3) demonstrates a dissolution profile where, on average, about 81% of the total suspension composition is dissolved after 12 hours under the test conditions. These results illustrate that compositions according to the present invention can exhibit dissolution profiles where a significant amount of mexiletine remains undissolved after several hours (at least about 40% remaining after 6 hours, at least about 30% remaining after 8 hours; at least about 20% remaining after 12 hours).

[0476] Example 9: Dispersible tablet example and test using same This example demonstrates the compositions of the dispersible tablets as well as their corresponding testing.

[0477] The ingredients for the dispersible tablets of Composition 1 (D1) and Composition 2 (D2) are given in Table 23 (below). [Table 24]

[0478] Dissolution tests on dispersible tablets of Suspension Composition 1 (D1) and Composition 2 (D2) were carried out in 0.1N HCl with 6 g glass beads at 37° C.±0.5° C. in a USP Type IV apparatus at a flow rate of 8 mL / min. The data are shown in Table 24 (below). [Table 25]

[0479] As shown in Table 24 (above), dispersible tablet compositions 1 and 2 (D1 and D2) demonstrate dissolution profiles in which, on average, about 98% and 98%, respectively, of the total dispersible tablet are dissolved after 8 hours under the test conditions. These results illustrate that compositions according to the present invention can exhibit dissolution profiles in which a significant amount of mexiletine remains undissolved after several hours (after 4 hours, at least about 25% remaining, such as about 20% to about 30% remaining; after 5 hours, at least 15% remaining, such as 10% to 20% remaining; after 8 hours, about 2% remaining).

[0480] A second set of dissolution tests for dispersible tablets of Composition 1 (D1) and Composition 2 (D2) was carried out in 500 mL of 0.1 N HCl for the first (1) hour, then in 700 mL pH 4.5 acetate buffer replacement medium for (1) hour, then in 900 mL pH 6.8 phosphate buffer replacement medium for (2) hours, using USP Type II (paddle) at 75 rpm and 37°C ± 0.5°C. The data is shown in Table 25 (below). [Table 26]

[0481] As shown in Table 25 (above), dispersible tablet compositions 1 and 2 (D1 and D2) demonstrate dissolution profiles in which, on average, about 94% and 95% of the total dispersible tablet, respectively, is dissolved after the three applied test conditions. These results illustrate that compositions according to the present invention can exhibit dissolution profiles in which a significant amount of mexiletine remains undissolved after several hours (at least about 68% remaining, such as about 55% to about 60% remaining after 1 hour; at least about 20% remaining, such as 7% to 20% remaining after 1 hour at pH 4.5; at least about 5% remaining, such as 5% to 6% remaining after 2 hours at pH 6.8).

[0482] Stability test for dispersible tablet composition 1 and 2 (D1 and D2): Samples were kept for stability test for a period of 6 months. After that, assay % by HPLC method and decomposition product test were carried out to evaluate the stability of the samples. Details of the stability test are shown below for 40°C / 75%RH.

[0483] Stability studies were conducted on dispersible tablet compositions 1 and 2 (D1 and D2) and the data are shown in Table 26 (below). [Table 27]

[0484] The above results clearly demonstrate that the formulations of the present invention are stable under these conditions for a significant period of time. From the data, one of ordinary skill in the art would be able to see minimal loss of less than about 1%.

[0485] Example 10 - Relative bioavailability studies Fasting test: This example demonstrates a relative bioavailability study comparing an exemplary mexiletine hydrochloride extended release oral suspension 400 mg / 5 mL (7.5 mL administered once daily) to a formulation containing Namuscla® (mexiletine) capsules 167 mg (administered three times daily).

[0486] The objective of the study was to compare the relative bioavailability of two mexiletine hydrochloride extended release oral suspension 400 mg / 5 mL (single dose of 7.5 mL) formulations, including Namuscla® (mexiletine) capsules 167 mg (dose three times daily), in healthy adult male human subjects under fasting conditions and to monitor the safety of the subjects.

[0487] The study design and plan was as follows.

[0488] Test product (T1 and T2): Mexiletine hydrochloride extended release oral suspension 400 mg / 5 mL. Dose: 1 x 7.5 mL of extended release oral suspension 400 mg / 5 mL administered once daily (0.00 hours).

[0489] Reference Product(R): Namuscla(R) (mexiletine) capsules 167 mg (equivalent to 200 mg mexiletine HCl). Dose: 3 x 167 mg IR capsules: three times daily with an interval of 8.00 hours between each dose (0.00 hours, 8.00 hours and 16.00 hours).

[0490] Study Design: An open-label, balanced, randomized, single-dose, three-treatment, three-sequence, three-period crossover oral relative bioavailability study.

[0491] NUMBER OF SUBJECTS: Twenty-four healthy adult male subjects were enrolled and dosed in the study. All subjects fasted for at least 10.00 hours prior to dosing.

[0492] Administration: The test formulation was administered orally and the reference formulation was administered to subjects over a 60 minute period.

[0493] Test Product: After an overnight fast of at least 10.00 hours, 7.5 mL of either Test Product 1 (T1) or Test Product 2 (T2) was dispensed into the subject's mouth in a sitting position using an oral syringe according to randomization. The subject was instructed to swallow this together with approximately 50 mL of water from the 240 mL of administration water at ambient temperature. From this, a portion of the water (3 x approximately 5 mL) was used to carefully rinse the syringe three times, and then a thorough mouth check was performed to ensure that the drug had been swallowed. The remaining 240 mL of administration water was then administered to the subject, thus ensuring complete administration of the dosed test product in each period. This procedure was completed within 2 minutes of the actual start of dose administration.

[0494] Reference Product: Dose Administration Monitoring (0.00 hours): After an overnight fast of at least 10.00 hours, one capsule of the Reference Product (R) was administered orally to each subject in a seated position with approximately 240 mL of water at ambient temperature according to the randomization plan in each period.

[0495] Evening (8.00 hours) dose administration: After a fast of at least 2.00 hours, one capsule of the reference product (R) was administered orally to each subject in a seated position with approximately 240 mL of water at ambient temperature according to the randomization plan in each period.

[0496] Evening (16.00 hours) dose administration: After a fast of at least 2.00 hours, one capsule of the reference product (R) was orally administered to each subject in a sitting position with approximately 240 mL of water at ambient temperature according to the randomization plan in each period.

[0497] Sampling Plan Sampling plan for subjects receiving test products: Twenty-six blood samples were collected from each subject in each period. A pre-dose (0.00 hour) blood sample of 4.0 mL was collected 1 hour or less prior to dosing in each period. Additional samples of 4.0 mL each were collected at 0.50 hours (30 minutes), 1.00 hours, 2.00 hours, 3.00 hours, 4.00 hours, 5.00 hours, 6.00 hours, 7.00 hours, 8.00 hours, 9.00 hours, 10.00 hours, 11.00 hours, 12.00 hours, 13.00 hours, 14.00 hours, 15.00 hours, 16.00 hours, 18.00 hours, 20.00 hours, 24.00 hours, 30.00 hours, 36.00 hours, 48.00 hours, 72.00 hours, and 96.00 hours after dosing in each period.

[0498] Sampling plan for subjects receiving the reference product: 48 blood samples were drawn from each subject in each period. A 4.0 mL pre-dose (0.00 hour) blood sample was drawn 1 hour or less prior to dosing in each period. Additional samples of 4.0 mL each were drawn at 0.33 hours (20 minutes), 0.67 hours (40 minutes), 1.00 hours, 1.50 hours, 2.00 hours, 2.50 hours, 3.00 hours, 3.50 hours, 4.00 hours, 4.50 hours, 5.00 hours, 6.00 hours, 7.00 hours, 8.00 hours, 8.33 hours, 8.67 hours, 9.00 hours, 9.50 hours, 10.00 hours, 10.50 hours, 11.00 hours, 11.50 hours, 12. Samples were taken at 00 hours, 12.50 hours, 13.00 hours, 14.00 hours, 15.00 hours, 16.00 hours, 16.33 hours, 16.67 hours, 17.00 hours, 17.50 hours, 18.00 hours, 18.50 hours, 19.00 hours, 19.50 hours, 20.00 hours, 20.50 hours, 21.00 hours, 22.00 hours, 23.00 hours, 24.00 hours, 30.00 hours, 36.00 hours, 48.00 hours, 72.00 hours and 96.00 hours.

[0499] Pharmacokinetic Analysis: For mexiletine, the primary pharmacokinetic parameter calculated was AUC 0~24 and the second pharmacokinetic parameter is C max , T max , AUC0~t , AUC 0~∞ , K el and t 1 / 2 It was.

[0500] Statistical analysis: Statistical analysis was performed using the SAS® system for Windows version 9.4 or later. Log-transformed pharmacokinetic parameters AUC for mexiletine 0~24 The within-subject CVs, statistical power, ratio analysis, and 90% confidence intervals for the geometric least squares means were calculated for the log-transformed pharmacokinetic parameters AUC 0~24 was calculated by computer.

[0501] The % relative bioavailability is calculated as follows: (AUC 0~24 Test / AUC 0~24 Reference) x 100

[0502] Conclusion: Ratio of test (T1) and reference (R) product means (least squares means) and their 90% confidence.

[0503] Intervals derived from the analysis of log-transformed pharmacokinetic parameters were calculated using the AUC 0~24 139.60% (90%CI:132.20%~147.40%) and C max The rate was 130.09% (90% CI: 120.74%-140.15%).

[0504] The ratios of test (T2) and reference (R) product means (least squares means) and their 90% confidence intervals derived from the analysis of log-transformed pharmacokinetic parameters were calculated as AUC 0~24 106.50% (90%CI:100.77%~112.57%) and C max The rate was 86.72% (90% CI: 80.39%-93.55%).

[0505] T max The median values ​​(in hours) were found to be 6.00 and 8.00 hours for T1 and T2, respectively, and the corresponding Tmax The ranges observed were 3.00 hours to 12.02 hours for T1 and 5.00 hours to 16.00 hours for T2.

[0506] The relative bioavailability of mexiletine C to T1 is max and higher than the reference product based on a comparison of AUC.

[0507] The relative bioavailability of mexiletine C to T2 max and AUC comparison. Test product 1 (T1), test product 2 (T2) and the reference product (R) were found to be safe and well tolerated following administration of a single dose in healthy adult male subjects under fasting conditions.

[0508] Comparison of geometric least squares means, ratios, 90% CI and ISCV for mexiletine HCl for test product 1 versus reference product, these data are presented in Table 27 (table below). [Table 28]

[0509] As shown in Table 27 (above), the AUC 0~24 is 15965.7530 h*ng / mL when administered once daily, which is greater than the reference product, which is 11437.1890 h*ng / mL when administered three times daily. As shown in Table 27 (above), the C for test product 1 max is 1085.7073 ng / mL when administered once daily and 834.5941 ng / mL when administered three times daily, which is greater than the reference product. These results demonstrate that the compositions of the present invention, when administered once daily, have an AUC 0~24 is about 15900 h*ng / mL (e.g., about 15500 h*ng / mL to 16500 h*ng / mL), and C maxThese results demonstrate that the bioavailability of the compound can be greater than that of the reference product when administered three times daily, such as about 1080 ng / mL (e.g., about 1050 ng / mL to 1150 ng / mL).

[0510] Comparison of the geometric least squares means, ratios, 90% CI and ISCV for mexiletine HCl for the test product 2 versus the reference product, these data are presented in Table 28 (table below). [Table 29]

[0511] As shown in Table 28 (above), the AUC 0~24 is 12180.9070 h*ng / mL when administered once daily, and is greater than the reference product, which is 11437.1890 h*ng / mL when administered three times daily. As shown in Table 27 (above), the C for test product 2 max is greater than the reference product, which is 723.7411 ng / mL when administered once daily and 834.5941 ng / mL when administered three times daily. These results show that the AUC 0~24 is about 12180 h*ng / mL (e.g., about 12000 h*ng / mL to 13000 h*ng / mL), and C max These results demonstrate that the bioavailability of the compound can be greater than that of the reference product when administered three times daily, such as about 720 ng / mL (e.g., about 700 ng / mL to 800 ng / mL).

[0512] A summary of the PK parameters for Test Product 2 is shown in Table 29 (below). [Table 30]

[0513] As shown in Table 29 (above), the AUC 0~24The mean value is 12826.7066 h*ng / mL when administered once daily. As shown in Table 29 (above), the C max The mean value is 763.2237 ng / mL when administered once daily. These results indicate that the composition of the present invention, when administered once daily, 0~24 The average value is about 12820 h*ng / mL (e.g., about 12000 h*ng / mL to 13000 h*ng / mL), and C max It is illustrated that the bioavailability can be greater than that of the reference product (administered three times a day), with a mean value of about 760 ng / mL (eg, about 700 ng / mL to 800 ng / mL).

[0514] Linear mean plots of plasma concentration (ng / mL) versus time (hours) for Reference, Test Product 1 and Test Product 2 are shown in FIG.

[0515] As shown in Figure 1, both T1 and T2 show a gradual increase in plasma concentration with one peak in plasma concentration by once daily administration compared to the reference product (administered three times a day) which shows a lower peak in plasma concentration. As further shown in Figure 1 (top), T1 shows a maximum plasma concentration of about 1000ng / mL at about 8 hours after administration. In addition, as shown in Figure 1 (top), T2 shows a maximum plasma concentration of about 700ng / mL at about 8 hours after administration. These results show that plasma levels for T2 exhibit: (1) a maximum plasma concentration of about 700 ng / mL, such as about 650 ng / mL to 750 ng / mL, at about 8 hours, such as about 7 hours to about 10 hours; (2) a period of about 8 hours, such as about 7 hours to 10 hours after dosing, beginning at about 8 hours after dosing and continuing for a period of about 8 hours, such as about a 7 to 10 hour period, in which the change in plasma concentration over any hour of the period is less than about 2%, such as less than about 0.5% to 2.5%, from the time thereafter; and (3) a steep drop in plasma concentration beginning at about 15 hours after dosing, such as about 12 hours to 20 hours after dosing, in which the drop in plasma concentration over any hour of the period is greater than 10%, such as greater than 9% to 15% from the time thereafter.

[0516] Example 11 - Food Effect Test The objective of the study was to evaluate the effect of food on the pharmacokinetics of mexiletine hydrochloride extended release oral suspension 400 mg / 5 mL (dose: 7.5 mL) administered under fasted and fed conditions (standard breakfast and high-fat; high-calorie non-vegetarian breakfast) in healthy adult male subjects and to monitor the safety of the subjects.

[0517] The study design and plan was as follows. Test product: Mexiletine hydrochloride extended-release oral suspension 400 mg / 5 mL. Dosage: 1 × 7.5 mL of 400 mg / 5 mL extended-release oral suspension given once daily. Study Design: An open-label, balanced, randomized, single-dose, three-treatment, three-sequential, three-period crossover oral food-effect study. Test treatment: Treatment A: Test product 2 (T2) was administered under fasting conditions. Treatment B: Test product 2 (T2) was administered under fed conditions after a standard breakfast (approximately 500 Kcal) served 30 minutes prior to dosing. Treatment C: Test product 2 (T2) was administered under fed conditions after a high fat; high calorie non-vegetarian breakfast (approximately 1000 calories) served 30 minutes prior to dosing. NUMBER OF SUBJECTS: Twenty-four healthy adult male subjects were enrolled and dosed in the study. Dosage: For those receiving Treatment A: After an overnight fast of at least 10.00 hours, a single dose of 7.5 mL of test product 2 (T2) according to randomization was dispensed into the subject's mouth in a beaker in a sitting position. The subject was instructed to swallow it together with about 50 mL of water from about 240 mL of administration water at ambient temperature. The beaker was rinsed three times with about 3×5 mL of water, and the rinse was administered to the subject, and then a thorough mouth check was performed to ensure that the drug was swallowed. This procedure was completed within 2 minutes of the actual start of dose administration. The remaining 240 mL of administration water was then administered to the subject, thus ensuring complete administration of the dosed test product in each period. For those receiving Treatment B: After an overnight fast of at least 10.00 hours, a standard breakfast was served 30 minutes before administration. Subjects must consume the entire standard breakfast within 30 minutes of the breakfast being served. Exactly 30 minutes after the actual start time of the standard breakfast, a single dose of 7.5 mL of test product 2 (T2) according to randomization was served to the subject's mouth in a beaker in a sitting position. Subjects were instructed to swallow this together with about 50 mL of water from about 240 mL of administration water at ambient temperature. The beaker was rinsed three times with about 3×5 mL of water, and the rinse was administered to the subject, followed by a thorough mouth check to ensure that the drug was swallowed. This procedure was completed within 2 minutes of the actual start of dose administration. The remaining 240 mL of dosing water is then administered to the subject, thus ensuring complete dosing of the dosed test product in each period. For those receiving Treatment C: After an overnight fast of at least 10.00 hours, a standard breakfast was served 30 minutes before administration. The subjects must consume the entire standard high-fat, high-calorie, non-veg breakfast within 30 minutes of the breakfast being served. Exactly 30 minutes after the actual start time of the standard high-fat, high-calorie, non-veg breakfast, a single dose of 7.5 mL of test product 2 (T2) according to randomization was served to the subjects' mouths in a beaker in a sitting position. The subjects were instructed to swallow this together with about 50 mL of water from about 240 mL of administration water at ambient temperature. The beaker was rinsed three times with about 3×5 mL of water, the rinse was administered to the subject, and then a thorough mouth check was performed to ensure that the drug had been swallowed. This procedure was completed within 2 minutes of the actual start of dose administration. The remaining 240 mL of dosing water is then administered to the subject, thus ensuring complete dosing of the dosed test product in each period. Sampling Plan: 26 blood samples are drawn from each subject at each period.

[0518] A pre-dose (0.00 hour) blood sample of 4.0 mL is collected no more than 1 hour before dosing in each period. Additional samples of 4.0 mL each are collected at 0.50 hours (30 minutes), 1.00 hours, 2.00 hours, 3.00 hours, 4.00 hours, 5.00 hours, 6.00 hours, 7.00 hours, 8.00 hours, 9.00 hours, 10.00 hours, 11.00 hours, 12.00 hours, 13.00 hours, 14.00 hours, 15.00 hours, 16.00 hours, 18.00 hours, 20.00 hours, 24.00 hours, 30.00 hours, 36.00 hours, 48.00 hours, 72.00 hours, and 96.00 hours after dosing in each period.

[0519] Pharmacokinetic Analysis: The concentration versus time profile of mexiletine is estimated by using Phoenix WinNonlin® version 8.3.3 or later version from Pharsight Corporation, USA, and the pharmacokinetic parameters are calculated.

[0520] Primary parameter: C max and AUC 0~∞

[0521] Secondary parameter: AUC 0~t , T max , K el and T 1 / 2 .

[0522] Statistical analysis: Statistical analysis was performed using the SAS® System for Windows version 9.4 or later (SAS® Institute., USA). Log-transformed pharmacokinetic parameters for mexiletine, C max , and AUC 0~∞ The within-subject CV, statistical power, ratio analysis, and 90% confidence intervals for the ratio of geometric least squares means are calculated for the log-transformed pharmacokinetic parameter C max , and AUC 0~∞ is calculated by a computer.

[0523] Conclusion: The C observed in the fed state (both standard and high-calorie breakfasts) compared with the fasted state max In conclusion, food increased the C and AUC of mexiletine hydrochloride. max (about 39%) and AUC (about 16%).

[0524] Food effect studies were conducted on Test Product 2 (T2), Treatment B, and Treatment A. These data are presented by comparison in Table 30 (below). [Table 31]

[0525] As shown in Table 30 (above), C for Treatment A max The geometric mean was 825.1137 ng / mL, and the AUC 0~∞ The geometric mean is 19807.1980*ng / mL under fasting conditions. As further shown in Table 30, C for Treatment B max The geometric mean was 1143.4828 ng / mL, and the AUC 0~∞ The geometric mean value was 23063.0820 h*ng / mL under standard breakfast conditions. These results indicate that the composition of the present invention max The geometric mean is about 1140 ng / mL (e.g., about 1100 ng / mL to 1200 ng / mL), and the AUC 0~∞ The geometric mean is about 23,000 h*ng / mL (e.g., about 22,500 h*ng / mL to 23,500 h*ng / mL), demonstrating that greater bioavailability can be demonstrated when administered with food rather than under fasting conditions.

[0526] Food effect studies were conducted on Test Product 2 (T2), Treatment C, and Treatment A. These data are presented comparatively in Table 31 (below). [Table 32]

[0527] As shown in Table 31 (above), C for Treatment A max The geometric mean was 825.1137 ng / mL, and the AUC 0~∞ The geometric mean is 19807.1980*ng / mL under fasting conditions. As further shown in Table 31, C for Treatment C max The geometric mean was 1036.8176 ng / mL, and the AUC 0~∞ The geometric mean value was 22382.1160 h*ng / mL under the condition of a standard high-fat, high-calorie, non-vegetarian breakfast. These results indicate that the composition of the present invention can max The geometric mean is about 1030 ng / mL (e.g., about 1000 ng / mL to 1100 ng / mL) and the AUC 0~∞ The geometric mean was about 22,300 h*ng / mL (e.g., about 22,500 h*ng / mL to 23,500 h*ng / mL), illustrating that greater bioavailability can be demonstrated when administered with a standard full high-fat, high-calorie, non-vegetarian breakfast rather than under fasting conditions.

[0528] A linear plot of plasma concentration (ng / mL) versus time (hours) for data collected from food effect studies for Composition A, Composition B, and Composition C is shown in FIG.

[0529] As shown in FIG. 2, all three compositions show a gradual increase in plasma concentration with one peak in plasma concentration upon once-daily administration. As further shown in FIG. 2 (top), composition B administered under conditions including a standard breakfast shows the highest maximum plasma concentration of about 1200 ng / mL, such as about 1150 ng / mL to 1300 ng / mL, at about 6 hours after administration, such as about 5 hours to 7 hours after administration. As further shown in FIG. 2 (top), composition C administered under conditions including a high-fat, high-calorie non-veg breakfast shows the second highest maximum plasma concentration of about 1000 ng / mL, such as about 950 ng / mL to 1050 ng / mL, at about 6 hours after administration, such as about 5 hours to 7 hours after administration. And as shown in FIG. 2 (top), composition A administered under fasting conditions shows the lowest maximum plasma concentration of about 750 ng / mL, such as about 700 ng / mL to 800 ng / mL, at about 6 hours after administration, such as about 5 hours to 7 hours after administration.

[0530] As a result of this study, and as further illustrated above, the present invention provides various forms of compositions and methods of making that may be advantageous for treatment populations, particularly under conditions involving standard post-breakfast administration.

Claims

1. 1. An orally administered pharmaceutical composition for treating myotonia comprising a therapeutically effective amount of mexiletine or a pharma- ceutical acceptable salt thereof and at least one release retarding agent, An orally administered pharmaceutical composition for treating myotonia, which is orally administered once daily to be effective in treating myotonia.

2. 10. The composition of claim 1 comprising between 100 mg and 600 mg of mexiletine hydrochloride, or between 200 mg and 600 mg of mexiletine hydrochloride.

3. T ｍａｘ The median is between 5 hours and 8 hours, or t １／２ 10. The composition of claim 1, wherein the average value is between 10 hours and 13.5 hours, or both.

4. 4. The composition of claim 3, further exhibiting at least one of the following pharmacokinetic profile characteristics after a single dose: (a) C ｍａｘ The mean value is between 700 ng / mL and 1250 ng / mL; (b) AUC ０～２４ the mean value is between 12,000 ng·h / mL and 17,500 ng·h / mL; (c) AUC ０～ｔ A mean value between 20,000 ng·hr / mL and 24,500 ng·hr / mL; and (d) AUC ０～∞ The average value is 20,000 ng·hr / mL to 26,000 ng·hr / mL.

5. Compared to fasting conditions, C ｍａｘ 2. The composition of claim 1, which exhibits an increase in mean, mean AUC, or both.

6. Compared to fasting conditions, C ｍａｘ 4. The composition of claim 3, which exhibits an increase in mean, mean AUC, or both.

7. 10. The composition of claim 1, exhibiting an in vitro dissolution profile characterized by: (a) When measured at 37° C.±0.5° C. in 0.1 N HCl medium using a USP Type IV apparatus with 6 gm glass beads and a flow rate of 8 ml / min. (1) after 0 to 2 hours, 0% to 30% by weight of mexiletine is released from the composition; (2) 10% to 40% by weight of mexiletine is released from the composition after 0 to 4 hours; (3) 30% to 70% by weight of mexiletine is released from the composition after 4 to 12 hours; (4) greater than 60% by weight of mexiletine is released from the composition in between 6 and 14 hours; and (5) greater than 80% by weight of mexiletine is released from the composition within 24 hours; (b) When measured using a USP Type IV apparatus having a flow rate of 8 ml / min with 6 gm glass beads in a pH 5.0 acetate buffer medium at 37° C.±0.5° C. (1) after 0 to 2 hours, 0% to 25% by weight of mexiletine is released from the composition; (2) 10% to 40% by weight of mexiletine is released from the composition after 0 to 4 hours; and (3) after 4 to 12 hours, 30% to 100% by weight of mexiletine is released from the composition within 24 hours; (c) When measured using a USP Type IV apparatus having a flow rate of 8 ml / min with 6 gm glass beads in a pH 6.8 phosphate buffer medium at 37° C.±0.5° C. (1) after 0 to 2 hours, 0% to 35% by weight of mexiletine is released from the composition; (2) 10% to 50% by weight of mexiletine is released from the composition after 0 to 4 hours; (3) 30% to 100% by weight of mexiletine is released from the composition after 4 to 12 hours; (d) when measured in a United States Pharmacopeia (USP) Type II dissolution apparatus rotating at 75 rpm at a temperature of 37° C.±0.5° C. (1) 50% or less by weight of mexiletine is released from the composition in 500 mL 0.1 N HCl in the first hour; and (2) 65% or more by weight of mexiletine is released from the composition in 2 hours in 700 mL pH 4.5 acetate buffer exchange medium, and then further (3) 85% or more by weight of mexiletine is released from the composition in 4 hours in 900 mL pH 6.8 phosphate buffer exchange medium; or (e) any combination of (a) through (d), or all combinations of (a) through (d).

8. A single oral administration of the composition results in: (1) a T ｍａｘ and (2) in most human patients, the plasma concentration of mexiletine at 16 hours after administration is ｍａｘ The composition of claim 3, wherein the difference is at least 33% from

9. In most human patients receiving a single oral dose of the composition, the plasma concentration of mexiletine is increased over a period of at least 4 hours. ｍａｘ The composition of claim 3, wherein the difference is within 20% from

10. 4. The composition of claim 3, wherein in most human patients receiving a single oral dose of the composition, the plasma concentration of mexiletine at 3 hours post-administration, 4 hours post-administration, or both, is within 25% difference from the plasma concentration of mexiletine at 18 hours post-administration, 20 hours post-administration, or both.

11. The composition of claim 1, wherein the at least one release retardant is a pharma- ceutically acceptable cation exchange resin, and the composition further comprises a pharma- ceutically acceptable carrier.

12. The composition of claim 11, wherein the at least one release retarding agent is selected from a hydrophilic release retarding polymer, a hydrophobic release retarding polymer, and both.

13. 1. A pharmaceutical composition for oral administration comprising a therapeutically effective amount of mexiletine or a pharma- ceutically acceptable salt thereof and an effective amount of at least one release retarding agent, the composition exhibiting at least one of the following pharmacokinetic profile characteristics after a single dose: (a) T ｍａｘ The median time is 5 to 8 hours; (b) C ｍａｘ The mean value is between 700 ng / mL and 1250 ng / mL; (c) the mean AUC0-24 is 12,000 ng·hr / mL to 17,500 ng·hr / mL; (d) AUC ０～ｔ The mean value is between 20,000 ng·h / mL and 24,500 ng·h / mL; (e) AUC ０～∞ A mean value between 20,000 ng-hr / mL and 26,000 ng-hr / mL; and (f) T １／２ The average value is between 10 hours and 13.5 hours. wherein each dose comprises 100 mg to 600 mg of mexiletine hydrochloride, or 200 mg to 600 mg of mexiletine hydrochloride.

14. t １／２ The average value is between 10 hours and 13.5 hours, or T ｍａｘ 14. The composition of claim 13, wherein the median value is between 5 hours and 8 hours, or both.

15. (a) a therapeutically effective amount of mexiletine or a pharma- ceutically acceptable salt thereof; (b) a pharma- ceutically acceptable cation exchange resin, and at least one or more pharma- ceutically acceptable excipients; 13. A pharmaceutical composition for oral administration comprising:

16. 16. The composition of claim 15, wherein the weight ratio of mexiletine or a pharma- ceutically acceptable salt thereof to the pharma- ceutically acceptable cation exchange resin in the composition is from 1:0.5 to 1:

5.

17. 16. The composition of claim 15, wherein the mexiletine or a pharma- ceutically acceptable salt thereof and the cation exchange resin form a pharma- ceutically acceptable mexiletine resin complex, and the cation exchange resin is 30%-85% of the mexiletine resin complex on a weight / weight basis.

18. 16. The pharmaceutical composition of claim 15, further comprising (c) a suitable release retardant selected from hydrophilic release retarding polymers, hydrophobic release retarding polymers, and both.

19. 16. The composition of claim 15, further comprising a suspending base selected from starch, a disaccharide, and both.

20. 20. Use of a composition according to any one of claims 1 to 19 for the preparation of a pharmaceutical agent for the treatment of myotonia.

Images