Lamotrigine ready-to-use non-aqueous solution

Abstract

This application discloses a ready-to-use non-aqueous formulation of lamotrigine. The lamotrigine is dissolved in a solvent comprising propylene glycol and optionally at least one cosolvent, and wherein if water is present in the ready-to-use non-aqueous formulation, the water is not at least one cosolvent. This application also discloses a method for treating neurological disorders or mental disorders by administering the ready-to-use non-aqueous formulation of lamotrigine, a method for preparing the ready-to-use non-aqueous formulation of lamotrigine, and a kit containing lamotrigine for preparing the ready-to-use non-aqueous formulation of lamotrigine.

Description

Cross-references to related applications

[0001] This application claims the benefit of U.S. Provisional Application No. 63 / 595,974, filed November 3, 2023, the disclosure of which is incorporated herein by reference in its entirety.

[0002] This disclosure of the field This disclosure relates to a ready-to-use non-aqueous formulation of lamotrigine, a method of treating neurological disorders or mental disorders using the ready-to-use non-aqueous formulation of said lamotrigine, a method of preparing the ready-to-use non-aqueous formulation of said lamotrigine, and a kit containing the ready-to-use non-aqueous formulation of said lamotrigine.

[0003] background Lamotrigine (also known as 3,5-diamino-6-(2,3-dichlorophenyl)-1,2,4-triazine) is an active pharmaceutical ingredient used to treat a variety of indications, including epilepsy and bipolar disorder. For epilepsy, it is used to treat partial seizures, primary and secondary tonic-clonic seizures, and seizures associated with Lennox-Gastaut syndrome. Lamotrigine also acts as a mood stabilizer. Because lamotrigine is chemically independent of other anticonvulsants (as it belongs to the phenyltriazine class), it has relatively few side effects and does not require blood monitoring in monotherapy.

[0004] Lamotrigine is a BCS Class II drug with low solubility and high permeability. Oral administration is accompanied by a delayed onset of the desired pharmacological action because lamotrigine is poorly soluble in water, which results in a low dissolution rate of the drug in aqueous media, including biological fluids such as gastrointestinal fluids.

[0005] Although lamotrigine can be administered in solid form, there remains a need for liquid formulations. Currently, there are no commercially available liquid formulations of lamotrigine; therefore, hospital pharmacists often crush lamotrigine tablets to administer to pediatric patients who cannot swallow tablets.

[0006] Overview This disclosure provides a ready-to-use non-aqueous solution comprising lamotrigine dissolved in a solvent, wherein the solvent comprises propylene glycol and optionally at least one co-solvent, and wherein if water is present in the ready-to-use non-aqueous solution, the water is not the at least one co-solvent.

[0007] This disclosure also provides a ready-to-use non-aqueous solution comprising lamotrigine dissolved in a solvent, wherein the solvent comprises polyethylene glycol or glycerol and optionally at least one co-solvent, and wherein if water is present in the ready-to-use non-aqueous solution, the water is not the at least one co-solvent.

[0008] This disclosure also provides a method for treating neurological disorders or mental disorders in individuals in need, comprising administering to the individual a ready-to-use non-aqueous solution of lamotrigine of this disclosure, wherein the ready-to-use non-aqueous solution comprises a therapeutically effective amount of lamotrigine.

[0009] This disclosure also provides a method for preparing a ready-to-use non-aqueous solution of lamotrigine of the present disclosure, comprising: mixing lamotrigine with the solvent to dissolve lamotrigine in the solvent.

[0010] This disclosure also provides a kit comprising: a first container containing lamotrigine; and a second container containing a solvent (the solvent comprising propylene glycol and optionally at least one cosolvent), wherein the contents of the first container and the second container are mixed in use to form a ready-to-use non-aqueous solution of this disclosure, wherein if water is present in the ready-to-use non-aqueous solution, the water is not the at least one cosolvent.

[0011] This disclosure also provides a kit comprising: a first container containing lamotrigine; and a second container containing a solvent (the solvent comprising polyethylene glycol or glycerin and optionally at least one cosolvent), wherein the contents of the first and second containers are mixed in use to form a ready-to-use non-aqueous solution of this disclosure, wherein if water is present in the ready-to-use non-aqueous solution, the water is not the at least one cosolvent.

[0012] Brief description of the attached figures The accompanying drawings are exemplary in nature and should not be interpreted in a restrictive manner with respect to the appended claims.

[0013] The attached figure is a graph showing the average plasma concentration versus time according to an embodiment of the present disclosure.

[0014] Detailed description Liquid formulations can take many forms. One well-known type of liquid formulation is a suspension. However, for lamotrigine, suspensions may be undesirable because they have been found to have, for example, increased dose variability and / or the need to remix or resuspend any solids that form. Another disadvantage of lamotrigine suspensions is the difficulty in maintaining the chemical stability of the drug in the dosage form.

[0015] Another well-known type of liquid formulation is the solution. However, there are considerable obstacles in preparing suitable lamotrigine solutions because lamotrigine is difficult to dissolve or stabilize in aqueous media, for reasons such as its tendency to form suspensions and / or precipitates in the presence of water.

[0016] Liquid solutions of lamotrigine have been developed. However, if water is used as one of the solvents, such formulations can only accommodate low concentrations of lamotrigine due to its very limited solubility. Furthermore, such formulations lack sufficient stability, leading to the formation of suspensions and / or precipitation.

[0017] Traditionally, LAMICITAL tablets are recommended for individuals aged 2 years and older, with the dosage titrated based on the individual's body weight. Titrating the correct dosage becomes more difficult when LAMICITAL is prescribed with other concomitant medications. Currently, there are no ready-to-use oral liquid lamotrigine formulations available on the market.

[0018] Advantageously, this disclosure provides a ready-to-use non-aqueous lamotrigine solution. This ready-to-use non-aqueous lamotrigine solution is not a suspension and is capable of holding significantly higher lamotrigine concentrations than previously possible. Furthermore, even if some water is present in the ready-to-use non-aqueous solution, the water is not used as a solvent. That is, water is not a co-solvent, and the ready-to-use non-aqueous lamotrigine solution disclosed herein can tolerate the presence of a certain amount of water and still maintain the ability to retain high concentrations of lamotrigine without forming a precipitate and / or suspension.

[0019] Furthermore, the ready-to-use non-aqueous lamotrigine solution helps reduce errors associated with titration or dilution, thereby enabling precise dosing, especially for pediatric individuals. Additionally, the ready-to-use non-aqueous lamotrigine solution provides improved swallowability for individuals who may have difficulty swallowing conventional tablets or capsules. Moreover, due to the flexibility of precise dosing, the ready-to-use non-aqueous lamotrigine solution can meet the individualized needs of such individuals.

[0020] As used herein, the term "solution" refers to a homogeneous, single-phase liquid mixture comprising two or more substances. In such a mixture, the term "solute" is a substance dissolved in another substance, referred to as the term "solvent." For example, propylene glycol (a solvent) dissolves lamotrigine (a solute). As is known in the art, solute particles are invisible in solution and do not cause light scattering. The dissolved solute cannot be separated by mechanical filtration. The solute will not precipitate unless the amount added exceeds the solubility of the mixture. If more than one solvent is present in the solution, each solvent may be referred to as a "co-solvent," and each co-solvent or combination of co-solvents may be referred to individually or collectively as a "solvent." Solutions include aqueous solutions and non-aqueous solutions. Solutions do not include suspensions.

[0021] As used herein, the term "suspension" refers to a heterogeneous liquid mixture containing solid particles (which may be large enough to settle). The solid particles may be visible and cause light scattering. The solid particles are not dissolved in the liquid fluid.

[0022] As used herein, the term "dissolution" refers to the solute being solubilized by the solvent (and optionally a co-solvent). As is known in the art, if the attractive force between the solvent (and optionally a co-solvent) and the solute molecules is greater than the attractive force binding the solute molecules together, the solvent molecules pull the solute molecules away from and surround them. The surrounded solute molecules move away from the solute and into the solution.

[0023] As used herein, the term "aqueous solution" refers to a solution in which water is a solvent or optionally a co-solvent.

[0024] As used herein, the term "non-aqueous solution" refers to a solution in which water is neither a solvent nor an optional co-solvent. The non-aqueous solution may contain water, but the water molecules do not participate in the dissolution of the solute.

[0025] As used herein, the term "ready-to-use" non-aqueous formulation refers to a non-aqueous formulation of a drug that is readily administered directly to an individual without further processing (e.g., dilution). Such "ready-to-use" non-aqueous formulations help reduce errors associated with the preparation and administration of the drug.

[0026] As used in this article, the term "standard temperature and pressure" refers to 15-25 °C and 1 atm.

[0027] As used herein, a "stable solution" is one in which particles do not settle under gravity for a certain period of time (e.g., at least 7 days). Since the particles of the solute are invisible in the solution and do not cause light scattering, the stability of the solution can be quantified by turbidity, which is the opacity of the fluid caused by particles that may be present in the solution. Turbidity is expressed using turbidimetric turbidity units (NTU).

[0028] As used herein, the term "about" means plus or minus 10% of the indicated value. Unless otherwise stated, weight percentages are provided based on the total amount of the composition described herein.

[0029] As used in this article, the singular forms "a", "an" and "the" include plural referents unless otherwise stated.

[0030] As used herein, the term "therapeuticly effective amount" is intended to mean that the ready-to-use, non-aqueous formulation of the lamotrigine will elicit a biological or medical response in a tissue, system, animal, or human as sought by an investigator, veterinarian, MD, or other clinician. In a preferred embodiment, the term "therapeuticly effective amount" means an amount that alleviates at least one clinical symptom in a human patient. The term "preventively effective (or effective) amount" and similar descriptions (e.g., "effective for prevention") are intended to mean an amount that will prevent or reduce the risk of biological or medical events in a tissue, system, animal, or human as sought by an investigator, veterinarian, MD, or other clinician.

[0031] As used herein, the disclosure of numerical ranges in this specification is considered a disclosure of all numerical values ​​and ranges within that range. For example, if the range is from about 1 to about 50, it is considered to include, for example, 1, 7, 34, 46.1, 23.7, 50, or any other value or range within that range. Furthermore, as used herein, the term "at least" includes the stated numerical value; for example, "at least 50" includes 50.

[0032] As used herein, the term "administration" and variations thereof (e.g., "administering"), when referring to the active agents of this disclosure, mean the administration of said active agent to an individual in need of treatment. Administration of said active agent to said individual includes self-administration and administration by another person (including a healthcare professional). Administration can be performed via any common route and in a form suitable for each route. Such routes include, but are not limited to, parenteral (e.g., subcutaneous, intramuscular, intraperitoneal, or intravenous) and oral administration. For example, said administration can be taken orally after fasting, or said administration can be taken orally after a meal.

[0033] As used herein, "fasting" means abstaining from all types of food and / or fluids for a period of time before and / or after administration. For example, fasting may mean abstaining from food for at least ten hours before administration and for at least four hours after administration. Water may be restricted (no fluids except water administered with the drug if necessary) for at least one hour before administration and for at least one hour after administration.

[0034] As used in this article, "healthy adult" means a human individual who is 18 years of age or older and does not have any medical condition or disease for which lamotrigine is being tested or administered for treatment.

[0035] As used herein, "treatment" includes treatment intended to cure or improve a neurological condition or mental disorder, or to inhibit the progression, occurrence, or recurrence of said neurological condition or mental disorder, or to alleviate one or more related symptoms.

[0036] As used herein, "daily administration," "daily," "once a day," or "every day, once a day" includes a dosing schedule based on a regimen of administration on each day of a treatment cycle (i.e., during treatment). For example, the active ingredient may be administered on each day of a treatment cycle. In some embodiments, a "drug rest day" may be provided at the end of each treatment cycle. In some embodiments, the active agent is administered once during a treatment cycle.

[0037] As used herein, a "treatment period" refers to a time interval during which the method of this disclosure is administered. During a treatment period, the active agents of the method are administered sequentially or simultaneously as described herein.

[0038] As used herein, "intermittent dosing" is not particularly limited, as long as the dosing interval (the number of days between a dosing day and the next dosing day) is at least twice during the said treatment period.

[0039] As used herein, "bioequivalence" means that, in a properly designed pharmacokinetic study, when administered at the same molar dose under similar conditions, there is no significant difference in the rate and extent to which the active ingredient in a drug equivalent becomes available at the site of action. For example, if, under fasting conditions, the relative average Cg of the ready-to-use non-aqueous formulation compared to a reference commercially available product is... max AUC t and AUC i If the 90% confidence interval (CI) is between 80% and 125%, then the two products are bioequivalent.

[0040] As used in this article, "C" max "This refers to the maximum measurable plasma concentration."

[0041] As used in this article, "AUC" t "It refers to the area under the curve of plasma concentration versus time from time zero to the final quantifiable concentration."

[0042] As used in this article, "AUC" i "It refers to the area under the plasma concentration versus time curve from time zero to infinity."

[0043] This disclosure provides a ready-to-use non-aqueous solution comprising lamotrigine dissolved in a solvent, wherein the solvent comprises propylene glycol and optionally at least one co-solvent, and wherein if water is present in the ready-to-use non-aqueous solution, the water is not the at least one co-solvent.

[0044] Lamotrigine in ready-to-use non-aqueous solutions disclosed herein is dissolved in one or more non-aqueous solvents. Non-limiting examples of such ready-to-use non-aqueous solvents include at least one alcohol and / or at least one diol, such as propylene glycol, glycerin, polypropylene glycol, polyethylene glycol, and ethanol.

[0045] In some embodiments, the solvent comprises propylene glycol. In some embodiments, the solvent may optionally comprise at least one co-solvent. The at least one co-solvent comprises at least one selected from glycerol, polypropylene glycol, polyethylene glycol, and ethanol.

[0046] In some embodiments, the ready-to-use non-aqueous solution comprises a solvent, and the solvent comprises propylene glycol. Optionally, the solvent of the ready-to-use non-aqueous solution further comprises a co-solvent. The co-solvent may be glycerol.

[0047] In an alternative embodiment, the solvent comprises polyethylene glycol. In an alternative embodiment, the solvent comprises glycerol. In an alternative embodiment, the solvent comprises both polyethylene glycol and glycerol. Optionally, the solvent may further comprise at least one co-solvent. The at least one co-solvent comprises at least one selected from polypropylene glycol and ethanol.

[0048] In some embodiments, the ready-to-use non-aqueous formulation of lamotrigine comprises varying amounts of lamotrigine. In some embodiments, the lamotrigine concentration of the ready-to-use non-aqueous formulation is from about 0.4 mg / mL to about 40 mg / mL or any subrange thereof. For example, in some embodiments, the lamotrigine concentration of the ready-to-use non-aqueous preparation is about 0.01 mg / mL to about 40 mg / mL, about 0.05 mg / mL to about 40 mg / mL, about 0.1 mg / mL to about 40 mg / mL, about 0.2 mg / mL to about 40 mg / mL, about 0.3 mg / mL to about 40 mg / mL, about 0.01 mg / mL to about 35 mg / mL, about 0.05 mg / mL to about 35 mg / mL, about 0.1 mg / mL to about 35 mg / mL, about 0.1 mg / mL to about 35 mg / mL, about 0.2 mg / mL to about 35 mg / mL, about 0.3 mg / mL to about 35 mg / mL, about 0.4 mg / mL to about 35 mg / mL, about 0.5 mg / mL to about 35 mg / mL, about 0.5 mg / mL to about 40 mg / mL, about 1 mg / mL to about 40 mg / mL, about 0.4 mg / mL to about 30 mg / mL. mg / mL, about 0.4 mg / mL to about 20 mg / mL, about 0.4 mg / mL to about 10 mg / mL, about 0.4 mg / mL to about 5 mg / mL, about 0.4 mg / mL to about 2 mg / mL, about 0.5 mg / mL to about 30 mg / mL, about 0.5 mg / mL to about 20 mg / mL, about 0.5 mg / mL to about 10 mg / mL, about 0.5 mg / mL to about 5 mg / mL, about 0.5 mg / mL to about 2 mg / mL, about 1 mg / mL to about 30 mg / mL, about 1 mg / mL to about 20 mg / mL, about 1 mg / mL to about 10 mg / mL, about 15 mg / mL to about 5 mg / mL, about 1 mg / mL to about 2 mg / mL, about 10 mg / mL to about 40 mg / mL, about 10 mg / mL to about 30 mg / mL, about 10 mg / mL to about 20 mg / mL, about 15 mg / mL to about 25 mg / mL, about 16 mg / mL to about 24 mg / mL mg / mL, about 17 mg / mL to about 23 mg / mL, about 18 mg / mL to about 22 mg / mL, or about 19 mg / mL to about 21 mg / mL. In some embodiments, the lamotrigine concentration of the ready-to-use non-aqueous formulation is about 20 mg / mL.

[0049] In some embodiments, the ready-to-use non-aqueous formulation of lamotrigine may contain water. However, if water is present in the ready-to-use non-aqueous formulation, it is neither the sole solvent nor at least one of the co-solvents.

[0050] Therefore, the ready-to-use non-aqueous formulations of lamotrigine disclosed herein are water-resistant, and thus do not form precipitates or suspensions even in the presence of some water. For example, in some embodiments, the ready-to-use non-aqueous formulation may contain up to about 20% w / w or any subrange of water without forming precipitates or suspensions, even after storage at standard temperature and pressure for at least 7 days.

[0051] In some embodiments, the water content of the ready-to-use non-aqueous agent is equal to or less than about 20% w / w, equal to or less than about 15% w / w, equal to or less than about 10% w / w, equal to or less than about 5% w / w, equal to or less than about 4% w / w, equal to or less than about 3% w / w, equal to or less than about 2% w / w, equal to or less than about 1% w / w, equal to or less than about 0.9% w / w, equal to or less than about 0.8% w / w, equal to or less than about 0.7% w / w, equal to or less than about 0.6% w / w, equal to or less than about 0.5% w / w, equal to or less than about 0.4% w / w, equal to or less than about 0.3% w / w, equal to or less than about 0.2% w / w, equal to or less than about 0.1% w / w, equal to or less than about 0.01% w / w, or equal to or less than about 0.001% of the ready-to-use non-aqueous agent. w / w, equal to or less than about 0.0001% w / w, equal to or less than about 0.00001% w / w, or equal to or less than about 0.000001% w / w, or any concentration in between.

[0052] In some embodiments, the pH meter reading of the ready-to-use non-aqueous solution is about 7 to about 8 or any subrange thereof. For example, in some embodiments, the pH meter reading of the ready-to-use non-aqueous solution is about 7 to about 8, about 7.2 to about 8, or about 7.5 to about 7.8. In some embodiments, the pH meter reading of the ready-to-use non-aqueous solution is about 7.53. The pH meter reading of the ready-to-use non-aqueous solution can be determined by various standard techniques, such as by using a pH meter with electrodes suitable for aqueous or non-aqueous solutions.

[0053] In some embodiments, the density of the ready-to-use non-aqueous agent is from about 1.0 g / mL to about 1.3 g / mL or any subrange thereof. For example, in some embodiments, the density of the ready-to-use non-aqueous agent is from about 1.0 g / mL to about 1.3 g / mL, from about 1.1 g / mL to about 1.3 g / mL, from about 1.2 g / mL to about 1.3 g / mL, from about 1.0 g / mL to about 1.2 g / mL, from about 1.0 g / mL to about 1.1 g / mL, or from about 1.1 g / mL to about 1.2 g / mL.

[0054] In some embodiments, the viscosity of the ready-to-use non-aqueous solution is from about 50 centipoise to about 500 centipoise or any subrange thereof. For example, in some embodiments, the viscosity of the ready-to-use non-aqueous solution is from about 50 centipoise to about 500 centipoise, from about 50 centipoise to about 400 centipoise, from about 50 centipoise to about 300 centipoise, from about 100 centipoise to about 500 centipoise, from about 200 centipoise to about 500 centipoise, from about 200 centipoise to about 400 centipoise, or from about 200 centipoise to about 300 centipoise. The viscosity of the ready-to-use non-aqueous solution can be determined using a commercially available viscometer (e.g., Viscometer DVEELVTJ0). When using the commercially available viscometer, the following example conditions can be implemented: S62 rotor head, 30 rpm, FB-100-50 beaker, 40 mL sample. The viscosity is measured when the reading of the commercially available viscometer stabilizes.

[0055] In some embodiments, the turbidity of the ready-to-use non-aqueous agent is from 0 NTU to 20 NTU or any subrange thereof. For example, in some embodiments, the turbidity of the ready-to-use non-aqueous agent is from about 0 NTU to about 20 NTU, from about 0 NTU to about 15 NTU, from about 0 NTU to about 10 NTU, or from about 0 NTU to about 5 NTU. The turbidity of the ready-to-use non-aqueous agent can be measured using standard procedures known in the art.

[0056] In some embodiments, the ready-to-use non-aqueous solution exists in the liquid phase at standard temperature and pressure. In some embodiments, the ready-to-use non-aqueous lamotrigine solution is a clear and colorless to pale yellow liquid. In some embodiments, the ready-to-use non-aqueous lamotrigine solution does not form a precipitate when stored at standard temperature and pressure for at least 7 days.

[0057] For example, in some embodiments, the ready-to-use non-aqueous agent is a stable ready-to-use non-aqueous agent that does not form a precipitate and / or become a suspension when stored at standard temperature and pressure for at least 7 days, is a clear and colorless to pale yellow liquid, and / or has a turbidity of about 0 NTU to about 20 NTU, about 0 NTU to about 15 NTU, about 0 NTU to about 10 NTU, or about 0 NTU to about 5 NTU. In some embodiments, ready-to-use non-aqueous agents with a propylene glycol to glycerol weight ratio of 10:90, 90:10, 25:75, and 40:60 exhibit sufficient stability.

[0058] The ready-to-use non-aqueous formulation of lamotrigine may contain solvents and co-solvents in varying ratios. In some embodiments, the weight ratio of propylene glycol to glycerol in the ready-to-use non-aqueous formulation is from about 100:0 to about 10:90 or any subrange thereof. For example, in some embodiments, the weight ratio of propylene glycol to glycerol in the ready-to-use non-aqueous formulation is from about 100:0 to about 10:90, from about 90:10 to about 10:90, from about 80:20 to about 20:80, from about 70:30 to about 30:70, from about 60:40 to about 40:60, or from about 45:55 to about 55:45.

[0059] The ready-to-use non-aqueous formulation of lamotrigine may contain varying amounts of solvent (e.g., propylene glycol). In some embodiments, the propylene glycol content of the ready-to-use non-aqueous formulation is from about 0% to about 100% w / w or any subrange thereof. For example, in some embodiments, the propylene glycol content of the ready-to-use non-aqueous agent is about 10% to about 87% w / w, about 15% to about 85% w / w, about 20% to about 80% w / w, about 25% to about 75% w / w, about 30% to about 70% w / w, about 45% to about 55% w / w, about 15% to about 87% w / w, about 20% to about 87% w / w, about 25% to about 87% w / w, about 35% to about 87% w / w, about 45% to about 87% w / w, about 55% to about 87% w / w, about 65% to about 87% w / w, or about 70% to about 87% w / w.

[0060] The ready-to-use non-aqueous formulation of lamotrigine may contain varying amounts of glycerol. In some embodiments, the glycerol content of the ready-to-use non-aqueous formulation is from about 0% to about 100% w / w or any subrange thereof. For example, in some embodiments, the glycerol content of the ready-to-use non-aqueous agent is about 11% to about 88% w / w, about 11% to about 85% w / w, about 11% to about 80% w / w, about 11% to about 75% w / w, about 11% to about 70% w / w, about 11% to about 60% w / w, about 11% to about 50% w / w, about 11% to about 40% w / w, about 11% to about 30% w / w, about 15% to about 88% w / w, about 20% to about 88% w / w, about 30% to about 88% w / w, about 40% to about 88% w / w, about 50% to about 88% w / w, or about 60% to about 88% w / w. In some embodiments, the ready-to-use non-aqueous agent, in addition to glycerol, also contains a cosolvent, which is polypropylene glycol and / or ethanol.

[0061] The ready-to-use non-aqueous formulation of lamotrigine may comprise different types of polyethylene glycol. For example, in some embodiments, the polyethylene glycol is present in the liquid phase at standard temperature and pressure. In some embodiments, the average molecular weight of the polyethylene glycol is equal to or less than about 1000 g / mol or any subrange thereof. For example, in some embodiments, the average molecular weight of the polyethylene glycol is about 100 g / mol to about 1000 g / mol, about 200 g / mol to about 800 g / mol, about 200 g / mol to about 600 g / mol, equal to or less than about 600 g / mol, equal to or less than about 500 g / mol, equal to or less than about 400 g / mol, or equal to or less than about 300 g / mol. In some embodiments, the polyethylene glycol is at least one selected from polyethylene glycol 600 (PEG-600), polyethylene glycol 500 (PEG-500), polyethylene glycol 400 (PEG-400), polyethylene glycol 300 (PEG-300), and polyethylene glycol 200 (PEG-200).

[0062] The ready-to-use non-aqueous lamotrigine solution may contain a variety of additives, such as antioxidants, buffers, flavoring agents, coloring agents, and / or preservatives. Antioxidants include free radical scavengers and reactive oxygen species scavengers, such as 3-tert-butyl-4-hydroxyanisole, butylated hydroxytoluene, and citric acid. Buffers include combinations of acids and bases with pH buffering capacity. Some buffers include, for example, citrates, phosphates, acetates, borates, ethylenediaminetetraacetic acid (EDTA), their conjugate acids, and combinations thereof. Preservatives include compounds that increase the usable shelf life of the pharmaceutical composition. For example, some preservatives are antioxidants, some are antifungal agents, and some are antimicrobial agents. Flavoring agents may be added to improve the taste of the ready-to-use non-aqueous lamotrigine solution and include, for example, ethyl maltol, sucralose, and cherry flavoring. Colorants may be added to improve the visual appearance of the ready-to-use non-aqueous lamotrigine solution, and include, for example, disodium 2-(2-quinolinyl)-1,3-indanedione disulfonate (D&C Yellow #10). In some embodiments, the ready-to-use non-aqueous solution contains at least one additive selected from 3-tert-butyl-4-hydroxyanisole, citric acid, ethylenediaminetetraacetic acid, ethyl maltol, propylparaben, and methylparaben.

[0063] In some embodiments, the ready-to-use non-aqueous solution contains sugar (e.g., sucrose and sucralose) or any subrange thereof, equal to or less than about 10% by weight of the total weight of the ready-to-use non-aqueous solution. For example, in some embodiments, the ready-to-use non-aqueous solution contains sugar equal to or less than about 10% by weight, equal to or less than about 5% by weight, equal to or less than about 3% by weight, or equal to or less than about 1% by weight of the total weight of the ready-to-use non-aqueous solution. In some embodiments, the ready-to-use non-aqueous solution does not contain sugar.

[0064] The ready-to-use non-aqueous formulation of lamotrigine can be prepared by various methods. For example, in some embodiments, the ready-to-use non-aqueous formulation containing lamotrigine is prepared by mixing lamotrigine with the solvent to dissolve the lamotrigine in the solvent. The mixing step can be performed at different temperatures using different tools for different durations. For example, the mixing step can be performed at room temperature using any standard mixing apparatus for any duration, as long as the lamotrigine becomes soluble in the solvent.

[0065] The ready-to-use non-aqueous formulation of lamotrigine can be prepared in various kits. In some embodiments, the kit includes a first container containing lamotrigine; and a second container containing a solvent (the solvent comprising propylene glycol and optionally at least one cosolvent), wherein the contents of the first and second containers are mixed upon use to form the ready-to-use non-aqueous formulation containing lamotrigine, wherein if water is present in the ready-to-use non-aqueous formulation, the water is not the at least one cosolvent.

[0066] In an alternative embodiment, the kit includes a first container containing lamotrigine; and a second container containing a solvent (the solvent comprising polyethylene glycol or glycerin and optionally at least one cosolvent), wherein the contents of the first and second containers are mixed upon use to form a ready-to-use non-aqueous solution containing lamotrigine, wherein if water is present in the ready-to-use non-aqueous solution, the water is not at least one cosolvent.

[0067] In some embodiments, at least one cosolvent comprises at least one selected from glycerol, polypropylene glycol, polyethylene glycol, and ethanol. In some embodiments, the cosolvent comprises glycerol. In some embodiments, at least one cosolvent comprises polypropylene glycol and / or ethanol.

[0068] The pillbox may include a container for containing individual components, such as a separator bottle or separator foil pouch. Other examples of containers include syringes, boxes, and bags. In some embodiments, the pillbox includes instructions for use of the individual components. The pillbox form is particularly advantageous when the individual components are administered in different dosage forms (e.g., oral and parenteral), at different dose intervals, or when a prescribing healthcare professional expects to titrate the individual components of the combination.

[0069] The ready-to-use, non-aqueous formulation of lamotrigine can be used in methods for treating neurological disorders or mental disorders. In some embodiments, methods for treating neurological disorders or mental disorders in an individual in need include administering a therapeutically effective amount of the ready-to-use, non-aqueous formulation to the individual.

[0070] Neurological disorders and mental illnesses include, for example, epilepsy, drug-resistant focal epilepsy, tonic-clonic seizures, absence seizures, myoclonic seizures, atonic seizures, Lennox-Gastaut syndrome, bipolar disorder (e.g., bipolar I and bipolar II), depression, schizophrenia, peripheral neuropathy, trigeminal neuralgia, cluster headache, migraine, visual snowflake syndrome, neuropathic pain, obsessive-compulsive disorder, depersonalization disorder, hallucinogenic persistent perception disorder, schizoaffective disorder, borderline personality disorder, post-traumatic stress disorder, attention deficit hyperactivity disorder, dementia, cognitive impairment, and combinations thereof.

[0071] The dosage regimen of the ready-to-use, non-aqueous formulation of lamotrigine is selected based on a number of factors, including the patient's type, species, age, weight, sex, and medical condition; the severity of the condition to be treated; the potency of the selected compound; the route of administration; and the patient's renal and hepatic function. Consideration of these factors is entirely within the capabilities of a general technical clinician to determine the therapeutically effective or preventatively effective dose required to prevent, counteract, or halt the progression of the condition. It should be understood that a particular daily dose can be both a therapeutically effective dose (e.g., for the treatment of neurological disorders or mental disorders) and a preventatively effective dose (e.g., for the prevention of neurological disorders or mental disorders).

[0072] For administration to humans, such as in the therapeutic or preventative treatment of the conditions and disorders identified herein, the ready-to-use non-aqueous formulation may be administered such that the dose of lamotrigine is from about 0.05 mg / kg / day to about 50 mg / kg / day, or at least 0.05 mg / kg, or at least 0.08 mg / kg, or at least 0.1 mg / kg, or at least 0.2 mg / kg, or at least 0.3 mg / kg, or at least 0.4 mg / kg, or at least 0.5 mg / kg and any amount between thereof, to about 50 mg / kg or less, or about 40 mg / kg or less, or about 30 mg / kg or less, or about 20 mg / kg or less, or about 10 mg / kg or less and any amount between thereof, which may be, for example, from about 2.5 mg / day (0.5 mg / kg × 5 kg) to about 5000 mg / day (50 mg / kg × 100 kg). For example, the dosage of the compound may be from about 0.1 mg / kg / day to about 50 mg / kg / day, or from about 0.05 mg / kg / day to about 10 mg / kg / day, or from about 0.05 mg / kg / day to about 5 mg / kg / day, or from about 0.05 mg / kg / day to about 3 mg / kg / day, or from about 0.07 mg / kg / day to about 3 mg / kg / day, or from about 0.09 mg / kg / day to about 3 mg / kg / day, or from about 0.05 mg / kg / day to about 0.1 mg / kg / day, or from about 0.1 mg / kg / day to about 1 mg / kg / day, or from about 1 mg / kg / day to about 10 mg / kg / day, or from about 1 mg / kg / day to about 5 mg / kg / day, or from about 1 mg / kg / day to about 3 mg / kg / day, or from about 3 mg / day to about 500 mg / day, or from about 5 mg / day to about 250 mg / day, or from about 10 The dosage can be approximately 100 mg / day to about 100 mg / day, or approximately 3 mg / day to about 10 mg / day, or approximately 100 mg / day to about 250 mg / day. Such dosages may be administered as a single dose or divided into multiple doses.

[0073] In some embodiments, the therapeutically effective amount of lamotrigine is about 2 mg to about 700 mg or any subrange thereof.For example, in some embodiments, the therapeutically effective amount of lamotrigine is about 1 mg to about 1000 mg, about 1 mg to about 900 mg, about 1 mg to about 800 mg, about 1 mg to about 700 mg, about 1 mg to about 600 mg, about 1 mg to about 500 mg, about 1 mg to about 400 mg, about 1 mg to about 300 mg, about 1 mg to about 200 mg, about 1 mg to about 100 mg, about 2 mg to about 1000 mg, about 2 mg to about 900 mg, about 2 mg to about 800 mg, about 2 mg to about 700 mg, about 2 mg to about 600 mg, about 2 mg to about 500 mg, about 2 mg to about 400 mg, about 2 mg to about 300 mg, about 2 mg to about 200 mg, about 2 mg to about 100 mg, about 5 mg to about 1000 mg, about 5 mg to about 900 mg, about 5 mg to about 800 mg, about 5 mg to about 700 mg, about 5 mg to about 600 mg, about 5 mg to about 600 mg, about 5 mg to about 7 ... mg to about 500 mg, about 5 mg to about 400 mg, about 5 mg to about 300 mg, about 5 mg to about 200 mg, about 5 mg to about 100 mg, about 10 mg to about 1000 mg, about 10 mg to about 900 mg, about 10 mg to about 800 mg, about 10 mg to about 700 mg, about 10 mg to about 600 mg, about 10 mg to about 500 mg, about 10 mg to about 400 mg, about 10 mg to about 300 mg, about 10 mg to about 200 mg, about 10 mg to about 100 mg, about 10 mg to about 80 mg, about 10 mg to about 60 mg, about 20 mg to about 1000 mg, about 20 mg to about 900 mg, about 20 mg to about 800 mg, about 20 mg to about 700 mg, about 20 mg to about 600 mg, about 20 mg to about 500 mg, about 20 mg to about 400 mg, about 20 mg to about 300 mg, about 20 mg to about 300 mg, about 20 mg to about 500 mg, about 20 mg to about 4 ... mg to about 200 mg, about 20 mg to about 100 mg, about 20 mg to about 80 mg, about 20 mg to about 60 mg, about 40 mg to about 1000 mg, about 40 mg to about 900 mg, about 40 mg to about 800 mg, about 40 mg to about 700 mg, about 40 mg to about 600 mg, about 40 mg to about 500 mg, about 40 mg to about 400 mg, about 40 mg to about 300 mg, about 40 mg to about 200 mg, about 40 mg to about 100 mg, about 40 mg to about 80 mg, or about 40 mg to about 60 mg.In some embodiments, the therapeutically effective amount of lamotrigine is about 25 mg, about 50 mg, about 100 mg, about 200 mg, about 300 mg, about 400 mg, or about 500 mg.

[0074] The ready-to-use non-aqueous formulation of lamotrigine can be administered as a drug to animals, preferably mammals, and particularly humans, on its own, in mixtures with each other, or as a pharmaceutical composition. The terms "individual" or "patient" include animals, preferably mammals and particularly humans, that use the active agent of the invention for the prevention or treatment of a medical condition. Administration of the drug to the individual includes self-administration and administration by another person to the patient. The individual may need or expect treatment for an existing disease or medical condition, or may need or expect preventative treatment to prevent or reduce the risk of developing the disease or medical condition. As used herein, an individual "in need" treatment for an existing condition or preventative treatment encompasses both a healthcare professional's determination of need and a patient's expectation of such treatment.

[0075] Therefore, this disclosure also provides ready-to-use non-aqueous formulations of lamotrigine as a medicament, its use in treating neurological disorders or mental disorders, and in particular its use in the treatment and prevention of the aforementioned diseases or conditions, as well as its use in the preparation of medicaments for these purposes.

[0076] In some embodiments, the ready-to-use non-aqueous formulation of the lamotrigine is bioequivalent to commercially available products containing lamotrigine. Non-limiting examples of commercially available products containing lamotrigine include LAMICITAL tablets.

[0077] In some embodiments, administration of the ready-to-use, non-aqueous formulation of lamotrigine produces in the individual a lamotrigine C concentration of about 800 ng / mL to about 1,000 ng / mL or any subrange thereof. maxvalue. For example, in some embodiments, administration of the ready-to-use non-aqueous formulation of lamotrigine produces in the individual approximately 100 ng / mL to approximately 2,000 ng / mL, approximately 100 ng / mL to approximately 1,800 ng / mL, approximately 100 ng / mL to approximately 1,600 ng / mL, approximately 100 ng / mL to approximately 1,400 ng / mL, approximately 100 ng / mL to approximately 1,200 ng / mL, approximately 100 ng / mL to approximately 1,000 ng / mL, approximately 200 ng / mL to approximately 2,000 ng / mL, approximately 200 ng / mL to approximately 1,800 ng / mL, approximately 200 ng / mL to approximately 1,600 ng / mL, approximately 200 ng / mL to approximately 1,400 ng / mL, approximately 200 ng / mL to approximately 1,200 ng / mL, approximately 200 ng / mL to approximately 1,000 ng / mL. ng / mL, about 400 ng / mL to about 2,000 ng / mL, about 400 ng / mL to about 1,800 ng / mL, about 400 ng / mL to about 1,600 ng / mL, about 400 ng / mL to about 1,400 ng / mL, about 400 ng / mL to about 1,200 ng / mL, about 400 ng / mL to about 1,000 ng / mL, about 600 ng / mL to about 2,000 ng / mL, about 600 ng / mL to about 1,800 ng / mL, about 600 ng / mL to about 1,600 ng / mL, about 600 ng / mL to about 1,400 ng / mL, about 600 ng / mL to about 1,200 ng / mL, about 600 ng / mL to about 1,000 ng / mL, about 800 ng / mL to about 2,000 ng / mL Lamotrigine C at concentrations of approximately 800 ng / mL to approximately 1,800 ng / mL, approximately 800 ng / mL to approximately 1,600 ng / mL, approximately 800 ng / mL to approximately 1,400 ng / mL, approximately 800 ng / mL to approximately 1,200 ng / mL, approximately 800 ng / mL to approximately 1,000 ng / mL, or any subrange thereof. max value.

[0078] In some embodiments, administration of the ready-to-use, non-aqueous formulation of lamotrigine produces 35,000 ng / mL in the individual. hr to approximately 40,000 ng / mL The AUC value of lamotrigine within the hr range or any subrange thereof. For example, in some embodiments, administration of the ready-to-use, non-aqueous formulation of said lamotrigine produces approximately 10,000 ng / mL in the individual. From hr to approximately 100,000 ng / mL hr, approximately 10,000 ng / mL hr to approximately 90,000 ng / mL hr, approximately 10,000 ng / mL hr to approximately 80,000 ng / mL hr, approximately 10,000 ng / mL hr to approximately 70,000 ng / mL hr, approximately 10,000 ng / mL hr to approximately 60,000 ng / mL hr, approximately 10,000 ng / mL hr to approximately 50,000 ng / mL hr, approximately 10,000 ng / mL hr to approximately 40,000 ng / mL hr, approximately 20,000 ng / mL From hr to approximately 100,000 ng / mL hr, approximately 20,000 ng / mL hr to approximately 90,000 ng / mL hr, approximately 20,000 ng / mL hr to approximately 80,000 ng / mL hr, approximately 20,000 ng / mL hr to approximately 70,000 ng / mL hr, approximately 20,000 ng / mL hr to approximately 60,000 ng / mL hr, approximately 20,000 ng / mL hr to approximately 50,000 ng / mL hr, approximately 20,000 ng / mL hr to approximately 40,000 ng / mL hr, approximately 30,000 ng / mL hr to approximately 100,000 ng / mL hr, approximately 30,000 ng / mL hr to approximately 90,000 ng / mL hr, approximately 30,000 ng / mL hr to approximately 80,000 ng / mL hr, approximately 30,000 ng / mL hr to approximately 70,000 ng / mL hr, approximately 30,000 ng / mL hr to approximately 60,000 ng / mL hr, approximately 30,000 ng / mL hr to approximately 50,000 ng / mL hr, approximately 30,000 ng / mL hr to approximately 40,000 ng / mL hr, approximately 35,000 ng / mL From hr to approximately 100,000 ng / mL hr, approximately 35,000 ng / mL hr to approximately 90,000 ng / mL hr, approximately 35,000 ng / mL hr to approximately 80,000 ng / mL hr, approximately 35,000 ng / mL hr to approximately 70,000 ng / mL hr, approximately 35,000 ng / mL hr to approximately 60,000 ng / mL hr, approximately 35,000 ng / mL hr to approximately 50,000 ng / mL hr, or approximately 35,000 ng / mL hr to approximately 40,000 ng / mL AUC value of lamotrigine in hr or any of its subranges.

[0079] In addition, this disclosure provides pharmaceutical compositions comprising the ready-to-use non-aqueous formulation (which contains an effective dose of lamotrigine as the active ingredient) and a conventionally pharmaceutically acceptable carrier, namely one or more pharmaceutically acceptable carrier substances and / or additives.

[0080] Therefore, this disclosure provides, for example, a ready-to-use non-aqueous formulation of lamotrigine as a pharmaceutical composition comprising an effective dose of lamotrigine as an active ingredient and a conventionally pharmaceutically acceptable carrier, as well as the use of lamotrigine in the treatment or prevention of the aforementioned diseases or conditions (e.g., neurological disorders or mental disorders), and its use in the preparation of medicaments for these purposes.

[0081] The pharmaceutical compositions according to this disclosure can be administered orally. Administration can also be performed parenterally, such as subcutaneously, intramuscularly, or intravenously by injection or infusion.

[0082] The amount of lamotrigine in the pharmaceutical composition may be from about 0.01 to about 700 mg per dose, or from about 0.1 to about 200 mg, or from about 1 to about 200 mg, but may be higher depending on the type of pharmaceutical composition. In some embodiments, the amount of lamotrigine in the pharmaceutical composition is from 0.01 to 10 mg per dose. The pharmaceutical composition may contain about 0.5 to about 90% by weight of lamotrigine. For this purpose, the ready-to-use non-aqueous formulation of the lamotrigine is combined with one or more solid or liquid drug carrier substances and / or additives (or excipients), and, if desired, with other pharmaceutically active compounds having therapeutic or preventative effects, to formulate a suitable form or dosage form for use as a medicine in human or veterinary medicine.

[0083] In addition to the active compound and carrier, the pharmaceutical composition may also contain conventional additives such as fillers, disintegrants, binders, lubricants, wetting agents, stabilizers, emulsifiers, dispersants, preservatives, sweeteners, colorants, flavorings, aromatizers, thickeners, diluents, buffers, solvents, solubilizers, reagents for achieving reservoir effects, salts for altering osmotic pressure, coating agents, and / or antioxidants.

[0084] One or more additional pharmacologically active agents may be administered in combination with the ready-to-use non-aqueous formulation of lamotrigine. These additional pharmacologically active agents may include, for example, anticonvulsants, antipsychotics, antimanic drugs, valproate, carbamazepine, clozapine, phenytoin, phenobarbital, primidone, and combinations thereof. "Additional one or more active agents" is intended to represent one or more pharmaceutically active agents that are active in vivo, different from lamotrigine, including prodrugs that are converted to their pharmaceutically active form after administration. These additional active agents also include free acids, free bases, and pharmaceutically acceptable salts of the additional active agents. Generally, any suitable additional one or more active agents, including chemotherapeutic agents or therapeutic antibodies, may be used in any combination with the ready-to-use non-aqueous formulation of lamotrigine in a single-dose formulation (e.g., a fixed-dose drug combination), or in one or more single-dose formulations capable of simultaneously or sequentially administering the active agents to an individual (co-administration of individual active agents). Furthermore, the ready-to-use non-aqueous formulation of lamotrigine may be administered in combination with radiotherapy, hormone therapy, surgery, or immunotherapy.

[0085] This application also provides methods of combination therapy, wherein the additional active agent is known to modulate other pathways, or other components of the same pathway, or even overlapping groups of target enzymes used in combination with a ready-to-use non-aqueous formulation of lamotrigine. In one embodiment, such therapy includes, but is not limited to, combinations of a ready-to-use non-aqueous formulation of lamotrigine with chemotherapeutic agents, immunotherapeutic agents, hormones and anti-hormonal agents, targeted therapies, and anti-angiogenic agents to provide synergistic or additive therapeutic effects. In another embodiment, such therapy includes radiation therapy to provide synergistic or additive therapeutic effects.

[0086] Furthermore, the agent can be an agonist, antagonist, allosteric modulator, toxin, or more generally, can act to inhibit or stimulate its target (e.g., receptor or enzyme activation or inhibition). For example, it is suitable to use one or more agents (e.g., antibodies, antigen-binding domains, or soluble receptors) that specifically bind to and inhibit the activity of growth factors.

[0087] The ready-to-use non-aqueous formulation of lamotrigine may be used in combination with the agents disclosed herein or other suitable agents, depending on the condition being treated. Therefore, in some embodiments, the ready-to-use non-aqueous formulation of lamotrigine may be co-administered with other agents as described above. When used in combination therapy, the ready-to-use non-aqueous formulation of lamotrigine described herein may be administered simultaneously or separately from the second agent. Such combination administration may include simultaneous administration of the two agents in the same dosage form, simultaneous administration in separate dosage forms, and separate administration. That is, the ready-to-use non-aqueous formulation of lamotrigine and any of the aforementioned agents may be formulated together in the same dosage form and administered simultaneously. Alternatively, the ready-to-use non-aqueous formulation of lamotrigine and any of the aforementioned agents may be administered simultaneously, wherein the two agents are present in separate formulations. In another alternative, the ready-to-use non-aqueous formulation of lamotrigine may be administered immediately after any of the aforementioned agents, or vice versa. In some embodiments of the separate dosing regimen, the ready-to-use non-aqueous solution of lamotrigine and any of the above-described agents are administered minutes, hours, or days apart. The ready-to-use non-aqueous solution of lamotrigine can be administered at different frequencies, such as 1 to 20 times per week (or any number thereof), or 1 to 90 times per month (or any number thereof). For example, the ready-to-use non-aqueous lamotrigine solution can be administered once daily, twice daily, three times daily, or more than three times daily. The ready-to-use non-aqueous lamotrigine solution can be administered for different durations, such as one week, one month, two months, one year, or more than one year. For example, in some embodiments, the ready-to-use non-aqueous lamotrigine solution is administered daily for one week, one month, two months, one year, or more than one year.

[0088] In some embodiments, the ready-to-use non-aqueous formulation of lamotrigine is administered daily or intermittently. In some embodiments, administration according to the method of this disclosure is continuous for at least one treatment cycle. In some embodiments, the ready-to-use non-aqueous formulation of lamotrigine is administered daily, intermittently, or once during a treatment cycle.

[0089] In some implementations, the treatment period is 1–365 days. In one implementation, the treatment period is 1 day, 2 days, one week (i.e., 7 days), 2 weeks (i.e., 14 days), 3 weeks (i.e., 21 days), 4 weeks (i.e., 28 days), 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks or 20 weeks, one month, 2 months, 3 months, 6 months or about one year. As used herein, "week" means seven consecutive days.

[0090] In some embodiments, the administration is continuous for one treatment cycle. In some embodiments, the administration is continuous for at least one treatment cycle and one additional treatment cycle (i.e., at least two treatment cycles). In some embodiments, the administration is continuous for at least two treatment cycles, or at least three treatment cycles, or at least four treatment cycles, or at least five treatment cycles, or at least six treatment cycles, or at least seven treatment cycles, or at least eight treatment cycles, or at least nine treatment cycles, or at least ten treatment cycles, or at least eleven treatment cycles, or at least twelve treatment cycles, or at least fifteen treatment cycles, or at least twenty treatment cycles, or at least twenty-five treatment cycles, or at least thirty treatment cycles, or at least thirty-five treatment cycles, or at least forty treatment cycles. In some embodiments, the treatment continues until an endpoint can be determined by a medical professional. In some embodiments, the administration is continuous for fewer than or equal to 35 treatment cycles.

[0091] In some embodiments, the dosage of the active agent of this disclosure remains constant during one treatment cycle. In some embodiments, the dosage of the active agent of this disclosure remains constant for at least one treatment cycle and at least one additional treatment cycle (i.e., more than one treatment cycle). In some embodiments, the dosage of the active agent of this disclosure may be increased in a second or subsequent treatment cycle (i.e., another treatment cycle). In some embodiments, the dosage of the active agent of this disclosure may remain constant for at least two treatment cycles and decrease in a third or subsequent treatment cycle. In some embodiments, the dosage of the active agent of this disclosure may remain constant for at least two treatment cycles and increase in a third or subsequent treatment cycle.

[0092] In some embodiments, the ready-to-use non-aqueous formulation of lamotrigine is administered once daily for each day of the treatment cycle. In some embodiments, the ready-to-use non-aqueous formulation of lamotrigine is administered intermittently during the treatment cycle.

[0093] Examples of other non-limiting embodiments of this disclosure are provided below.

[0094] The ready-to-use non-aqueous agent according to any embodiment of the present disclosure, wherein the ready-to-use non-aqueous agent comprises lamotrigine, wherein the ready-to-use non-aqueous agent has at least one of the following properties: the turbidity of the ready-to-use non-aqueous agent is from about 0 NTU to about 20 NTU, the ready-to-use non-aqueous agent is a clear and colorless to pale yellow liquid, and the ready-to-use non-aqueous agent does not form a precipitate or suspension when stored at standard temperature and pressure for at least 7 days.

[0095] The ready-to-use non-aqueous agent according to any embodiment of the present disclosure, wherein the ready-to-use non-aqueous agent has at least two of the following properties: the turbidity of the ready-to-use non-aqueous agent is from about 0 NTU to about 20 NTU, the ready-to-use non-aqueous agent is a clear and colorless to pale yellow liquid, and the ready-to-use non-aqueous agent does not form a precipitate or suspension when stored at standard temperature and pressure for at least 7 days.

[0096] The ready-to-use non-aqueous agent according to any embodiment of this disclosure, wherein the ready-to-use non-aqueous agent has all of the following properties: the turbidity of the ready-to-use non-aqueous agent is from about 0 NTU to about 20 NTU, the ready-to-use non-aqueous agent is a clear and colorless to pale yellow liquid, and the ready-to-use non-aqueous agent does not form a precipitate or suspension when stored at standard temperature and pressure for at least 7 days.

[0097] The ready-to-use non-aqueous agent according to any embodiment of the present disclosure, wherein the turbidity of the ready-to-use non-aqueous agent is from about 0 NTU to about 15 NTU.

[0098] The ready-to-use non-aqueous agent according to any embodiment of the present disclosure, wherein the turbidity of the ready-to-use non-aqueous agent is from about 0 NTU to about 10 NTU.

[0099] The ready-to-use non-aqueous agent according to any embodiment of the present disclosure, wherein the turbidity of the ready-to-use non-aqueous agent is from about 0 NTU to about 5 NTU.

[0100] The ready-to-use non-aqueous preparation according to any embodiment of the present disclosure, wherein the ready-to-use non-aqueous preparation comprises a pharmaceutically effective amount of lamotrigine.

[0101] The ready-to-use non-aqueous preparation according to any embodiment of the present disclosure, wherein the ready-to-use non-aqueous preparation contains lamotrigine at a concentration of about 1 mg / mL to about 40 mg / mL, about 10 mg / mL to about 30 mg / mL, or about 15 mg / mL to about 25 mg / mL based on the total volume of the ready-to-use non-aqueous preparation.

[0102] The ready-to-use non-aqueous agent according to any embodiment of the present disclosure, wherein the ready-to-use non-aqueous agent contains propylene glycol in an amount of about 1% to about 99.9% by weight of the total weight of the ready-to-use non-aqueous agent.

[0103] The ready-to-use non-aqueous agent according to any embodiment of the present disclosure further comprises glycerol in an amount of about 5% to about 95% by weight of the total weight of the ready-to-use non-aqueous agent.

[0104] The ready-to-use non-aqueous agent according to any embodiment of the present disclosure, wherein the ready-to-use non-aqueous agent has water equal to or less than about 20% by weight based on the total weight of the ready-to-use non-aqueous agent.

[0105] The ready-to-use non-aqueous agent according to any embodiment of the present disclosure, wherein the ready-to-use non-aqueous agent has water equal to or less than about 1% by weight based on the total weight of the ready-to-use non-aqueous agent.

[0106] The ready-to-use non-aqueous agent according to any embodiment of the present disclosure further comprises at least one selected from glycerol, propylene glycol, polypropylene glycol, polyethylene glycol and ethanol.

[0107] The ready-to-use non-aqueous agent according to any embodiment of the present disclosure further comprises at least one additive selected from antioxidants, buffers and preservatives.

[0108] The ready-to-use non-aqueous agent according to any embodiment of the present disclosure further comprises at least one additive selected from 3-tert-butyl-4-hydroxyanisole, citric acid, ethylenediaminetetraacetic acid, ethyl maltol, propylparaben, and methylparaben.

[0109] The ready-to-use non-aqueous agent according to any embodiment of this disclosure has a pH meter reading of about 7 to about 8.

[0110] The ready-to-use non-aqueous agent according to any embodiment of the present disclosure, wherein the viscosity of the ready-to-use non-aqueous agent is from about 50 centipoise to about 500 centipoise.

[0111] The ready-to-use non-aqueous agent according to any embodiment of the present disclosure, wherein the density of the ready-to-use non-aqueous agent is from about 1.0 g / mL to about 1.2 g / mL.

[0112] The ready-to-use non-aqueous agent according to any embodiment of the present disclosure, wherein the ready-to-use non-aqueous agent comprises propylene glycol, glycerin, polypropylene glycol, polyethylene glycol and ethanol in a total weight percentage of about 80% to about 100% by weight of the total weight of the ready-to-use non-aqueous agent.

[0113] The ready-to-use non-aqueous agent according to any embodiment of the present disclosure, wherein the ready-to-use non-aqueous agent comprises propylene glycol, glycerin, polypropylene glycol, polyethylene glycol and ethanol in a total weight percentage of about 90% to about 100% by weight of the total weight of the ready-to-use non-aqueous agent.

[0114] The ready-to-use non-aqueous agent according to any embodiment of the present disclosure, wherein the ready-to-use non-aqueous agent comprises propylene glycol, glycerin, polypropylene glycol, polyethylene glycol and ethanol in a total weight percentage of about 95% to about 100% by weight of the total weight of the ready-to-use non-aqueous agent.

[0115] According to any embodiment of the present disclosure, the ready-to-use non-aqueous agent is provided in which water is present in an amount of up to about 20% by weight of the total weight of the ready-to-use non-aqueous agent, and the ready-to-use non-aqueous agent will not form a precipitate when stored at standard temperature and pressure for up to 7 days.

[0116] According to any embodiment of the present disclosure, the ready-to-use non-aqueous agent is provided in which water is present in an amount of about 10% to about 20% by weight of the total weight of the ready-to-use non-aqueous agent, and the ready-to-use non-aqueous agent does not form a precipitate when stored at standard temperature and pressure for up to 7 days.

[0117] The ready-to-use non-aqueous solution according to any embodiment of the present disclosure, wherein the ready-to-use non-aqueous solution contains sugar equal to or less than 10% by weight based on the total weight of the ready-to-use non-aqueous solution.

[0118] The ready-to-use non-aqueous agent according to any embodiment of the present disclosure contains sucrose equal to or less than about 10% by weight based on the total weight of the ready-to-use non-aqueous agent.

[0119] The ready-to-use non-aqueous agent according to any embodiment of the present disclosure, wherein the ready-to-use non-aqueous agent does not contain sucrose.

[0120] A method for treating a neurological condition or mental disorder in an individual in need, comprising administering to the individual a ready-to-use non-aqueous preparation according to any of the foregoing embodiments, wherein the ready-to-use non-aqueous preparation comprises a therapeutically effective amount of lamotrigine.

[0121] Example The following embodiments are provided for illustrative purposes only and are not intended to limit the scope of this disclosure.

[0122] Example 1 The solubility of lamotrigine in various non-aqueous solvents and pure water was determined, as shown below.

[0123] Table 1

[0124] Example 2 Add 1 g of lamotrigine to 90 g of propylene glycol. Mix the mixture until the lamotrigine dissolves. Add propylene glycol until the total volume of the solution is 100 mL. Then mix the solution until homogeneous.

[0125] Example 3 Add 1 g of lamotrigine to 90 g of glycerol. Mix the mixture until the lamotrigine dissolves. Add glycerol until the total volume of the solution is 100 mL. Then mix the solution until homogeneous.

[0126] Example 4 Prepare a 10 / 90 (w / w) propylene glycol / glycerol solvent mixture. Add 1 g of lamotrigine to 90 g of the 10 / 90 (w / w) propylene glycol / glycerol mixture. Mix the mixture until the lamotrigine dissolves. Add the solvent mixture until the total solution volume is 100 mL. Then mix the solution until homogeneous.

[0127] Example 5 Prepare a 10 / 90 (w / w) propylene glycol / glycerol solvent mixture. Add 0.01 g of 3-tert-butyl-4-hydroxyanisole (BHA) to a 90 g solvent. g The solvent mixture is added and mixed until the BHA dissolves. Then, 1 g of lamotrigine is added to the mixture and mixed until the lamotrigine dissolves. The solvent mixture is added until the total volume of the solution is 100 mL. The solution is then mixed until homogeneous.

[0128] Example 6 A solvent mixture was prepared using 10 g propylene glycol and 50 g glycerol. Then, 1 g lamotrigine was added to the solvent mixture and mixed until dissolved. Glycerol was then added until the total solution volume was 100 mL. Next, 1% citric acid and 0.1% EDTA were added to the 100 mL solution. The solution was then mixed until homogeneous.

[0129] Example 7 Prepare a 10 / 90 (w / w) propylene glycol / glycerol solvent mixture. Then, add 0.5 g of ethyl maltol to 240 g of the solvent mixture and mix until dissolved. Then, add 2.5 g of lamotrigine and mix until dissolved. Add the solvent mixture until the total solution volume is 250 mL. Then mix the solution until homogeneous.

[0130] Example 8 Prepare a solvent mixture of 10 / 90 (w / w) propylene glycol / glycerol. Then, add 1.2 g of ethyl maltol to 700 g of the solvent mixture and mix until dissolved. Then, add 8 g of lamotrigine and mix until dissolved. Add the solvent mixture until the total solution volume is 800 mL. Then mix the solution until homogeneous.

[0131] Example 9 Prepare a solvent mixture of 25 / 75 (w / w) propylene glycol / glycerol. Then, add 1.2 g of ethyl maltol to 700 g of the solvent mixture and mix until dissolved. Then, add 8 g of lamotrigine and mix until dissolved. Add the solvent mixture until the total solution volume is 800 mL. Then mix the solution until homogeneous.

[0132] Example 10 Prepare a solvent mixture of 40 / 60 (w / w) propylene glycol / glycerol. Then, add 1.2 g of ethyl maltol to 700 g of the solvent mixture and mix until dissolved. Then, add 8 g of lamotrigine and mix until dissolved. Add the solvent mixture until the total solution volume is 800 mL. Then mix the solution until homogeneous.

[0133] Example 11 Table 2

[0134] Add ethyl maltol to propylene glycol in a clean container and mix until completely dissolved. Then, add lamotrigine to the container and mix until dissolved. Next, add glycerol to reach a total volume of 1.2 L. Then mix the solution until it is clear and homogeneous.

[0135] Example 12 Using a procedure similar to that of Example 11, and with the addition of 0.1% w / v flavoring agent, the formulation shown below was obtained.

[0136] Table 3

[0137] Example 13 Using a procedure similar to that of Example 11, and with the addition of 1%, 10%, or 5% w / v purified water, the formulation shown below was obtained.

[0138] Table 4

[0139] Example 14 Using a procedure similar to that of Example 11, with the addition of citric acid (0.02% w / v), the following formulation with 10% w / v purified water was obtained.

[0140] Table 5

[0141] Example 15 The procedure is similar to that in Example 14, except that purified water is omitted.

[0142] Table 6

[0143] Example 16 Based on the following formulations, ready-to-use non-aqueous formulations of lamotrigine with a concentration of 20 mg / mL were prepared using propylene glycol and glycerol in different proportions.

[0144] Table 7

[0145] Sample 16A (51.1% w / w and / or 57.8% w / v propylene glycol, 47.0% w / w and / or 53.2% w / v glycerol) Sample 16B (74.1% w / w and / or 80% w / v propylene glycol, 23.9% w / w and / or 25.8% w / v glycerol) Example 17 Using a procedure similar to that of Example 11, and with the addition of D&C Yellow #10 (0.00067 mg / mL), the following formulation was obtained.

[0146] Table 8

[0147] Example 18 Lamotrigine at a concentration of 20 mg / mL was prepared using propylene glycol and glycerol in different proportions as shown in the following formulation.

[0148] Table 9

[0149] Sample 18A (9.9% w / w and / or 12.3% w / v propylene glycol, 88.4% w / w and / or 110.3% w / v glycerol) Sample 18B (86.7 w / w and / or 93.6% w / v propylene glycol, 11.3% w / w and / or 12.2 w / v glycerol) Example 19 Table 10

[0150] Sample 19A: 20% w / v purified water in the formulation, no precipitation within 7 days. Sample 19B: 30% w / v purified water in the formulation, precipitate formed within 7 days. Example 20 Using a procedure similar to that of Example 11, and with the additional addition of propylparaben (0.02% w / v) and methylparaben (0.18% w / v), the following formulation was obtained.

[0151] Table 11

[0152] Example 21 Using a procedure similar to that of Example 11, with the addition of alcohol, D&C Yellow #10, sucralose and berry flavoring, the following formulation was obtained.

[0153] Table 12

[0154] Example 22 A single-dose, fasted pharmacokinetic study was conducted using the aforementioned ready-to-use non-aqueous formulation. The ready-to-use non-aqueous formulation has the composition shown in Table 13.

[0155] Table 13

[0156] An open-label, randomized, three-period, three-treatment [treatment A (test product administered under fasting conditions) vs. treatment B (reference product administered under fasting conditions (LAMICTAL)) and treatment C (test product administered under eating conditions) vs. treatment A (test product administered under fasting conditions)], three-sequence, crossover, balanced, single-dose oral clinical pharmacokinetic (fasting condition bioequivalence and food effect) study was conducted in healthy adult individuals to evaluate the oral fasting bioequivalence of the test formulation relative to the reference formulation and to evaluate the food effect of the test formulation under eating conditions relative to fasting conditions.

[0157] The results of using 50 mg lamotrigine (equivalent to 2.5 mL of the ready-to-use non-aqueous solution) in treatment A (fasting state) and treatment C (eating state) were compared with those of using 2 × 25 mg (50 mg) LAMICTAL tablets in treatment B (fasting state). Individuals in treatments A and B fasted for at least 10 hours before administration and for at least 4 hours after administration, and restricted fluid intake for at least 1 hour before administration and for at least 1 hour after administration, except when given fluids to drink while administering the LAMICTAL tablets.

[0158] In each period of the study, administration was performed in healthy adult human individuals on a randomized schedule. Results are provided in the figures and Table 14 below, showing the bioequivalence (BE) of the said ready-to-use non-aqueous formulation compared to LAMICTAL (lamotrigine) tablets. max AUC t and AUC i The values ​​are each in natural logarithmic form (Ln), and the time t is 168 hours.

[0159] Table 14

[0160] Example 23 Stability studies were conducted using ready-to-use non-aqueous formulations with water contents of 1%, 5%, and 10%. Although water was present, it did not act as a solvent. The results are presented in Table 15 below, all showing excellent stability. Impurity A was 3-amino-6-(2,3-dichlorophenyl)-1,2,4-triazine-5(4H)-one.

[0161] Table 15

[0162] Example 24 Stability studies were conducted using ready-to-use non-aqueous solutions with various propylene glycol to glycerol weight ratios as shown in Table 16 below.

[0163] Table 16 Ethyl maltol was added to propylene glycol in a clean container and mixed until completely dissolved. Lamotrigine was then added to the container and mixed until dissolved. Glycerin was then added to bring the final volume to 800 mL. The solution was then mixed until clear and homogeneous. The results are provided in Table 17 below, all showing excellent stability. Impurity A was 3-amino-6-(2,3-dichlorophenyl)-1,2,4-triazine-5(4H)-one.

[0164] Table 17

[0165] While this disclosure has been described above with reference to specific embodiments thereof, it will be apparent that many changes, modifications, and variations can be made without departing from the concept disclosed herein. Therefore, it is intended to cover all such changes, modifications, and variations that fall within the spirit and broad scope of the appended claims.

Claims

1. A ready-to-use non-aqueous solution containing lamotrigine dissolved in a solvent. The solvent comprises propylene glycol and at least one co-solvent, and If water is present in the ready-to-use non-aqueous solution, then the water is not one of the at least one cosolvent.

2. The ready-to-use non-aqueous solution of claim 1, wherein the concentration of lamotrigine in the ready-to-use non-aqueous solution is about 0.01 mg / mL to about 40 mg / mL, about 0.4 mg / mL to about 40 mg / mL, about 10 mg / mL to about 30 mg / mL, or about 15 mg / mL to about 25 mg / mL.

3. The ready-to-use non-aqueous solution of claim 1 or 2, wherein the concentration of lamotrigine in the ready-to-use non-aqueous solution is about 20 mg / mL.

4. The ready-to-use non-aqueous solution of any one of claims 1-3, wherein the water content is equal to or less than about 20% w / w, equal to or less than about 15% w / w, equal to or less than about 10% w / w, equal to or less than about 5% w / w, equal to or less than about 3% w / w, or equal to or less than about 1% w / w.

5. The ready-to-use non-aqueous solution of any one of claims 1-4, wherein the at least one cosolvent comprises at least one selected from glycerol, polypropylene glycol, polyethylene glycol and ethanol.

6. The ready-to-use non-aqueous solution of any one of claims 1-5, wherein the at least one cosolvent is glycerol.

7. The ready-to-use non-aqueous solution of claim 5 or 6, wherein the weight ratio of propylene glycol to glycerin is 100:0 to 10:90, 80:20 to 20:80, 70:30 to 30:70, or 60:40 to 40:

60.

8. The ready-to-use non-aqueous solution of any one of claims 5-7, wherein the propylene glycol content is about 10% to about 87% w / w, about 30% to about 87% w / w, or about 45% to about 87% w / w of the ready-to-use non-aqueous solution.

9. The ready-to-use non-aqueous preparation of any one of claims 5-8, wherein the glycerol content is about 11% to about 88% w / w, about 11% to about 68% w / w, or about 11% to about 60% w / w of the ready-to-use non-aqueous preparation.

10. A ready-to-use non-aqueous solution according to any one of claims 5-9, wherein the propylene glycol content is about 40% to about 80% w / w of the non-aqueous solution, and the glycerol content is about 20% to about 60% w / w of the ready-to-use non-aqueous solution.

11. The ready-to-use non-aqueous solution of any one of claims 5-10, wherein the propylene glycol content is about 45% to about 55% w / w of the ready-to-use non-aqueous solution, and the glycerol content is about 45% to about 55% w / w of the ready-to-use non-aqueous solution.

12. The ready-to-use non-aqueous solution of any one of claims 1-11, further comprising at least one selected from antioxidants, buffers and preservatives.

13. The ready-to-use non-aqueous solution of any one of claims 1-12, comprising at least one selected from 3-tert-butyl-4-hydroxyanisole, citric acid, ethylenediaminetetraacetic acid, ethyl maltol, propylparaben, and methylparaben.

14. A ready-to-use non-aqueous preparation containing lamotrigine dissolved in a solvent. The solvent comprises polyethylene glycol or glycerol and optionally at least one co-solvent, and If water is present in the ready-to-use non-aqueous solution, then the water is not one of the at least one cosolvent.

15. The ready-to-use non-aqueous preparation of claim 14, wherein the concentration of lamotrigine in the ready-to-use non-aqueous preparation is about 0.01 mg / mL to about 40 mg / mL, about 0.4 mg / mL to about 40 mg / mL, about 10 mg / mL to about 30 mg / mL, about 15 mg / mL to about 25 mg / mL, or about 19 mg / mL to about 21 mg / mL.

16. The ready-to-use non-aqueous solution of claim 14 or 15, wherein the concentration of lamotrigine in the ready-to-use non-aqueous solution is about 20 mg / mL.

17. The ready-to-use non-aqueous solution of any one of claims 14-16, wherein the water content is equal to or less than about 20% w / w, equal to or less than about 15% w / w, equal to or less than about 10% w / w, equal to or less than about 5% w / w, equal to or less than about 3% w / w, or equal to or less than about 1% w / w.

18. The ready-to-use non-aqueous solution of any one of claims 14-17, wherein the at least one cosolvent comprises polypropylene glycol and / or ethanol.

19. The ready-to-use non-aqueous solution of any one of claims 14-18, wherein the polyethylene glycol is in liquid form.

20. The ready-to-use non-aqueous solution of any one of claims 14-19, wherein the average molecular weight of polyethylene glycol is equal to or less than 600 g / mol.

21. The ready-to-use non-aqueous solution of any one of claims 14-20, wherein the polyethylene glycol is at least one selected from polyethylene glycol 600, polyethylene glycol 500, polyethylene glycol 400, polyethylene glycol 300 and polyethylene glycol 200.

22. The ready-to-use non-aqueous solution of any one of claims 1-21, wherein the density of the ready-to-use non-aqueous solution is from about 1.0 g / mL to about 1.3 g / mL or from about 1.1 g / mL to about 1.2 g / mL.

23. The ready-to-use non-aqueous solution of any one of claims 1-22, wherein the pH meter reading of the ready-to-use non-aqueous solution is about 7.5 to about 7.

8.

24. The ready-to-use non-aqueous solution of any one of claims 1-23, wherein the viscosity of the ready-to-use non-aqueous solution is about 200 centipoise to about 300 centipoise.

25. A method for treating a neurological disorder or mental disorder in an individual in need, comprising administering to the individual a ready-to-use non-aqueous solution of any one of claims 1-24, wherein the ready-to-use non-aqueous solution comprises a therapeutically effective amount of lamotrigine.

26. The ready-to-use non-aqueous solution of any one of claims 1-24, for the treatment of neurological disorders or mental disorders in individuals in need.

27. Use of the ready-to-use non-aqueous formulation of any one of claims 1-24 in the preparation of a medicament for treating neurological disorders or mental disorders in individuals in need.

28. The method of any one of claims 25-27, the ready-to-use non-aqueous solution for the said use, or the said use, wherein the neurological condition is epilepsy.

29. The method of any one of claims 25-27, the ready-to-use non-aqueous solution for the said use, or the said use, wherein the mental disorder is bipolar disorder.

30. The method of any one of claims 25-29, the ready-to-use non-aqueous solution for said use, or said use, wherein the individual is a person.

31. The method of any one of claims 25-30, the ready-to-use non-aqueous formulation for the said use, or the said use, wherein the therapeutically effective amount is administered orally.

32. The method of any one of claims 25-31, the ready-to-use non-aqueous formulation for said use, or said use, wherein the therapeutically effective amount of lamotrigine is about 2 mg to about 700 mg.

33. The method of any one of claims 25-32, ready-to-use non-aqueous solution for said use, or said use, wherein the administration results in a C max value of lamotrigine in the individual of about 800 ng / mL to about 1000 ng / mL.

34. The method of any one of claims 25-33, the ready-to-use non-aqueous formulation for said use, or said use, wherein the administration results in an AUC of about 35,000 ng / mL for lamotrigine in the individual. hr to approximately 40000 ng / mL hr.

35. The method of any one of claims 25-34, the ready-to-use non-aqueous preparation for the said use, or the said use, wherein the therapeutically effective amount is administered orally after fasting.

36. The method of any one of claims 25-35, the ready-to-use non-aqueous formulation for the said use, or the said use, wherein the therapeutically effective amount is administered orally after a meal.

37. A method for preparing a non-aqueous solution of any one of claims 1-24, comprising: Lamotrigine is mixed with the solvent to dissolve the lamotrigine in the solvent.

38. A medicine box, comprising: The first container contains lamotrigine; and The second container contains a solvent comprising propylene glycol and, optionally, at least one co-solvent. The contents of the first container and the second container are mixed during use to form a ready-to-use non-aqueous solution according to any one of claims 1-13 or 22-24. If water is present in the ready-to-use non-aqueous solution, then the water is not one of the at least one cosolvent.

39. The kit of claim 38, wherein the at least one cosolvent comprises at least one selected from glycerol, polypropylene glycol, polyethylene glycol and ethanol.

40. A medicine box, comprising: The first container contains lamotrigine; and The second container contains a solvent comprising polyethylene glycol or glycerol and optionally at least one co-solvent. The contents of the first container and the second container are mixed during use to form a ready-to-use non-aqueous solution according to any one of claims 14-21. If water is present in the non-aqueous solution, then the water is not one of the at least one cosolvent.

41. The kit of claim 40, wherein the at least one cosolvent comprises polypropylene glycol and / or ethanol.

42. A ready-to-use non-aqueous solution comprising: Lamotrigine at a concentration of approximately 15 mg / mL to approximately 25 mg / mL; and Solvent, the solvent comprising: Propylene glycol of approximately 45% to approximately 55% w / w; and Glycerin at approximately 45% to approximately 55% w / w; and If water is present in the ready-to-use non-aqueous solution, then the water is not the solvent.

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