Pharmaceutical Compositions

Abstract

Described herein are bumetanide dibenzylamide, methods for synthesizing bumetanide dibenzylamide, pharmaceutical compositions thereof, and methods of administering bumetanide dibenzylamide to treat epilepsy or other indications for which bumetanide is effective.

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application is a PCT international application claiming benefit to U.S. Provisional Application No. 63 / 477,264, filed December 27, 2022, and U.S. Provisional Application No. 63 / 295,076, filed December 30, 2021, each of which is incorporated by reference in its entirety herein.

[0002] Described herein are compositions comprising bumetanide dibenzylamide for treating selected conditions of the central and peripheral nervous system using non-synaptic mechanisms.More specifically, the present disclosure relates to methods and compositions for treating neurological disorders by administering agents that disrupt hypersynchronous neuronal activity without reducing neuronal excitability.These compositions are useful for seizure disorders, including epilepsy and related indications. [Background technology]

[0003] Epilepsy is characterized by abnormal discharges of cerebral neurons, typically manifesting as various types of seizures. Many anticonvulsants that were initially developed for the treatment of epilepsy and other seizure disorders are also applied to the treatment of non-epileptic conditions, including neuropathic pain, mood disorders (such as bipolar affective disorder), and schizophrenia (for a review of the use of anti-epileptic drugs in the treatment of non-epileptic conditions, see Rogawski and Loscher, Nat. Medicine, 10:685-692, 2004). Thus, it has been suggested that epilepsy, neuropathic pain, and affective disorders have a common pathophysiological mechanism (Rogawski & Loscher, ibid.; Ruscheweyh & Sandkuhler, Pain 105:327-338, 2003), i.e., a pathological increase in neuronal excitability, with a corresponding inappropriately high frequency of spontaneous neuronal firing. However, only some, but not all, antiepileptic drugs are effective in treating neuropathic pain, and furthermore, such antiepileptic drugs are effective only in a specific subset of patients with neuropathic pain (McCleane, Expert. Opin. Pharmacother. 5:1299-1312, 2004).

[0004] Epileptiform activity is identified by spontaneously occurring synchronous discharges of neuronal populations that can be measured using electrophysiological techniques. This synchronous activity, which distinguishes epileptiform activity from non-epileptiform activity, is called "hypersynchrony" to describe a state in which individual neurons are increasingly likely to discharge each other in a time-locked manner. Hypersynchrony is typically induced in experimental models of epilepsy by either increasing excitability or decreasing inhibitory synaptic currents. Thus, hyperexcitability itself was assumed to be the defining feature responsible for the generation and maintenance of epileptiform activity. Similarly, neuropathic pain was thought to involve the conversion of neurons involved in pain transmission from a state of normal sensitivity to a state of hypersensitivity (Costigan & Woolf, Jnl. Pain l: 35-44, 2000). Therefore, the focus of developing treatments for both epilepsy and neuropathic pain has been on suppressing neuronal hyperexcitability by either (a) suppressing action potential generation, (b) increasing inhibitory synaptic transmission, or (c) decreasing excitatory synaptic transmission.

[0005] Most drugs currently used for treatment target synaptic activity in excitatory pathways, for example, by modulating the release or activity of excitatory neurotransmitters, enhancing inhibitory pathways, blocking ion channels involved in impulse generation, and / or acting as membrane stabilizers. Thus, conventional drugs and therapeutic approaches for the treatment of epilepsy and neuropsychiatric disorders reduce neuronal excitability and inhibit synaptic firing. One serious drawback of these therapies is that they are nonselective and exert their action on both normal and abnormal neuronal populations. This leads to negative unintended side effects that can affect normal CNS functions such as cognition, learning, and memory in treated patients, resulting in adverse physiological and psychological effects. Common side effects include oversedation, dizziness, memory loss, and liver damage. However, it has been shown that hypersynchronous epileptiform activity can be dissociated from hyperexcitability, and that the cation-chloride cotransport inhibitor furosemide can reversibly block synchronous discharges without reducing hyperexcitable synaptic responses (Hochman et al. Science 270:99-102, 1995). Cation-chloride cotransporters (CCCs) are important regulators of neuronal chloride concentration that are thought to influence intercellular communication as well as various aspects of neuronal development, plasticity, and injury. The CCC gene family consists of three broad groups: Na + -C1 - cotransporter (NCC), K + -C1 - Cotransporter (KCC) and Na + -K + -2C1 -The Na-K-Cl cotransporter is composed of the Na-K-Cl cotransporter (NKCC). The Na-K-Cl cotransporter in all cells and tissues is inhibited by loop diuretics, including furosemide, bumetanide, and benzmethanide. Espinosa et al. and Ahmad et al. have previously suggested that furosemide may be useful in treating certain types of epilepsy (Medicina Espanola 61:280-281, 1969, and Brit. J. Clin. Pharmacol. 3:621-625, 1976). Bumetanide is a potentially more potent drug for treating epilepsy, but also has a more pronounced diuretic effect. Thus, there is a continuing need for methods and compositions for treating neuronal disorders that are not diuretic and that disrupt hypersynchronous neuronal activity without reducing neuronal excitability and spontaneous synchronization that are required for normal function of the peripheral and central nervous systems. [Prior art documents] [Non-patent literature]

[0006] [Non-Patent Document 1] Rogawski and Loscher, Nat. Medicine, 10:685-692, 2004 [Non-Patent Document 2] Ruscheweyh&Sandkuhler,Pain 105:327-338,2003 [Non-Patent Document 3] McCleane,Expert.Opin.Pharmacother.5:1299-1312,2004 [Non-Patent Document 4] Costigan&Woolf,Jnl.Pain l:35-44,2000 [Non-Patent Document 5] Hochman et al.Science 270:99-102,1995 [Non-Patent Document 6] Medicina Espanola 61:280-281,1969 [Non-Patent Document 7] Brit.J.Clin.Pharmacol.3:621-625,1976 Summary of the Invention

[0007] One embodiment of the disclosure includes a pharmaceutical composition comprising bumetanide dibenzylamide and one or more solubilizing agents.

[0008] In one embodiment, the composition comprises from about 2.5 mg / mL to about 42 mg / mL of bumetanide dibenzylamide. In one embodiment, the composition comprises from about 0.25% w / w to about 15% w / w of bumetanide dibenzylamide. In one embodiment, the composition comprises from about 0.1% w / w to about 99.75% w / w of one or more solubilizing agents. In one embodiment, the one or more solubilizing agents comprise short chain triglycerides, long chain triglycerides, or a combination thereof. In one embodiment, the one or more solubilizing agents comprise polyoxyl 35 castor oil, glyceryl monolinoleate, or any combination thereof. In one embodiment, the one or more solubilizing agents comprise caprylocaproyl polyoxylglycerides, phosphatidylcholine, caprylic / capric triglycerides, lauroyl pryoxyl-32 glycerides, sorbitan esters, or any combination thereof. In one embodiment, the one or more solubilizers include ethanol, propylene glycol, polyethylene glycol 600, polyethylene glycol 3350, oleyl alcohol, or any combination thereof. In one embodiment, the one or more solubilizers include PEG-400, Vitamin E TPGS, or any combination thereof. In one embodiment, the one or more solubilizers include soybean oil. In one embodiment, the one or more solubilizers include water. In one embodiment, the one or more solubilizers include polyvinylpyrrolidone (K30), poloxamer 407 (P407), sodium carboxymethylcellulose (CMC), or any combination thereof. In one embodiment, the one or more solubilizers include at least one superdisintegrant. In one embodiment, the one or more solubilizers include at least one wetting agent. In one embodiment, the one or more solubilizers include at least one surfactant. In one embodiment, the one or more solubilizing agents include Ceolus KG (microcrystalline cellulose), Mannogem EZ (spray dried mannitol), Polyplasdone XL (super disintegrant), poloxamer 407, lauroyl puroxyl-32 glyceride, sorbitan esters, Neusilin US2 (magnesium aluminometasilicate), citric acid monohydrate, Cabosil M5P (fumed silica), magnesium stearate, or any combination thereof.

[0009] One embodiment of the disclosure includes a pharmaceutical composition comprising about 1.79% w / w bumetanide dibenzylamide, about 33.48% w / w polyoxyl 35 castor oil, about 32.37% w / w glyceryl monolinoleate, and about 32.37% w / w soybean oil.

[0010] One embodiment of the disclosure includes a pharmaceutical composition comprising about 1.76% w / w bumetanide dibenzylamide, about 32.93% w / w polyoxyl 35 castor oil, about 31.83% w / w glyceryl monolinoleate, about 31.83% w / w soybean oil, and about 10.37% w / w ethanol.

[0011] One embodiment of the present disclosure includes a pharmaceutical composition comprising about 1.59% w / w bumetanide dibenzylamide, about 22% w / w phosphatidylcholine, about 70% w / w caprylocaproyl polyoxylglyceride, and about 6.41% w / w caprylic / capric triglyceride.

[0012] One embodiment of the disclosure includes a pharmaceutical composition comprising about 1.98% w / w bumetanide dibenzylamide, about 19.39% w / w lauroyl puroxyl-32 glyceride, about 37.62% w / w sorbitan esters, and about 41.01% w / w soybean oil.

[0013] One embodiment of the disclosure includes a pharmaceutical composition comprising about 1.98% w / w bumetanide dibenzylamide, about 39.72% w / w caprylocaproyl polyoxylglyceride, about 25.94% w / w sorbitan ester, and about 49.78% w / w soybean oil.

[0014] One embodiment of the disclosure includes a pharmaceutical composition comprising about 1.73% w / w bumetanide dibenzylamide, about 32.40% w / w polyoxyl 35 castor oil, about 31.32% w / w glyceryl monolinoleate, about 31.32% w / w soybean oil, and about 3.24% w / w ethanol.

[0015] One embodiment of the disclosure includes a pharmaceutical composition comprising about 1.7% w / w bumetanide dibenzylamide, about 31.91% w / w polyoxyl 35 castor oil, about 30.85% w / w glyceryl monolinoleate, about 30.85% w / w soybean oil, and about 4.68% w / w ethanol.

[0016] An embodiment of the present disclosure includes a pharmaceutical composition comprising about 10% w / w to about 100% w / w caprylocaproyl polyoxylglyceride. An embodiment of the present disclosure includes a pharmaceutical composition comprising about 12% w / w to about 20% w / w propylene glycol. An embodiment of the present disclosure includes a pharmaceutical composition comprising about 57% w / w to about 80% w / w PEG 400. An embodiment of the present disclosure includes a pharmaceutical composition comprising about 1% Vitamin E TPGS.

[0017] One embodiment of the disclosure includes a pharmaceutical composition comprising about 2.73% w / w bumetanide dibenzylamide, about 10% w / w caprylocaproyl polyoxylglyceride, about 12.05% w / w propylene glycol, about 67.22% w / w polyethylene glycol 400, and about 8% w / w water.

[0018] One embodiment of the disclosure includes a pharmaceutical composition comprising about 2.82% w / w bumetanide dibenzylamide, about 4.65% w / w caprylocaproyl polyoxylglyceride, about 13.01% w / w propylene glycol, about 67.97% w / w polyethylene glycol 400, about 0.92% w / w polyvinylpyrrolidone (K30), and about 10.62% w / w water.

[0019] One embodiment of the disclosure includes a pharmaceutical composition comprising about 0.6% w / w bumetanide dibenzylamide, about 10% w / w caprylocaproyl polyoxylglyceride, about 9.15% w / w propylene glycol, about 53.84% w / w polyethylene glycol 400, about 3.6% w / w polyvinylpyrrolidone (K30), about 2.4% w / w poloxamer 407 (P407), about 0.41% w / w sodium CMC, and about 20% w / w water.

[0020] One embodiment of the disclosure includes a pharmaceutical composition comprising about 0.6% w / w bumetanide dibenzylamide, about 10% w / w caprylocaproyl polyoxylglyceride, about 9.15% w / w propylene glycol, about 66.75% w / w polyethylene glycol 400, about 3.% w / w polyvinylpyrrolidone (K30), about 2.4% w / w poloxamer 407 (P407), and about 7.5% w / w polyethylene glycol 3350.

[0021] One embodiment of the disclosure includes a pharmaceutical composition comprising about 15% w bumetanide dibenzylamide, about 20% w microcrystalline cellulose, about 51% w spray dried mannitol, about 7% w Polyplasdone XL (super disintegrant), about 3% w poloxamer 407, about 1.5% w citric acid monohydrate, about 1.0% w Cabosil M5P, and about 1.5% w magnesium stearate.

[0022] One embodiment of the disclosure includes a pharmaceutical composition comprising about 7.4% w bumetanide dibenzylamide, about 9.9% w lauroyl puroxyl-32 glyceride, about 9.9% w sorbitan ester, about 54.3% w Polyplasdone XL (super disintegrant), about 0.5% w poloxamer 407, about 0.7% w citric acid monohydrate, about 2.0% w Cabosil M5P (fumed silica), about 14.8% w Neusilin US2 (magnesium aluminometasilicate), and about 0.5% w magnesium stearate.

[0023] One embodiment of the present disclosure is a solution of 55% polyethylene glycol 400 (PEG-400) in water, or 41% PEG-400, 12% ethanol, 47% water, or 45% PEG-400, 10% DMSO, 45% water, or 31% PEG-400, 31% tetraglycol, 15% caprylocaproyl polyoxylglyceride, 23% water, or 30% PEG-400, 10% N-methylpyrrolidone, 10% DMSO, 50% water, or 25% PEG-400, 10% DMSO, 20% tetraglycol, 45% water, or The pharmaceutical compositions include a vehicle composition comprising 20% ​​ethanol in water, or 20% hydroxypropyl-β-cyclodextrin in water, or 11% DMSO, 22% PEG-400, 22% tetraglycol, 44% water, or 44% PEG-400, 0.4% poloxamer-188, 22% N-methylpyrrolidone, 33% water, or 20% PEG-400, 15% hydroxypropyl-β-cyclodextrin in water, or 40% PEG-400, 20% propylene glycol, 5% ethanol, and 35% water.

[0024] One embodiment of the present disclosure includes a pharmaceutical composition comprising about 28 g of bumetanide dibenzylamide and about 3 ml of a solvent, wherein the 50 g of solvent contains about 5 g of caprylocaproyl polyoxylglyceride, about 10 g of propylene glycol, about 28.5 g of PEG-400, about 0.5 g of Vitamin E TPGS, about 1 g of ethanol, and about 4.5 g of water.

[0025] One embodiment of the disclosure includes a method for treating a patient in need of treatment comprising administering a pharmaceutical composition comprising bumetanide dibenzylamide and one or more solubilizing agents.

[0026] In an alternative embodiment, the present disclosure includes a pharmaceutical composition comprising bumetanide dibenzylamide and one or more solubilizing agents for use in medicine.

[0027] In further alternative embodiments, there is provided the use of a pharmaceutical composition comprising bumetanide dibenzylamide and one or more solubilizing agents in the manufacture of a medicament. In further embodiments, a pharmaceutical composition comprising bumetanide dibenzylamide and one or more solubilizing agents may be used in the manufacture of a medicament for the therapeutic and / or prophylactic treatment of other indications such as seizures, epilepsy, and / or neuropathic pain. In some embodiments, a pharmaceutical composition comprising bumetanide dibenzylamide and one or more solubilizing agents may be used in the manufacture of a medicament for the therapeutic and / or prophylactic treatment of epilepsy and / or neurological syndromes specific to children. In some embodiments, a pharmaceutical composition comprising bumetanide dibenzylamide and one or more solubilizing agents may be used in the manufacture of a medicament for the therapeutic and / or prophylactic treatment of one or more indications listed in FIG. 18 (Fisher et al.), as well as for treating any terms that may replace the old and current terms describing the indications listed in FIG. 18 in the future. In some embodiments, the pharmaceutical composition comprising bumetanide dibenzylamide and one or more solubilizing agents may be used in the manufacture of a medicament for the therapeutic and / or prophylactic treatment of migraine or tinnitus. In some embodiments, the pharmaceutical composition comprising bumetanide dibenzylamide and one or more solubilizing agents may be used in the manufacture of a medicament for the therapeutic and / or prophylactic treatment of depression and / or anxiety. In some embodiments, the pharmaceutical composition comprising bumetanide dibenzylamide and one or more solubilizing agents may be used in the manufacture of a medicament for the therapeutic and / or prophylactic treatment of neuropsychiatric disorders. In some embodiments, the pharmaceutical composition comprising bumetanide dibenzylamide and one or more solubilizing agents may be used in the manufacture of a medicament for the therapeutic and / or prophylactic treatment of neurodegenerative disorders, including but not limited to Alzheimer's disease, amyotrophic lateral sclerosis, Friedreich's ataxia, Huntington's disease, Lewy body disease, Parkinson's disease, or spinal muscular atrophy. In one embodiment, the pharmaceutical composition comprises from about 2.5 mg / mL to about 42 mg / mL of bumetanide dibenzylamide.In one embodiment, the pharmaceutical composition comprises from about 0.25% w / w to about 15% w / w of bumetanide dibenzylamide.In one embodiment, the one or more solubilizers include short chain triglycerides, long chain triglycerides, or a combination thereof. In one embodiment, the one or more solubilizers include polyoxyl 35 castor oil, glyceryl monolinoleate, or any combination thereof. In one embodiment, the one or more solubilizers include caprylocaproyl polyoxylglycerides, phosphatidylcholine, caprylic / capric triglycerides, lauroyl pryoxyl-32 glycerides, sorbitan esters, or any combination thereof. In one embodiment, the one or more solubilizers include ethanol, propylene glycol, polyethylene glycol 600, polyethylene glycol 3350, oleyl alcohol, or any combination thereof. In one embodiment, the one or more solubilizers include PEG-400, vitamin E TPGS, or any combination thereof. In one embodiment, the one or more solubilizers include soybean oil. In one embodiment, the one or more solubilizers include water. In one embodiment, the one or more solubilizers include polyvinylpyrrolidone (K30), poloxamer 407 (P407), sodium carboxymethylcellulose (CMC), or any combination thereof. In one embodiment, the one or more solubilizers include at least one superdisintegrant. In one embodiment, the one or more solubilizers include at least one wetting agent. In one embodiment, the one or more solubilizers include at least one surfactant. In one embodiment, the one or more solubilizers include Ceolus KG (microcrystalline cellulose), Mannogem EZ (spray-dried mannitol), Polyplasdone XL (superdisintegrant), poloxamer 407, lauroyl puroxyl-32 glyceride, sorbitan esters, Neusilin US2 (magnesium aluminometasilicate), citric acid monohydrate, Cabosil M5P (fumed silica), magnesium stearate, or any combination thereof. In one embodiment, a pharmaceutical composition comprising about 1.79% w / w bumetanide dibenzylamide, about 33.48% w / w polyoxyl 35 castor oil, about 32.37% w / w glyceryl monolinoleate, and about 32.37% w / w soybean oil.In one embodiment, a pharmaceutical composition comprising about 1.76% w / w bumetanide dibenzylamide, about 32.93% w / w polyoxyl 35 castor oil, about 31.83% w / w glyceryl monolinoleate, about 31.83% w / w soybean oil, and about 10.37% w / w ethanol. In one embodiment, a pharmaceutical composition comprising about 1.59% w / w bumetanide dibenzylamide, about 22% w / w phosphatidylcholine, about 70% w / w caprylocaproyl polyoxylglyceride, and about 6.41% w / w caprylic / capric triglyceride. In one embodiment, a pharmaceutical composition comprising about 1.98% bumetanide dibenzylamide w / w, about 19.39% lauroyl polyoxyl-32 glyceride w / w, about 37.62% sorbitan esters w / w, and about 41.01% soybean oil w / w. In one embodiment, a pharmaceutical composition comprising about 1.98% bumetanide dibenzylamide w / w, about 39.72% caprylocaproyl polyoxyl glyceride w / w, about 25.94% sorbitan esters w / w, and about 49.78% soybean oil w / w. In one embodiment, a pharmaceutical composition comprising about 1.73% w / w bumetanide dibenzylamide, about 32.40% w / w polyoxyl 35 castor oil, about 31.32% w / w glyceryl monolinoleate, about 31.32% w / w soybean oil, and about 3.24% w / w ethanol. In one embodiment, a pharmaceutical composition comprising about 1.7% w / w bumetanide dibenzylamide, about 31.91% w / w polyoxyl 35 castor oil, about 30.85% w / w glyceryl monolinoleate, about 30.85% w / w soybean oil, and about 4.68% w / w ethanol. In one embodiment, a pharmaceutical composition comprising about 10% w / w to about 100% w / w caprylocaproyl polyoxylglyceride. In one embodiment, the pharmaceutical composition comprises about 12% w / w to about 20% w / w propylene glycol. In one embodiment, the pharmaceutical composition comprises about 57% w / w to about 80% w / w PEG 400. In one embodiment, the pharmaceutical composition comprises about 1% Vitamin E TPGS. In one embodiment, the pharmaceutical composition comprises about 2.73% w / w bumetanide dibenzylamide, about 10% w / w caprylocaproyl polyoxylglyceride, about 12.05% w / w propylene glycol, about 67.22% w / w polyethylene glycol 400, and about 8% w / w water.In one embodiment, a pharmaceutical composition comprising about 2.82% w / w bumetanide dibenzylamide, about 4.65% w / w caprylocaproyl polyoxylglyceride, about 13.01% w / w propylene glycol, about 67.97% w / w polyethylene glycol 400, about 0.92% w / w polyvinylpyrrolidone (K30), and about 10.62% w / w water. In one embodiment, a pharmaceutical composition comprises about 0.6% w / w bumetanide dibenzylamide, about 10% w / w caprylocaproyl polyoxylglyceride, about 9.15% w / w propylene glycol, about 53.84% w / w polyethylene glycol 400, about 3.6% w / w polyvinylpyrrolidone (K30), about 2.4% w / w poloxamer 407 (P407), about 0.41% w / w sodium CMC, and about 20% w / w water. In one embodiment, a pharmaceutical composition comprising about 0.6% w / w bumetanide dibenzylamide, about 10% w / w caprylocaproyl polyoxylglyceride, about 9.15% w / w propylene glycol, about 66.75% w / w polyethylene glycol 400, about 3.6% w / w polyvinylpyrrolidone (K30), about 2.4% w / w poloxamer 407 (P407), and about 7.5% w / w polyethylene glycol 3350. In one embodiment, a pharmaceutical composition comprising about 15% w bumetanide dibenzylamide, about 20% w microcrystalline cellulose, about 51% w spray dried mannitol, about 7% w Polyplasdone XL (super disintegrant), about 3% w poloxamer 407, about 1.5% w citric acid monohydrate, about 1.0% w Cabosil M5P, and about 1.5% w magnesium stearate. In one embodiment, a pharmaceutical composition comprising about 7.4% w bumetanide dibenzylamide, about 9.9% w lauroyl puroxyl-32 glyceride, about 9.9% w sorbitan ester, about 54.3% w Polyplasdone XL (super disintegrant), about 0.5% w poloxamer 407, about 0.7% w citric acid monohydrate, about 2.0% w Cabosil M5P (fumed silica), about 14.8% w Neusilin US2 (magnesium aluminometasilicate), and about 0.5% w magnesium stearate.In one embodiment, 55% polyethylene glycol 400 (PEG-400) in water, or 41% PEG-400, 12% ethanol, 47% water, or 45% PEG-400, 10% DMSO, 45% water, or 31% PEG-400, 31% tetraglycol, 15% caprylocaproyl polyoxylglyceride, 23% water, or 30% PEG-400, 10% N-methylpyrrolidone, 10% DMSO, 50% water, or 25% PEG-400, 10% DMSO, 20% tetraglycol, 45% water, or water. 20% ethanol in water, or 20% hydroxypropyl-β-cyclodextrin in water, or a vehicle composition comprising 11% DMSO, 22% PEG-400, 22% tetraglycol, 44% water, or 44% PEG-400, 0.4% poloxamer-188, 22% N-methylpyrrolidone, 33% water, or 20% PEG-400, 15% hydroxypropyl-β-cyclodextrin in water, or 40% PEG-400, 20% propylene glycol, 5% ethanol, and 35% water. In one embodiment, a pharmaceutical composition comprising about 28 g of bumetanide dibenzylamide and about 3 ml of solvent, the 50 g of solvent containing about 5 g of caprylocaproyl polyoxylglyceride, about 10 g of propylene glycol, about 28.5 g of PEG-400, about 0.5 g of Vitamin E TPGS, about 1 g of ethanol, and about 4.5 g of water. In one embodiment, the pharmaceutical composition is an oral capsule. In one embodiment, the pharmaceutical composition is a nasal solution. In one embodiment, the pharmaceutical composition is a rectal gel. In one embodiment, the pharmaceutical composition is a rectal paste. In one embodiment, the pharmaceutical composition is a sublingual tablet. In one embodiment, the pharmaceutical composition is an injectable composition. In one embodiment, the administration of the patient with the pharmaceutical composition is oral. In one embodiment, the administration of the patient with the pharmaceutical composition is intranasal. In one embodiment, the administration of the patient with the pharmaceutical composition is rectal. In one embodiment, the administration of the patient with the pharmaceutical composition is sublingual. In one embodiment, the administration of the patient with the pharmaceutical composition is performed subcutaneously. In one embodiment, the administration of the patient with the pharmaceutical composition is performed intramuscularly.

[0028] One embodiment of the present disclosure includes a pharmaceutical composition comprising bumetanide dibenzylamide and one or more organic anion transporter (OAT) inhibitors. The role of active transport in the tissue distribution of bumetanide has been extensively studied in the kidney and liver, but not in the BBB. In mice and humans, OAT is believed to mediate the renal transport of bumetanide. These transporters may be essentially related to the transport of bumetanide in the luminal and basolateral membrane sites of renal proximal tubule cells. Bumetanide does not appear to be transported by OATP in the kidney or liver, but in this regard, members of this transporter family have been little studied. Probenecid inhibits OAT, which explains its shown reduction in plasma and renal clearance of bumetanide in dogs. Consistent with these observations in dogs, probenecid significantly increased the plasma half-life of bumetanide in mice. However, this did not reduce the diuretic effect of bumetanide. Systemic administration of organic anion transport inhibitors may have beneficial effects on brain levels of bumetanide or its products. For background teachings, see Tollner et al., European Journal of Pharmacology, 746 (2015) 167-173, which is incorporated herein by reference for such teachings.

[0029] In one embodiment, the one or more OAT inhibitors are competitive antagonists. In one embodiment, the bumetanide dibenzylamide and the one or more OAT inhibitors are formulated with different release profiles. In one embodiment, the at least one OAT inhibitor is formulated to be released prior to the release of the bumetanide dibenzylamide. In one embodiment, the at least one OAT inhibitor is formulated to be released prior to the release of the bumetanide dibenzylamide. In one embodiment, the at least one OAT inhibitor is formulated to be released prior to the release of the bumetanide dibenzylamide at a maximum plasma concentration (C max In one embodiment, the one or more OAT inhibitors are selected from the group consisting of probenecid, aspirin, ibuprofen, acetylsalicylic acid, diclofenac, aspartame, and valproic acid.

[0030] One embodiment of the present disclosure includes a pharmaceutical composition comprising bumetanide dibenzylamide in a self-emulsifying drug delivery system (SEDDS). In one aspect, the SEDDS comprises an isotropic mixture of oil, solubilizer, surfactant, and co-solvent.

[0031] One embodiment of the present disclosure includes a pharmaceutical composition comprising bumetanide dibenzylamide in an oral lymphatic-targeted formulation.

[0032] In one embodiment, the composition comprises bumetanide dibenzylamide, polyoxyl 35 castor oil (Kolliphor EL), glyceryl monolinoleate (Maisine CC), soybean oil, and ethanol. In one embodiment, the composition comprises about 1-2 w / w% bumetanide dibenzylamide, about 30-35 w / w% polyoxyl 35 castor oil (Kolliphor EL), about 30-35 w / w% glyceryl monolinoleate (Maisine CC), about 30-35 w / w% soybean oil, and about 2.5-5 w / w% ethanol. In one embodiment, the composition comprises about 1.7% w / w bumetanide dibenzylamide, about 32.4% w / w polyoxyl 35 castor oil (Kolliphor EL), about 31.3% w / w glyceryl monolinoleate (Maisine CC), about 31.3% w / w soybean oil, and about 3.2% w / w ethanol.

[0033] One embodiment of the present disclosure includes a pharmaceutical composition comprising a prodrug of bumetanide and one or more oral lymphatic-targeted excipients. The prodrug of bumetanide may include any compound, including bumetanide, including but not limited to amide prodrug forms that have been demonstrated to provide one or more unexpected benefits over other prodrug forms.

[0034] In one embodiment, the prodrug of bumetanide is an amide prodrug. In one embodiment, the prodrug of bumetanide is one or more of bumetanide dibenzylamide, bumetanide diethylamide, and bumetanide morpholinoamide. In one embodiment, the composition comprises an alkoxylated castor oil. In one embodiment, the composition comprises polyoxyl 35 castor oil (Kolliphor EL). In one embodiment, the composition comprises one or more of monoglycerides, diglycerides, and triglycerides. In one embodiment, the composition comprises glyceryl monolinoleate (Maisine CC). In one embodiment, the composition comprises a fixed oil. In one embodiment, the composition comprises soybean oil. In one embodiment, the composition comprises a water-soluble solvent. In one embodiment, the composition comprises ethanol.

[0035] For the avoidance of doubt, prodrugs of bumetanide described herein (e.g., bumetanide dibenzylamide, bumetanide diethylamide, and bumetanide morpholinoamide), and compositions comprising prodrugs of bumetanide, may be suitable and / or preferred therapeutic agents for use in the methods of the present disclosure, including all aspects and embodiments thereof. Prodrugs of bumetanide may be used to treat epilepsy, Alzheimer's disease, and other diseases and indications, including seizures.

[0036] In one embodiment, the pharmaceutical composition comprises up to 17.5% w bumetanide dibenzylamide, about 20% w solubilizing agent, and about 15% w absorbing agent.

[0037] Throughout this disclosure, any description of a method may be construed as describing or supporting an equivalent use, manufacture for use, composition, composition for use, or other alternative description.

[0038] One or more embodiments or aspects may be combined in different embodiments or aspects, even if not specifically described, i.e. all embodiments and aspects may be combined in any manner or combination. [Brief description of the drawings]

[0039] [Figure 1A] 1 shows, on a linear scale, individual animal bumetanide dibenzylamide concentration-time profiles following IN administration of 15 mg bumetanide dibenzylamide to male and female dogs. [Figure 1B] FIG. 1 shows, on a log-linear scale, individual animal bumetanide dibenzylamide concentration-time profiles following IN administration of 15 mg bumetanide dibenzylamide to male and female dogs. [Figure 2A] 1 shows, on a linear scale, individual animal bumetanide dibenzylamide concentration-time profiles following SL administration of 30 mg bumetanide dibenzylamide to male and female dogs. [Figure 2B] FIG. 1 shows, on a log-linear scale, individual animal bumetanide dibenzylamide concentration-time profiles following SL administration of 30 mg bumetanide dibenzylamide to male and female dogs. [Figure 3A] 1 shows, on a linear scale, individual animal bumetanide dibenzylamide concentration-time profiles following IM administration of 15 mg bumetanide dibenzylamide to male and female dogs. [Figure 3B] 1 shows, on a log-linear scale, individual animal bumetanide dibenzylamide concentration-time profiles following IM administration of 15 mg bumetanide dibenzylamide to male and female dogs. [Figure 4A] 1 shows, on a linear scale, individual animal bumetanide dibenzylamide concentration-time profiles following PO administration of 30 mg bumetanide dibenzylamide to male and female dogs. [Figure 4B] 1 shows, on a log-linear scale, individual animal bumetanide dibenzylamide concentration-time profiles following PO administration of 30 mg bumetanide dibenzylamide to male and female dogs. [Figure 5A] 1 shows, on a linear scale, individual animal bumetanide dibenzylamide concentration-time profiles following SC administration of 15 mg bumetanide dibenzylamide to male and female dogs. [Figure 5B]1 shows, on a log-linear scale, individual animal bumetanide dibenzylamide concentration-time profiles following SC administration of 15 mg bumetanide dibenzylamide to male and female dogs. [Figure 6A] 1 shows, on a linear scale, individual animal bumetanide dibenzylamide concentration-time profiles following IR administration of 30 mg bumetanide dibenzylamide to male and female dogs. [Figure 6B] 1 shows, on a log-linear scale, individual animal bumetanide dibenzylamide concentration-time profiles following IR administration of 30 mg bumetanide dibenzylamide to male and female dogs. [Figure 7A] 1 shows, on a linear scale, the mean bumetanide dibenzylamide concentration-time profiles following various routes of administration of 30 mg bumetanide dibenzylamide to male and female dogs. [Figure 7B] 1 shows, on a log-linear scale, the mean bumetanide dibenzylamide concentration-time profiles following various routes of administration of 30 mg bumetanide dibenzylamide to male and female dogs. [Figure 8A] 1 shows, on a linear scale, the mean bumetanide dibenzylamide and bumetanide plasma concentration-time profiles following IV bolus administration of 10 mg / kg bumetanide dibenzylamide to male rats. [Figure 8B] 1 shows, on a semi-log scale, the mean bumetanide dibenzylamide and bumetanide plasma concentration-time profiles following IV bolus administration of 10 mg / kg bumetanide dibenzylamide to male rats. [Figure 9A] 1 shows, on a linear scale, the mean bumetanide dibenzylamide and bumetanide plasma concentration-time profiles following oral administration of 30 mg / kg bumetanide dibenzylamide to male rats. [Figure 9B] 1 shows, on a semi-log scale, the mean bumetanide dibenzylamide and bumetanide plasma concentration-time profiles following oral administration of 30 mg / kg bumetanide dibenzylamide to male rats. [Figure 10A]1 shows, on a linear scale, the mean bumetanide dibenzylamide and bumetanide plasma concentration-time profiles following IV (10 mg / kg) and oral (30 mg / kg) administration of bumetanide dibenzylamide to male rats. [Figure 10B] 1 shows, on a semi-log scale, the mean bumetanide dibenzylamide and bumetanide plasma concentration-time profiles following IV (10 mg / kg) and oral (30 mg / kg) administration of bumetanide dibenzylamide to male rats. [Figure 11A] 1 shows, on a linear scale, the bumetanide plasma concentration-time profile following oral administration of 30 mg / kg bumetanide dibenzylamide to dogs. [Figure 11B] 1 shows, on a semi-logarithmic scale, the bumetanide plasma concentration-time profile following oral administration of 30 mg / kg bumetanide dibenzylamide to dogs. [Figure 12] 1 shows an X-ray diffractogram analysis of bumetanide dibenzylamide. [Figure 13] 1 shows a DSC analysis of bumetanide dibenzylamide. [Figure 14] 1 shows a TGA analysis of bumetanide dibenzylamide. [Figure 15] 1 shows a DVS analysis of bumetanide dibenzylamide. [Figure 16] 1 shows a PSD analysis of bumetanide dibenzylamide. [Figure 17] 1 shows the morphology of bumetanide dibenzylamide under 40x magnification. [Figure 18] A list of indications to refer to variability in classification over time. [Figure 19-1] 13 is a tabular calculation of the permeability of test compounds in the Caco-2 assay of Example 9. [Figure 19-2] 13 is a tabular calculation of the permeability of test compounds in the Caco-2 assay of Example 9. [Figure 20-1] FIG. 13 is a tabular representation of LCMS data from the permeability of test compounds in the Caco-2 assay of Example 9. [Figure 20-2]FIG. 13 is a tabular representation of LCMS data from the permeability of test compounds in the Caco-2 assay of Example 9. [Figure 20-3] FIG. 13 is a tabular representation of LCMS data from the permeability of test compounds in the Caco-2 assay of Example 9. [Figure 20-4] FIG. 13 is a tabular representation of LCMS data from the permeability of test compounds in the Caco-2 assay of Example 9. [Figure 20-5] FIG. 13 is a tabular representation of LCMS data from the permeability of test compounds in the Caco-2 assay of Example 9. [Figure 20-6] FIG. 13 is a tabular representation of LCMS data from the permeability of test compounds in the Caco-2 assay of Example 9. [Figure 20-7] FIG. 13 is a tabular representation of LCMS data from the permeability of test compounds in the Caco-2 assay of Example 9. [Figure 20-8] FIG. 13 is a tabular representation of LCMS data from the permeability of test compounds in the Caco-2 assay of Example 9. [Figure 20-9] FIG. 13 is a tabular representation of LCMS data from the permeability of test compounds in the Caco-2 assay of Example 9. [Figure 20-10] FIG. 13 is a tabular representation of LCMS data from the permeability of test compounds in the Caco-2 assay of Example 9. [Figure 21-1] FIG. 13 is a tabular representation of the Lucifer Yellow rejection assay for testing monolayer integrity in relation to permeability of test compounds in the Caco-2 assay of Example 9. [Figure 21-2] FIG. 13 is a tabular representation of the Lucifer Yellow rejection assay for testing monolayer integrity in relation to permeability of test compounds in the Caco-2 assay of Example 9. [Figure 21-3] FIG. 13 is a tabular representation of the Lucifer Yellow rejection assay for testing monolayer integrity in relation to permeability of test compounds in the Caco-2 assay of Example 9. [Figure 21-4]FIG. 13 is a tabular representation of the Lucifer Yellow rejection assay for testing monolayer integrity in relation to permeability of test compounds in the Caco-2 assay of Example 9. [Figure 22A-1] Similarly, (A) tabular calculation of permeability of test compounds in the Caco-2 assay of Example 9, (B) tabular representation of LCMS data from permeability of test compounds in the Caco-2 assay of Example 9, and (C) tabular representation of the Lucifer Yellow rejection assay for monolayer integrity testing in relation to permeability of test compounds in the Caco-2 assay of Example 9. [Figure 22A-2] Similarly, (A) tabular calculation of permeability of test compounds in the Caco-2 assay of Example 9, (B) tabular representation of LCMS data from permeability of test compounds in the Caco-2 assay of Example 9, and (C) tabular representation of the Lucifer Yellow rejection assay for monolayer integrity testing in relation to permeability of test compounds in the Caco-2 assay of Example 9. [Figure 22B-1] Similarly, (A) tabular calculation of permeability of test compounds in the Caco-2 assay of Example 9, (B) tabular representation of LCMS data from permeability of test compounds in the Caco-2 assay of Example 9, and (C) tabular representation of the Lucifer Yellow rejection assay for monolayer integrity testing in relation to permeability of test compounds in the Caco-2 assay of Example 9. [Figure 22B-2] Similarly, (A) tabular calculation of permeability of test compounds in the Caco-2 assay of Example 9, (B) tabular representation of LCMS data from permeability of test compounds in the Caco-2 assay of Example 9, and (C) tabular representation of the Lucifer Yellow rejection assay for monolayer integrity testing in relation to permeability of test compounds in the Caco-2 assay of Example 9. [Figure 22B-3]Similarly, (A) tabular calculation of permeability of test compounds in the Caco-2 assay of Example 9, (B) tabular representation of LCMS data from permeability of test compounds in the Caco-2 assay of Example 9, and (C) tabular representation of the Lucifer Yellow rejection assay for monolayer integrity testing in relation to permeability of test compounds in the Caco-2 assay of Example 9. [Figure 22B-4] Similarly, (A) tabular calculation of permeability of test compounds in the Caco-2 assay of Example 9, (B) tabular representation of LCMS data from permeability of test compounds in the Caco-2 assay of Example 9, and (C) tabular representation of the Lucifer Yellow rejection assay for monolayer integrity testing in relation to permeability of test compounds in the Caco-2 assay of Example 9. [Figure 22B-5] Similarly, (A) tabular calculation of permeability of test compounds in the Caco-2 assay of Example 9, (B) tabular representation of LCMS data from permeability of test compounds in the Caco-2 assay of Example 9, and (C) tabular representation of the Lucifer Yellow rejection assay for monolayer integrity testing in relation to permeability of test compounds in the Caco-2 assay of Example 9. [Figure 22B-6] Similarly, (A) tabular calculation of permeability of test compounds in the Caco-2 assay of Example 9, (B) tabular representation of LCMS data from permeability of test compounds in the Caco-2 assay of Example 9, and (C) tabular representation of the Lucifer Yellow rejection assay for monolayer integrity testing in relation to permeability of test compounds in the Caco-2 assay of Example 9. [Figure 22B-7] Similarly, (A) tabular calculation of permeability of test compounds in the Caco-2 assay of Example 9, (B) tabular representation of LCMS data from permeability of test compounds in the Caco-2 assay of Example 9, and (C) tabular representation of the Lucifer Yellow rejection assay for monolayer integrity testing in relation to permeability of test compounds in the Caco-2 assay of Example 9. [Figure 22B-8]Similarly, (A) tabular calculation of permeability of test compounds in the Caco-2 assay of Example 9, (B) tabular representation of LCMS data from permeability of test compounds in the Caco-2 assay of Example 9, and (C) tabular representation of the Lucifer Yellow rejection assay for monolayer integrity testing in relation to permeability of test compounds in the Caco-2 assay of Example 9. [Figure 22C-1] Similarly, (A) tabular calculation of permeability of test compounds in the Caco-2 assay of Example 9, (B) tabular representation of LCMS data from permeability of test compounds in the Caco-2 assay of Example 9, and (C) tabular representation of the Lucifer Yellow rejection assay for monolayer integrity testing in relation to permeability of test compounds in the Caco-2 assay of Example 9. [Figure 22C-2] Similarly, (A) tabular calculation of permeability of test compounds in the Caco-2 assay of Example 9, (B) tabular representation of LCMS data from permeability of test compounds in the Caco-2 assay of Example 9, and (C) tabular representation of the Lucifer Yellow rejection assay for monolayer integrity testing in relation to permeability of test compounds in the Caco-2 assay of Example 9. [Figure 22C-3] Similarly, (A) tabular calculation of permeability of test compounds in the Caco-2 assay of Example 9, (B) tabular representation of LCMS data from permeability of test compounds in the Caco-2 assay of Example 9, and (C) tabular representation of the Lucifer Yellow rejection assay for monolayer integrity testing in relation to permeability of test compounds in the Caco-2 assay of Example 9. [Figure 22C-4] Similarly, (A) tabular calculation of permeability of test compounds in the Caco-2 assay of Example 9, (B) tabular representation of LCMS data from permeability of test compounds in the Caco-2 assay of Example 9, and (C) tabular representation of the Lucifer Yellow rejection assay for monolayer integrity testing in relation to permeability of test compounds in the Caco-2 assay of Example 9. [Diagram 23]FIG. 1 shows blood concentrations of formulated (black triangles) and unformulated (grey circles) bumetanide morpholinoamide at 2, 6, and 12 hours post-treatment. [Figure 24] Illustrates formulated and unformulated bumetanide morpholinoamide blood concentration time points prior to 2 hours using an exponential fit to the data. [Diagram 25] Blood concentrations of formulated (black triangles) and unformulated (grey circles) diethylamide are shown at 2, 6, and 12 hours post-treatment. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0040] As used herein, the terms "active ingredient," "active pharmaceutical ingredient," and "API" refer to a drug, active ingredient, compound, or substance, composition, or mixture thereof that provides a pharmacological, often beneficial, effect.

[0041] As used herein, the term "dose" refers to any form of formulation of active ingredient that contains a sufficient amount to produce a therapeutic effect in a single administration.

[0042] As used herein, the term "dosage" refers to the administration of a particular amount, number and frequency of doses over a specified period of time, typically daily.

[0043] As used herein, the term "active pharmaceutical ingredient load" or "drug load" refers to the amount (mass) of active pharmaceutical ingredient contained in a single soft capsule fill.

[0044] As used herein, the term "formulation" or "pharmaceutical composition" or "composition" refers to a drug in combination with a pharma- ceutically acceptable excipient.

[0045] As used herein, the term "particle size distribution" (PSD) refers to the average particle size from a statistical distribution of the particle size ranges described herein. The distribution can be Gaussian, normal, or non-normal.

[0046] Terms such as "d90", "d50", and "d10" refer to the percentage of particle sizes that are less than a specified size, range, or distribution (e.g., 90%, 50%, or 10%, respectively). For example, "d90≦100 μm" means that 90% of the particle sizes in a distribution of particles are less than or equal to 100 μm.

[0047] As used herein, the term "patient" refers to any subject, including mammals and humans. A patient may have a disease or may be suspected of having a disease and therefore is being treated with a drug. In some cases, a patient is a mammal, such as a human, non-human primate, dog, cat, horse, cow, goat, pig, rabbit, rat, mouse, or a premature newborn, newborn, infant, juvenile, juvenile, or adult thereof. In some cases, as used herein, the term "patient" refers to a human (e.g., male, female, or child). In some cases, as used herein, the term "patient" refers to an experimental animal in an animal model study. A patient or subject may be of any age, sex, or combination thereof.

[0048] As used herein, the term "biological sample" or "sample" refers to a sample obtained from or derived from a patient. By way of example, a biological sample includes material selected from the group consisting of bodily fluids, blood, whole blood, plasma, serum, mucous secretions, saliva, cerebrospinal fluid (CSF), bronchoalveolar lavage fluid (BALF), urine, ocular fluids (e.g., vitreous humor, aqueous humor), lymphatic fluid, lymph node tissue, splenic tissue, bone marrow, and fluids from the ear cavity.

[0049] The term "treating" refers to administering therapy in an amount, manner, or mode effective to ameliorate a condition, symptom, disorder, or parameter associated with a disorder, or the probability thereof (e.g., a therapeutic effect).

[0050] The term "prevention" refers to preventing or reducing the progression of a disorder, either to a statistically significant degree or to a degree detectable by one of ordinary skill in the art.

[0051] As used herein, the terms "essentially" or "substantially" mean to a great or significant extent, but not completely.

[0052] As used herein, the term "about" refers to any value, including both integer and fractional components, that is within a variance of up to ±10% of the value modified by the term "about."

[0053] Also described herein are pharmaceutical compositions and dosage forms that include one or more agents that reduce the rate at which the compositions described herein as active ingredients decompose. Such agents, referred to herein as "stabilizers," include, but are not limited to, antioxidants such as ascorbic acid, pH buffers, salts, sugars, and the like.

[0054] The phrase "solubilizer" is used to refer to a component or group of components that assist in solubilizing a composition or a portion of a composition.

[0055] The terms "may be administered by injection," "injectable," or "injectability" refer to a combination of factors such as a certain force applied to the plunger of a syringe containing the formulations described herein and a certain temperature, a needle of a given internal diameter connected to the outlet of such a syringe, and the time required to expel a certain volume of the bumetanide dibenzylamide composition from the syringe through the needle.

[0056] The ranges for each ingredient in the formulations described represent the space in which it may be combined with other ingredients to yield a suitable alternative(s), with the ratio adjusted to a total of 100% w / w. The ranges provided are estimates based on available data.

[0057] One embodiment described herein is a pharmaceutical composition comprising bumetanide dibenzylamide. In one aspect, the composition comprises any of the formulations shown in the tables or examples described herein. Any of the components in the formulations described herein, shown in the tables, or illustrated in the examples may be increased, decreased, combined, substituted, or omitted to provide a formulation that comprises about 100% by weight. Such compositions are disclosed herein as if they were expressly disclosed herein.

[0058] One embodiment described herein is a pharmaceutical composition comprising bumetanide dibenzylamide and one or more solubilizing agents. Another embodiment described herein is a pharmaceutical composition comprising bumetanide dibenzylamide. Another embodiment described herein is a pharmaceutical composition further comprising one or more additional solvents. Another embodiment described herein is a pharmaceutical composition further comprising one or more surfactants, co-surfactants, emulsifiers, or wetting agents. Another embodiment described herein is a pharmaceutical composition consisting essentially of bumetanide dibenzylamide. Another embodiment described herein is a pharmaceutical composition consisting essentially of aqueous bumetanide dibenzylamide. Another embodiment described herein is a pharmaceutical composition comprising bumetanide dibenzylamide and one or more solubilizing agents. Another embodiment described herein is a pharmaceutical composition consisting essentially of bumetanide dibenzylamide and one or more solubilizing agents. In one aspect, the composition is a dry powder compressed into a tablet. In one aspect, the composition is a dry powder filled into a capsule. In one aspect, the composition is a dry powder extruded into a film. In one aspect, the composition is a dry powder extruded into a tablet. One embodiment described herein is a pharmaceutical composition comprising about 2.5 mg to about 42 mg of bumetanide dibenzylamide.

[0059] One embodiment described herein is a pharmaceutical composition formulated as an oral capsule. In one aspect, the composition comprises up to about 0.25% w / w to about 15% w / w bumetanide dibenzylamide and one or more solubilizing agents. In one aspect, the solubilizing agent is a co-solvent. In one aspect, the solubilizing agent is a surfactant. In one aspect, the solubilizing agent comprises a triglyceride. In one aspect, the triglyceride comprises a medium chain triglyceride. In one aspect, the triglyceride comprises a long chain triglyceride. In one aspect, the triglyceride comprises a mixture of medium chain triglycerides and long chain triglycerides. In one aspect, the triglyceride comprises a polyoxylglyceride. In one embodiment, the polyoxylglyceride is selected from the group consisting of lauroyl polyoxylglyceride, linoleoyl polyoxylglyceride, oleoyl polyoxylglyceride, stearoyl polyoxylglyceride, caprylocaproyl polyoxylglyceride, and any combination thereof. In one embodiment, the triglyceride comprises a non-ionic surfactant, a solubilizer, and an emulsifier. In one embodiment, the long chain triglyceride is selected from the group consisting of polyoxyl 35 castor oil (Kolliphor EL), glyceryl monolinoleate (Maisine CC), and any combination thereof. In one aspect, the medium chain triglyceride is selected from the group consisting of caprylocaproyl polyoxylglycerides (Labrasol ALF), phosphatidylcholine (Phosal 75 SA), caprylic / capric triglyceride (Captex 300), lauroyl polyoxyl-32 glyceride (Gelucire 44 / 14), sorbitan esters (Span® 80), and any combination thereof.

[0060] In one aspect, a pharmaceutical composition is described herein comprising from about 0.1% w / w to about 99.75% w / w of one or more solubilizing agents. In one aspect, the solubilizing agent comprises soybean oil. In one aspect, the solubilizing agent is in the oil phase. In one aspect, the solubilizing agent is selected from the group consisting of peanut oil, soybean oil, castor oil, corn oil, safflower oil, olive oil, apricot kernel oil, sesame oil, cottonseed oil, sunflower seed oil, palm oil and rapeseed oil, Maisine 35-1, Maisine CC (glyceryl monolinoleate), and any combination thereof. In one aspect, the solubilizing agent comprises a co-solvent. In one aspect, the solubilizing agent is selected from the group consisting of propylene glycol, Capryol™ 90 (propylene glycol monocaprylate), Lauroglycol™ 90 (propylene glycol monolaurate), glycerin, polyethylene glycol, and any combination thereof. In one embodiment, the solubilizer comprises an antioxidant. In one embodiment, the solubilizer is selected from the group consisting of alpha tocopherol, ascorbyl palmitate, ascorbic acid, butylated hydroxyanisole, butylated hydroxyl toluene, and any combination thereof. In one embodiment, the solubilizer comprises an antimicrobial preservative, a solvent, and a water-soluble co-solvent. In one embodiment, the solubilizer comprises a solvent and a water-soluble co-solvent. In one embodiment, the solubilizer is selected from the group consisting of ethanol, propylene glycol, propylene glycol 300, propylene glycol 400, propylene glycol 600, oleyl alcohol, and any combination thereof. In one embodiment, the solubilizer is water. In one embodiment, the solubilizer is any diluent.

[0061] In one aspect, described herein are pharmaceutical compositions comprising about 0.5% w / w to about 1.8% w / w of bumetanide dibenzylamide.In one aspect, described herein are pharmaceutical compositions comprising about 9 mg of bumetanide dibenzylamide per capsule to about 12 mg of bumetanide dibenzylamide per capsule. In one aspect, described herein is a pharmaceutical composition comprising about 0% w / w to about 1.8% w / w bumetanide dibenzylamide, about 10% w / w to about 45% w / w polyoxyl 35 castor oil (Kolliphor EL), about 15% w / w to about 65% w / w glyceryl monolinoleate (Maisine CC), about 15% w / w to about 65% w / w soybean oil, about 0% w / w to about 15% w / w ethanol, and about 0% w / w to about 0.13% w / w butylated hydroxytoluene. In one aspect, described herein is a pharmaceutical composition comprising about 1.75% w / w bumetanide dibenzylamide, about 32.37% w / w polyoxyl 35 castor oil (Kolliphor EL), about 31.30% w / w glyceryl monolinoleate (Maisine CC), about 31.30% w / w soybean oil, about 3.25% w / w ethanol, and about 0.3% w / w butylated hydroxytoluene.

[0062] One embodiment described herein is a pharmaceutical composition formulated as a nasal solution. In one aspect, the composition comprises bumetanide dibenzylamide in a solvent system. In one aspect, the composition comprises about 3 ml of solvent and about 28 mg to about 32 mg of bumetanide dibenzylamide. In one aspect, the solubilizer comprises a triglyceride. In one aspect, the triglyceride comprises a medium chain triglyceride. In one aspect, the triglyceride comprises a long chain triglyceride. In one aspect, the triglyceride comprises a mixture of medium chain triglycerides and long chain triglycerides. In one aspect, the triglyceride comprises a polyoxylglyceride. In one aspect, the polyoxylglyceride is selected from the group consisting of lauroyl polyoxylglyceride, linoleoyl polyoxylglyceride, oleoyl polyoxylglyceride, stearoyl polyoxylglyceride, caprylocaproyl polyoxylglyceride, and any combination thereof.

[0063] In one embodiment, the triglyceride includes a non-ionic surfactant, a solubilizer, and an emulsifier. In one embodiment, the solubilizer includes caprylocaproyl polyoxylglyceride (Labrasol ALF). In one embodiment, the solvent system includes one or more solubilizers. In one embodiment, the solubilizer includes caprylocaproyl polyoxylglyceride (Labrasol ALF) and water. In one embodiment, the solubilizer includes caprylocaproyl polyoxylglyceride (Labrasol ALF), propylene glycol, and water. In one embodiment, the solubilizer includes caprylocaproyl polyoxylglyceride (Labrasol ALF), propylene glycol, PEG-400, and water. In one embodiment, the solubilizer includes caprylocaproyl polyoxylglyceride (Labrasol ALF), propylene glycol, PEG-400, Vitamin E TPGS, and water. In one embodiment, the solubilizer comprises caprylocaproyl polyoxylglyceride (Labrasol ALF), propylene glycol, PEG-400, Vitamin E TPGS, ethanol, and water. In one embodiment, the solubilizer comprises about 50g of caprylocaproyl polyoxylglyceride (Labrasol ALF) per 50g of solvent. In one embodiment, the solubilizer comprises about 25g of caprylocaproyl polyoxylglyceride (Labrasol ALF) and about 25g of water per 50g of solvent. In one embodiment, the solubilizer comprises about 6g of propylene glycol, about 40g of PEG-400, and about 4g of water per 50g of solvent. In one embodiment, the solubilizer comprises about 5g of caprylocaproyl polyoxylglyceride (Labrasol ALF), about 6g of propylene glycol, about 35g of PEG-400, and about 4g of water per 50g of solvent. In one embodiment, the solubilizer comprises about 10g of propylene glycol, about 35g or PEG-400, about 0.5g of vitamin E TPGS, and about 4.5g of water per 50g of solvent. In one embodiment, the solubilizer comprises about 5g of caprylocaproyl polyoxylglyceride (Labrasol ALF), about 10g of propylene glycol, about 28.5g of PEG-400, about 0.5g of vitamin E TPGS, about 1g of ethanol, and about 4.5g of water per 50g of solubilizer.In one embodiment, the solubilizer comprises glycofurol. In one embodiment, the solubilizer comprises a penetrant and a solvent. In one embodiment, the solubilizer comprises ethyl oleate. In one embodiment, the solubilizer comprises an oil vehicle, a solvent, and a solvent.

[0064] In one embodiment, the pharmaceutical composition comprises about 3% w / v bumetanide dibenzylamide, about 11% w / v caprylocaproyl polyoxylglyceride (Labrasol ALF), about 13.26% w / v propylene glycol, about 73.94% w / v PEG-400, and about 8.8% w / v water. In one embodiment, the pharmaceutical composition comprises about 0.01% w / w to about 40% w / w bumetanide dibenzylamide, about 5% w / w to about 100% w / w caprylocaproyl polyoxylglyceride (Labrasol ALF), about 4% w / w to about 20% w / w propylene glycol, about 50% w / w to about 80% w / w PEG-400, and about 0% w / w to about 10% w / w water. In one embodiment, the pharmaceutical composition comprises about 2.73% w / w bumetanide dibenzylamide, about 8% w / w caprylocaproyl polyoxylglyceride (Labrasol ALF), about 15% w / w propylene glycol, about 69.27% ​​w / w PEG-400, and about 5% w / w water. In one embodiment, the pharmaceutical composition comprises about 2.73% w / w bumetanide dibenzylamide, about 16% w / w caprylocaproyl polyoxylglyceride (Labrasol ALF), about 20% w / w propylene glycol, about 54.27% w / w PEG-400, and about 7% w / w water. In one embodiment, the pharmaceutical composition comprises about 2.73% w / w bumetanide dibenzylamide, about 5% w / w caprylocaproyl polyoxylglyceride (Labrasol ALF), about 4% w / w propylene glycol, about 78.27% w / w PEG-400, and about 10% w / w water.

[0065] One embodiment described herein is a pharmaceutical composition formulated as a rectal paste. One embodiment described herein is a composition formulated as a rectal gel. In one aspect, the composition is formulated with a target of about 6 mg of bumetanide dibenzylamide per gram of composition, based on a target dose of about 30 mg of bumetanide dibenzylamide in an amount of about 5 g of the composition. In one aspect, the composition is formulated with a different target dose of bumetanide dibenzylamide. In one aspect, if the drug substance shows some instability in water, the paste is determined to be a 100% non-aqueous formulation. In one embodiment, the rectal gel is formulated to contain about 0.6% w / w bumetanide dibenzylamide, about 10% w / w caprylocaproyl polyoxylglyceride (Labrasol ALF), about 9.15% w / w propylene glycol, about 53.84% w / w polyethylene glycol 600, about 3.6% w / w polyvinylpyrrolidone (K30), about 2.4% w / w poloxamer 407 (P407), about 0.41% w / w sodium carboxymethylcellulose (CMC), and about 20% w / w water. In one embodiment, the rectal paste is formulated to contain about 0.6% w / w bumetanide dibenzylamide, about 10% w / w caprylocaproyl polyoxylglyceride (Labrasol ALF), about 9.15% w / w propylene glycol, about 66.75% w / w polyethylene glycol 600, about 3.6% w / w polyvinylpyrrolidone (K30), about 2.4% w / w poloxamer 407 (P407), and about 7.5% w / w polyethylene glycol 3350.

[0066] One embodiment described herein is a pharmaceutical composition formulated as a sublingual tablet. In one aspect, the formulated composition is targeted to have about 30 mg of bumetanide dibenzylamide per tablet. In one aspect, a small tablet size is used. In one aspect, wetting and / or dissolution of the composition occurs within 30 seconds. In one embodiment, the sublingual tablet is formulated to include bumetanide dibenzylamide, one or more wetting agents, and one or more superdisintegrants. In one aspect, the sublingual tablet is formulated to include about 15% w bumetanide dibenzylamide, about 20% w Ceolus KG (microcrystalline cellulose), about 51% w Mannogem EZ (spray dried mannitol), about 7% w Polyplasdone XL (super disintegrant), about 3% w Poloxamer 407 (wetting agent), about 1.5% w citric acid monohydrate, about 1% w Cabosil M5P (fumed silica), and about 1.5% w magnesium stearate. In one embodiment, the sublingual tablet is formulated to include bumetanide dibenzylamide, one or more water dispersible surfactants, one or more wetting agents, and one or more super disintegrants. In one embodiment, the sublingual tablet is formulated to contain about 7.4% w bumetanide dibenzylamide, about 9.9% w lauroyl puroxyl-32 glyceride (Gelucire 44 / 14, a water dispersible surfactant), about 9.9% w sorbitan ester (Span® 80, a water dispersible surfactant), about 14.8% w Neusilin US2 (magnesium aluminometasilicate), about 0.5% w / w poloxamer 407 (a wetting agent), about 0.7% w citric acid monohydrate, about 2% w Cabosil M5P (fumed silica), about 54.3% w Polyplasdone XL (a superdisintegrant), and about 0.5% w magnesium stearate.

[0067] In one embodiment described herein, the preferred therapeutic agents and methods of the disclosure (including all aspects and embodiments of those agents and methods) are for use in the treatment of seizures (e.g., partial seizure onset), epilepsy, and / or other indications such as neuropathic pain, by modulating or disrupting the synchronization of neuronal population activity in areas of enhanced synchronization by reducing the activity of NKCC cotransporters without having a diuretic effect. In one embodiment described herein, the preferred therapeutic agents and methods of the disclosure for treating seizures that cannot be controlled by existing drug therapies, such as uncontrolled seizures, intractable seizures, refractory seizures, drug-resistant seizures, or medically resistant seizures. One embodiment described herein are preferred therapeutic agents and methods of the disclosure for treating epilepsy syndromes such as Angelman syndrome, benign rolandic epilepsy, CDKL5 disorder, childhood absence epilepsy, Dravet syndrome, GLUT1 deficiency syndrome, hypothalamic hamartoma, infantile spasms (also known as West syndrome), Lennox-Gastaut, PCDH19, progressive myoclonic epilepsy, Rasmussen encephalitis, ring chromosome 20 syndrome, or reflex epilepsy.

[0068] Preferred therapeutic agents and methods of the disclosure, in one embodiment described herein, including all aspects and embodiments of those agents and methods, are for use in the treatment of epilepsy and / or neurological syndromes that are specific to children, including, but not limited to, Dravet syndrome, infantile spasms, Landau-Kleffner syndrome, Lennox-Gastaut syndrome, Rasmussen syndrome, benign rolandic epilepsy, benign occipital epilepsy, childhood absence epilepsy, juvenile myoclonus, Rett syndrome, Angelman syndrome, tuberous sclerosis, and / or Sturge-Weber syndrome. Preferred therapeutic agents and methods of the disclosure, in one embodiment described herein, are for use in the treatment of epilepsy and / or neurological syndromes that may be observed in adults or children.

[0069] One embodiment described herein are preferred therapeutic agents and methods of the present disclosure (including all aspects and embodiments of those agents and methods) for use in treating one or more of the indications listed in FIG. 18 (Fisher et al.), as well as for treating any older and current terms that may in the future replace the indications listed in FIG. 18.

[0070] One embodiment described herein are preferred therapeutic agents and methods of the disclosure (including all aspects and embodiments of those agents and methods) for use in the treatment of co-morbidities of epilepsy or seizures, such as depression, anxiety disorders, attention deficit hyperactivity disorder (ADHD), schizophreniform interictal psychosis, autism, and psychiatric disorders such as suicidal behavior, sleep disorders, autism spectrum disorders, migraine, postictal headache, depression, anxiety, psychosis, attention deficit disorder (ADD) and attention deficit / hyperactivity disorder (ADHD), or mental retardation.

[0071] One embodiment described herein is the preferred therapeutic agents and methods of the present disclosure (including all aspects and embodiments of those agents and methods) for use in the treatment of migraine or tinnitus. In one aspect, the preferred therapeutic agents and methods of the present disclosure may be used to treat migraine with or without aura in adults. In another aspect, the preferred therapeutic agents and methods of the present disclosure may be used for acute treatment of migraine with aura, acute treatment of migraine without aura, or chronic treatment for the prevention of migraine without aura.

[0072] An embodiment described herein is a preferred therapeutic agent and method of the present disclosure (including all aspects and embodiments of those agents and methods) for use in the treatment of mild, moderate, or severe anxiety. In one aspect, the preferred therapeutic agent and method of the present disclosure may be used for the acute and maintenance treatment of major depressive disorder (MDD) in adults and adolescents aged 12-17 years, or the acute treatment of generalized anxiety disorder (GAD) in adults. In one aspect, the preferred therapeutic agent and method of the present disclosure may be used for the acute and maintenance treatment of obsessive-compulsive disorder (OCD), the acute and maintenance treatment of bulimia nervosa, or the acute treatment of panic disorder (PD) with or without agoraphobia. In another aspect, the preferred therapeutic agent and method of the present disclosure may be used to treat acute depressive episodes associated with bipolar I disorder, or to treat treatment-resistant depression.

[0073] In one embodiment described herein, the preferred therapeutic agents and methods of the present disclosure (including all aspects and embodiments of those agents and methods) may be for use in treating obsessions and compulsions in patients with Obsessive Compulsive Disorder (OCD), Major Depressive Disorder (MDD), Panic Disorder (PD), Social Anxiety Disorder (SAD), Premenstrual Dysphoric Disorder (PMDD), or Post-Traumatic Stress Disorder (PTSD). In one aspect, the obsessions or compulsions may cause significant distress, take time, or significantly interfere with social or occupational functioning to meet the DSM-III-R (circa 1989) diagnosis of OCD. Obsessions may be repetitive and persistent ideas, thoughts, images, or urges that are ego-dystopic. Compulsions may be repetitive, purposeful, and / or deliberate behaviors performed in response to obsessions or performed in a stereotyped manner. Compulsions may be perceived by the person as excessive or irrational.

[0074] One embodiment described herein are preferred therapeutic agents and methods of the present disclosure (including all aspects and embodiments of those agents and methods) for use in treating patients with mild, moderate, or severe depression, anxiety associated with depression, anxiety associated with alcoholism, depression and / or anxiety associated with organic disease, psychotic depressive disorder with associated anxiety including regressive depression and manic-depressive disorder. In one aspect, the preferred therapeutic agents and methods of the present disclosure may be used to target neurotic symptoms such as anxiety, tension, depression, physical symptoms and concerns, sleep disorders, guilt, lack of energy, fear, worry, and distress.

[0075] One embodiment described herein are preferred therapeutic agents and methods of the disclosure (including all aspects and embodiments of those agents and methods) for use in treating depression in patients with depressive neurosis (dysthymia), manic depression, or major depressive disorder. In one aspect, the preferred therapeutic agents and methods of the disclosure may be used for short-term, long-term, and maintenance treatment of major depressive disorder (MDD), generalized anxiety disorder, diabetic peripheral neuropathic pain (DPNP), fibromyalgia (FM), or chronic musculoskeletal pain.

[0076] One embodiment described herein is the disclosed therapeutic agent and method for treating progressive neurodegenerative disorders, including, for example, Alzheimer's disease. In one aspect, the disclosed preferred therapeutic agent and method can be used to treat or halt the progression of one or more of Alzheimer's disease, amyotrophic lateral sclerosis, Friedreich's ataxia, Huntington's disease, Lewy body disease, Parkinson's disease, or spinal muscular atrophy.

[0077] One embodiment described herein is the preferred therapeutic agent and method of the present disclosure, including use as monotherapy or adjunctive therapy. In one aspect, the preferred therapeutic agent and method of the present disclosure can be used as monotherapy for adults. In another aspect, the preferred therapeutic agent and method of the present disclosure can be used as adjunctive therapy with additional therapeutic agents for adults. In another aspect, the preferred therapeutic agent and method of the present disclosure can be used as monotherapy for pediatric patients aged 2 years or older. In another aspect, the preferred therapeutic agent and method of the present disclosure can be used as adjunctive therapy with additional therapeutic agents for pediatric patients aged 2 years or older. In another aspect, the preferred therapeutic agent and method of the present disclosure can be used as monotherapy for pediatric patients under 2 years old. In another aspect, the preferred therapeutic agent and method of the present disclosure can be used as adjunctive therapy with additional therapeutic agents for pediatric patients under 2 years old.

[0078] An embodiment described herein is the preferred therapeutic agents and methods of the present disclosure (including all aspects and embodiments of those agents and methods), including use as monotherapy or adjunctive therapy. In one aspect, the preferred therapeutic agents and methods of the present disclosure may be used as monotherapy for adults. In another aspect, the preferred therapeutic agents and methods of the present disclosure may be used as adjunctive therapy with additional therapeutic agents for adults. In another aspect, the preferred therapeutic agents and methods of the present disclosure may be used as monotherapy for pediatric patients aged 2 years or older. In another aspect, the preferred therapeutic agents and methods of the present disclosure may be used as adjunctive therapy with additional therapeutic agents for pediatric patients aged 2 years or older. In another aspect, the preferred therapeutic agents and methods of the present disclosure may be used as monotherapy for pediatric patients under the age of 2. In another aspect, the preferred therapeutic agents and methods of the present disclosure may be used as adjunctive therapy with additional therapeutic agents for pediatric patients under the age of 2.

[0079] The effective amount of active pharmaceutical ingredient administered therapeutically depends, for example, on the therapeutic situation and purpose. Those skilled in the art will understand that the appropriate dosage level for treatment will vary in part depending on the concentration of the bumetanide dibenzylamide composition (or a composition comprising any other prodrug of bumetanide described herein), the dosing regimen in which the bumetanide dibenzylamide composition (or a composition comprising any other prodrug of bumetanide described herein) is used, the route of administration, and the size (weight or body surface area) of the subject and the condition (age and general health) of the patient. Thus, the dosage can be titrated to obtain the optimal therapeutic effect.

[0080] The frequency of administration depends on the pharmacokinetic parameters of the therapeutic agent incorporated in the bumetanide dibenzylamide composition (or composition containing any other prodrug of bumetanide described herein) being used. The composition may be administered as a single dose, as two or more doses over an extended period of time (which may or may not contain the same amount of bumetanide dibenzylamide, or any other prodrug of bumetanide described herein), or as a continuous infusion of an injectable formulation via an implanted device or catheter. Further refinement of the appropriate dosage is routinely performed by those skilled in the art and is within the scope of the tasks routinely performed by them. Sublingual tablets may also be used for oral administration). The appropriate dosage may be ascertained by the use of appropriate dose-response data.

[0081] Opportunities for fine tuning may include the use of sustained or controlled release oral capsules or tablets, or transdermal formulations. The intramuscular data presented below supports the development of a potential transdermal therapy. The intramuscular data shows that bumetanide dibenzylamide or any other prodrug of bumetanide described herein can be absorbed into the circulation via muscle microvasculature, thus avoiding first-pass metabolism. Therefore, bumetanide dibenzylamide should also be absorbed by skin microvasculature, making it suitable for a transdermal formulation.

[0082] The bumetanide dibenzylamide composition (or a composition comprising any other prodrug of bumetanide described herein) may be administered, for example, once, twice, three times, four times, five times, six times, or even more times per day. One or more doses may be administered, for example, for 1, 2, 3, 4, 5, 6, 7 days, or even longer. One or more doses may be administered, for example, for 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 months, 1 year, 2 years, 3 years, 4 years, 5 years, more than 5 years, 10 years, decades, or even longer. One or more doses may be administered at regular intervals until the subject or subjects in need of treatment or prevention of epilepsy no longer need it. In one embodiment, the dose may be administered orally. In one embodiment, the dose may be administered sublingually. In one embodiment, the dose may be administered intravenously. In one aspect, the dose may be administered rectally. In one aspect, the dose may be administered intramuscularly. In one aspect, the dose may be administered intranasally. In one aspect, the dose may be administered subcutaneously.

[0083] In one embodiment, the pharmaceutical composition described herein is administered simultaneously in one or more doses.For example, two or more identical doses are administered at the same time.In another embodiment, two or more different doses are administered at the same time.Such dual or different simultaneous doses can be used to provide an effective amount of pharmaceutical composition to a subject in need thereof.

[0084] In one embodiment, the pharmaceutical compositions described herein may be used to treat, prevent, slow the progression of, delay the onset of, ameliorate, reduce the symptoms of, or prevent epilepsy.

[0085] In one embodiment, the bumetanide dibenzylamide composition described herein (or a composition comprising any other prodrug of bumetanide described herein) is administered in a composition sufficient to provide a therapeutically effective amount in one application. In one aspect, one application of the bumetanide dibenzylamide composition (or a composition comprising any other prodrug of bumetanide described herein) is sufficient for about 1 day, about 2 days, about 3 days, about 4 days, about 5 days, about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 1 month, 2 months, 3 months, 4 months, 6 months, 9 months, 1 year, 2 years, 3 years, 4 years, or even longer. In one aspect, one application of the bumetanide dibenzylamide composition (or a composition comprising any other prodrug of bumetanide described herein) is given more than once per day.

[0086] In another embodiment, the bumetanide dibenzylamide composition described herein (or a composition comprising any other prodrug of bumetanide described herein) is provided as a single dose, meaning that the container in which it is provided contains one pharmaceutical dose. In another embodiment, the composition is provided as a multi-dose composition, meaning that it contains two or more therapeutic doses. Preferably, a multi-dose composition contains at least two doses. Such a multi-dose bumetanide dibenzylamide composition (or a composition comprising any other prodrug of bumetanide described herein) can be used for different subjects in need thereof or is intended for use in one subject, with the remaining doses being stored after application of the first dose until needed. In another embodiment, the bumetanide dibenzylamide composition (or a composition comprising any other prodrug of bumetanide described herein) is included in one or more containers.

[0087] Critical to the efficacy of any treatment with a pharmaceutical composition is the overall systemic bioavailability of the pharmaceutical composition used in said treatment. Surprisingly, lipid formulations can be used to enhance the bioavailability and / or lymphatic absorption of pharmaceutical compositions. Log P is a measure of lipophilicity and is the octanol:water partition coefficient expressed as the logarithmic ratio of molecules in octanol to water after mixing. The log P of bumetanide is about 2.61, the log P of bumetanide diethylamide is about 3.11, and the log P of bumetanide dibenzylamide is about 5.9. A log P of 3 indicates a 1000-fold higher concentration in octanol than in water, so bumetanide dibenzylamide is about 1000 to about 10,000 times more lipophilic than bumetanide.

[0088] As described herein, bumetanide dibenzylamide or any other prodrug of bumetanide described herein has been found to disrupt the synchronization of neuronal population activity in areas of enhanced synchronization. In order to avoid first-pass metabolism of the composition and increase overall systemic bioavailability, a bumetanide dibenzylamide administration composition was developed targeting four administration routes. The administration routes were selected based on the possibility of maximizing the bioavailability of bumetanide dibenzylamide and generating measurable systemic concentrations of bumetanide dibenzylamide. Bumetanide dibenzylamide has been shown to be susceptible to high first-pass metabolism by the liver, and therefore the administration routes were selected to avoid liver metabolism.

[0089] The pharmacokinetic profile and bioavailability of the compositions were evaluated following oral (PO), sublingual (SL), intranasal (IN), intrarectal (IR), subcutaneous (SC), intravenous (IV), and intramuscular (IM) dose administration, as described below. Surprisingly, it was found that oral administration of bumetanide dibenzylamide formulated with triglycerides avoids first-pass metabolism of the composition by the liver.

[0090] In one embodiment described herein, the pharmacokinetic profile and bioavailability of bumetanide dibenzylamide after oral (PO), sublingual (SL), intranasal (IN), intrarectal (IR), subcutaneous (SC), and intramuscular (IM) dose administration is evaluated in male and female beagle dogs in a crossover design. The IN, IM, and SC dose levels are about 15 mg bumetanide dibenzylamide, with drug exposure highest after IM administration, followed by similar exposure for SC and IN administration. The PO, SL, and IR dose levels are about 30 mg bumetanide dibenzylamide, with drug exposure much higher for PO administration followed by IR administration. The bumetanide dibenzylamide concentration after SL administration is relatively low.

[0091] research design Male and female beagle dogs are assigned to two groups with two males and two females in each group. The study is conducted in three segments, segment 1 consisting of IM and SL dosing, segment 2 consisting of IN and PO dosing, and segment 3 consisting of SC and IR dosing. As illustrated in Table 1, animals in group 1 receive IM, IN, and SC dosing, and animals in group 2 receive SL, PO, and IR dosing, each in a crossover design. Animals in group 1 receive a dose of approximately 15 mg and group 2 receive a dose of approximately 30 mg of bumetanide dibenzylamide. [Table 1]

[0092] Administration Procedure Administration of the bumetanide dibenzylamide composition is as described herein. During intranasal administration, the composition is administered by gently tilting the animal's head back and delivering the intranasal dose via a syringe and atomizer. During sublingual administration, the composition is administered via a fast dissolving tablet. The tablet is placed in the sublingual space and the mouth is held closed for approximately 60-90 seconds. After 1 minute, the animal's mouth is opened to ensure the tablet has completely dissolved. During intramuscular administration, the composition is administered in the biceps femoris (rear of the thigh). The dose site is gently shaved prior to administration. A syringe with a 25g needle is utilized. During oral administration, the composition is administered via three capsules placed at the back of the animal's mouth, followed by placement with a 10 mL flush of drinking water to ensure the animal has swallowed the capsules. During subcutaneous administration, the composition is administered directly into the dorsal subcutaneous space at the nape of the animal's neck. The dose site is gently shaved prior to administration. A syringe with a 25g needle is utilized. During rectal administration, the composition is administered by gently placing a 1 cc syringe into the animal's rectum.

[0093] All animals are fasted for approximately 12 hours prior to dosing. Animals are fed 4 hours after dosing and water is provided ad libitum throughout the study. All animals completed the study. Body weights remain stable and no adverse reactions are noted throughout the study with all animals exhibiting normal behavior after dose administration. Blood and urine samples are collected for up to 24 hours. Table 2 contains information on the sex and weight of the animals in the study. [Table 2]

[0094] Plasma sample analysis for bumetanide dibenzylamide and bumetanide Blood samples are collected from the jugular vein or other suitable blood vessel via direct venipuncture, placed into chilled tubes containing K2EDTA as an anticoagulant, and mixed by inversion several times. Blood samples are kept on wet ice until centrifugation. Plasma is collected and stored on dry ice until placed in a freezer set to maintain 80°C until analysis.

[0095] Plasma samples are analyzed for bumetanide dibenzylamide and bumetanide concentrations using an LC-MS / MS method. The assays are validated with respect to standard bioanalytical methodology, including acceptable precision and accuracy, based on quality control sample analysis and results. The method range for both analytes is from about 0.250 ng / mL to about 250 ng / mL.

[0096] Plasma bumetanide dibenzylamide concentration-time data for all routes of administration are summarized in Tables 3-8. Individual animal data are plotted by formulation group on linear and log-linear axes in Figures 1-6.

[0097] Plasma concentration data following IN administration of approximately 15 mg doses are shown in Table 3 and plotted in Figures 1A-1B. Bumetanide dibenzylamide concentrations varied between dogs during the first 2 hours post-dose, with %CVs ranging from 75.5 to 105.9%. Variability then decreased until the %CV was 28.5% at 24 hours. Each of the female dogs exhibited higher concentrations than the two male dogs.

[0098] [Table 3]

[0099] Plasma concentration data following administration of SL at a dose of approximately 30 mg are shown in Table 4 and plotted in Figures 2A-2B. SL administration resulted in the lowest concentrations of any of the six formulations. Bumetanide dibenzylamide was absorbed slowly, with the first measurable concentration occurring 0.5 hours after dosing in one of the dogs. All dogs had measurable concentrations 2 hours after dosing. Concentrations varied throughout the 24-hour sampling period, with %CVs ranging from 111.7 to 200%. For the SL administration route, each of the male dogs showed higher concentrations than the two female dogs. [Table 4]

[0100] Results following administration of a 15 mg IM dose are illustrated in Table 5 and plotted in Figures 3A-3C. One of the male dogs (animal no. 1) showed very high concentrations beginning 0.25 hours after dosing and continuing throughout the sampling period, suggesting that the dose may have been inadvertently injected intravenously. Tmax for the remaining dogs occurred between 2 and 4 hours, indicating slower absorption from the IM injection site.

[0101] Plasma concentration data following PO administration of a 30 mg dose are illustrated in Table 6 and plotted in Figures 4A-4B. Bumetanide dibenzylamide Tmax was 2 hours post-dose in all four animals, with concentrations for all being consistently higher than with any of the other routes of administration. In addition, variability was lower than the other formulations, decreasing over time from 51.2% at 0.5 hours to only 9.9% at 24 hours. For the PO route of administration, each of the female dogs showed higher concentrations than the two male dogs.

[0102] Results following SC administration of a 15 mg dose are illustrated in Table 7 and plotted in Figures 5A-5B. Bumetanide dibenzylamide concentrations were relatively consistent between dogs throughout the 24 hour sampling period, but never reached concentrations that might be expected following SC administration. One animal (animal no. 1) showed a high concentration of 15.2 ng / mL 1 hour after administration, which appeared to be an outlier based on concentrations in nearby samples. With the exception of that 1 hour sample, variability in the remainder of the data is relatively low. [Table 5] [Table 6]

[0103] Plasma concentration data following IR administration of a 30 mg dose are illustrated in Table 8 and plotted in Figures 6A-6B. The mean concentration of bumetanide dibenzylamide was always less than 10 ng / mL following dosing. Concentrations varied throughout the 24 hour sampling period with %CVs ranging from 64.4 to 200%. For the IR route of administration, each of the female dogs again exhibited higher concentrations than the two male dogs. [Table 7] [Table 8]

[0104] The mean concentration-time profiles of bumetanide dibenzylamide are plotted on linear and log-linear axes for the overlaid formulations in Figures 7A-7B. Concentrations are substantially higher for PO administration than for any other route. The log-linear plots show that bumetanide dibenzylamide concentrations tend to decline in parallel after the 8 hour plasma samples.

[0105] Plasma bumetanide concentration-time data are measured for all routes of administration. Of any sample from a study with measurable concentrations of bumetanide, there are only two plasma samples. These measurements can be made in animal number 7 at 2 and 4 hours after administration of the PO dose formulation, which are 0.34 and 0.47 ng / mL, respectively (Table 9).

[0106] [Table 9]

[0107] Pharmacokinetic data analysis In another embodiment described herein, pharmacokinetic (PK) parameters were derived using non-compartmental methods using Phoenix WinNonlin® version 8.2 (Pharsight Corp, St. Louis, MO). The PK parameters defined in Table 10 are calculated by non-compartmental methods using individual animal concentration-time data. The area under the concentration-time curve from time zero (pre-dose) to the last time point is calculated by a combination of linear and logarithmic trapezoidal methods. The linear trapezoidal method is used for all incremental trapezoids resulting from increasing concentrations, and the logarithmic trapezoidal method is used for those resulting from decreasing concentrations (linear up / log down method). Nominal blood sampling times are used in the analysis. Concentrations of bumetanide dibenzylamide and bumetanide below the lower limit of quantification (LLOQ) of 0.25 ng / mL are treated as zero for the calculation of descriptive statistics for the construction of the mean concentration-time profiles. Individual results below the limit of quantification (BQL) are set to zero for all calculations. No animals are excluded from the analysis. In one aspect, non-compartmental pharmacokinetic analysis provides measured or calculated values ​​of Cmax, Tmax, and AUClast for all animals, as well as estimates of AUCinf and CL / F for animals in which the terminal half-life (t1 / 2) can be estimated. [Table 10]

[0108] Non-compartmental pharmacokinetic parameters for bumetanide dibenzylamide following each route of administration are summarized in Tables 11-16. In one embodiment, the 15 mg dose level data for IM, IN, and SC administration suggests that IM provides the highest exposure with a mean Cmax of 48.9 ng / mL and an AUCinf of 411 h*ng / mL. In one embodiment, SC administration provides the next highest exposure with a mean Cmax of 9.42 ng / mL and an AUCinf of 231 h*ng / mL. IN administration is comparable to SC, showing a higher Cmax of 22.0 ng / mL, but a slightly lower AUCinf of 211 h*ng / mL. In one embodiment, the 30 mg dose level data for PO, IR, and SL administration suggests that PO administration provides by far the highest exposure with a mean Cmax of 218 ng / mL and an average AUCinf of 814 h*ng / mL. In one embodiment, IR administration results in the next highest exposure, with a mean Cmax of 8.44 ng / mL and an AUCinf of 55.1 h*ng / mL. In one embodiment, SL administration results in very low and inconsistent exposure, with a mean Cmax of only 1.03 ng / mL and an AUClast of only 4.23 h*ng / mL. Half-life could only be estimated in one of four dogs following SL administration. As mentioned above, only two measurable bumetanide concentrations were observed in the study, so pharmacokinetic analysis was not possible. [Table 11] [Table 12] [Table 13] [Table 14] [Table 15] [Table 16]

[0109] In one embodiment, the pharmacokinetic profile of bumetanide dibenzylamide was evaluated when administered as a single oral gavage or as an intravenous dose to rats.

[0110] research design Male Hsd:Sprague Dawley rats were assigned to two groups and dosed as shown in Table 17. Animals were dosed via oral gavage or intravenous injection once on day 1 at a volume of 5 mL / kg for Group 1 and 10 mL / kg for Group 2. The vehicle was 40% (v / v) polyethylene glycol 400 (PEG400), 20% (v / v) propylene glycol, 5% (v / v) ethanol, and 35% (v / v) water for Group 1, and 0.5% (w / v) carboxymethylcellulose (medium viscosity) in reverse osmosis water for Group 2. [Table 17]

[0111] Oral dosing was selected because this is the intended route of administration in humans. Dose levels selected for Phase I were based on tolerability data following intravenous (IV) administration in dogs scaled allometrically to rats.

[0112] Plasma concentration data Blood samples (approximately 0.5 mL) were collected from non-fasted toxicokinetic animals via the jugular vein on day 1 of the dosing phase as shown in Table 18. [Table 18]

[0113] Blood was collected into tubes containing potassium (K2) EDTA as an anticoagulant. Samples were kept on wet ice and centrifuged within 30 minutes of collection. Plasma was collected and stored on dry ice until placed in a freezer set to maintain -60 to -80°C until shipped on dry ice to Origin Bioanalytical Laboratory, Inc. for analysis. Plasma samples were analyzed for bumetanide dibenzylamide and bumetanide content.

[0114] Pharmacokinetic data analysis Pharmacokinetic parameters were derived using non-compartmental methods using Phoenix WinNonlin® version 8.1 (Pharsight Corp, St. Louis, MO). PK parameters previously defined in Table 10 were calculated by non-compartmental methods using composite plasma concentration-time data obtained from 3 rats / sex / time point / dose. The area under the concentration-time curve from time zero (pre-dose) to the last time point was calculated by a combination of linear and logarithmic trapezoidal methods. The linear trapezoidal method was used for all incremental trapezoids resulting from increasing concentrations, and the logarithmic trapezoidal method was used for those resulting from decreasing concentrations (linear up / log down method). Nominal blood sampling times were used in the analysis. Concentrations of bumetanide dibenzylamide below the lower limit of quantification (LLOQ) of 0.25 ng / mL were treated as zero for the calculation of descriptive statistics for the construction of the mean concentration-time profiles. Individual BQL results were set to zero for all calculations. No animals were excluded from the analysis.

[0115] Plasma bumetanide dibenzylamide and bumetanide concentration-time data Plasma bumetanide dibenzylamide and bumetanide concentration time data following IV administration of 10 mg / kg bumetanide dibenzylamide are summarized in Tables 19-20, respectively. Mean concentration-time profiles are illustrated with analyte overlays in Figures 8A-8B, on linear and log-linear axes. Observed bumetanide dibenzylamide concentrations averaged 2510 ng / mL 5 minutes after IV bolus administration. Measurable concentrations in all three animals were observed 24 hours after administration. In contrast, bumetanide concentrations were lower, averaging 53.6 ng / mL at 5 minutes, and no animals had measurable concentrations 24 hours after administration. Plasma concentration time data following oral administration of 30 mg / kg bumetanide dibenzylamide are summarized in Tables 19-20, respectively, and mean concentration-time profiles with analyte overlays are shown in Error!Reference Source not found. The highest mean concentration of bumetanide dibenzylamide was 4.56 ng / mL, occurring 4 hours after dosing. Bumetanide concentrations were negligible, with only two rats having measurable concentrations: one at 0.30 ng / mL at 4 hours and the other at 0.28 ng / mL at the 6 hour sampling period.

[0116] The mean plasma bumetanide dibenzylamide concentrations plotted in Table 22 reveal that bumetanide dibenzylamide concentrations are significantly lower following oral administration compared to IV bolus administration. Individual rat plasma concentration-time data used for analysis are shown in Table 22. [Table 19] [Table 20] [Table 21] [Table 22]

[0117] Pharmacokinetic parameters for bumetanide dibenzylamide and bumetanide Noncompartmental PK parameters for bumetanide dibenzylamide and bumetanide after IV administration are summarized in Tables 23-24. The inverse predicted concentration of bumetanide dibenzylamide at time=0 was 2780 ng / mL and the terminal half-life was 2.61 hours. The CL was high at 2880 mL / hr / kg and the Vz was large at 10800 L / kg. Bumetanide concentrations were fairly low with a Cmax of 53.6 ng / mL occurring at 5 minutes. The half-life was similar to that of bumetanide dibenzylamide at 2.91 hours. Noncompartmental PK parameters for bumetanide dibenzylamide after oral administration are summarized in Table 25. The maximum concentration was low at 4.56 ng / mL occurring 4 hours after administration. The half-life was 2.61 hours, identical to the value obtained after IV administration. [Table 23] [Table 24] [Table 25]

[0118] Absolute bioavailability (Fabs) of bumetanide dibenzylamide following oral and IV administration to male rats Absolute bioavailability calculations for bumetanide dibenzylamide are summarized in Table 26. The AUCinf of bumetanide dibenzylamide after IV bolus administration at the 10 mg / kg dose level was 3470 h*ng / mL and the AUCinf after oral administration of 30 mg / kg was 35.4 h*ng / mL. Adjusted for the administered dose, the fraction of bumetanide dibenzylamide absorbed was 0.0034 or 0.34%. [Table 26]

[0119] Measurable concentrations of bumetanide dibenzylamide were observed in rats after IV and oral administration, however, the CL and Vz values ​​after IV administration (2680 mL / hr / kg and 10100 mL / kg, respectively) indicate that bumetanide dibenzylamide has high clearance and a large volume of distribution in rats. Absolute bioavailability was determined to be very low in rats with a fraction absorbed of 0.0032 (0.32%), suggesting the possibility of very high first-pass extraction by the liver. Bumetanide dibenzylamide Cmax averaged 2510 ng / mL 5 minutes after administration of the IV dose and 4.56 ng / mL at Tmax 4 hours after oral administration. Measurable concentrations of bumetanide were observed after IV administration of bumetanide dibenzylamide, with a mean Cmax of 53.6 ng / mL 5 minutes after dose administration. Bumetanide concentrations were below the bioanalytical lower limit of quantitation (0.25 ng / mL) in all but two samples following oral administration of 30 mg / kg bumetanide dibenzylamide. The terminal half-life for bumetanide dibenzylamide was 2.61 hours and was identical following each route of administration. The half-life of bumetanide following IV administration of bumetanide dibenzylamide was 2.91 hours. The CL and Vz values ​​following IV administration were 2680 mL / hr / kg and 10100 mL / kg, indicating that bumetanide dibenzylamide has a high clearance and large volume of distribution in rats.

[0120] Oral Delivery of Unformulated Bumetanide Dibenzylamide In one embodiment, the pharmacokinetic profile and bioavailability of bumetanide dibenzylamide, as well as the formation of bumetanide as a metabolite of bumetanide dibenzylamide, following oral administration of unformulated bumetanide dibenzylamide, were evaluated in beagle dogs.

[0121] The pharmacokinetic profile and bioavailability of bumetanide dibenzylamide following oral administration, as well as the formation of bumetanide as a metabolite of bumetanide dibenzylamide, were evaluated in beagle dogs. The dose level used was approximately 30 mg of bumetanide dibenzylamide. Two dogs were dosed and bumetanide dibenzylamide levels (Table 27) were recorded as illustrated in Figures 11A-11B. Bumetanide levels were not measurable. [Table 27]

[0122] The absolute bioavailability calculations for bumetanide dibenzylamide are summarized in Table 28. The absolute bioavailability was determined to be approximately 5.1%. [Table 28]

[0123] It will be apparent to those skilled in the relevant art that suitable modifications and adaptations to the compositions, formulations, methods, processes, reactions, and applications described herein may be made without departing from the scope of any embodiment or aspect thereof. The compositions and methods provided are exemplary and are not intended to limit the scope of any of the specified embodiments. All of the various embodiments, aspects, and options disclosed herein may be combined in any variation or iteration. The scope of the compositions, formulations, methods, and processes described herein includes all actual or potential combinations of the embodiments, aspects, options, examples, and preferences described herein. The exemplary compositions and formulations described herein may omit any component, may substitute any component disclosed herein, or may include any component disclosed elsewhere herein. The ratio of the mass of any component of any of the compositions or formulations disclosed herein to the mass of any other component in the formulation or to the total mass of other components in the formulation is disclosed herein as if they were expressly disclosed. In the event that the meaning of any term in any of the patents or publications incorporated by reference conflicts with the meaning of the term used in this disclosure, the meaning of the term or phrase in this disclosure shall control. Furthermore, the foregoing discussion discloses and describes merely exemplary embodiments. All patents and publications cited herein are incorporated by reference for their specific teachings. In one embodiment, the concentrations of bumetanide dibenzylamide and bumetanide in monkey plasma (K2EDTA) by LC-MS / MS were analyzed using formal bioanalytical methods.

[0124] research design Pharmacokinetic studies were conducted in cynomolgus monkeys after single gavage (nasogastric), sublingual, and intravenous administration. Briefly, bumetanide dibenzylamide and bumetanide, as well as the respective internal standards bumetanide dibenzylamide-d5 and bumetanide-d5, were extracted from 100 μL of monkey plasma using protein precipitation extraction. Calibration curves, blanks, and analytical QCs were prepared in monkey plasma (K2EDTA). Extracts were evaporated to dryness, reconstituted, and then analyzed by LC-MS / MS. The calibration range was 0.250-250 ng / mL for both analytes. Analytical runs in this study were evaluated for acceptability based on the criteria listed in Table 29. [Table 29]

[0125] If the criteria for either the calibration curve or analytical QCs were not met, the analytical run was rejected. If the dilution QCs for a given dilution scheme did not meet the criteria, all of the study samples associated with that dilution scheme were rejected. No deviations were observed during the bioanalytical phase of the study conducted by Origin. Calibration curves were derived from the individual analyte to internal standard peak area ratios using least squares regression of the ratios to the nominal concentrations of the calibration standards, prepared in duplicate. Regression was then used to back-calculate the concentrations of each calibration standard, QC sample, and study sample. For bumetanide dibenzylamide, quadratic (1 / x 2 ) regression, whereas for bumetanide it was linear (1 / x 2 ) regression was used. Analyst® software version 1.6.3 (Applied Biosystems-MDS Sciex) operated on Windows® (Microsoft) was used for instrument control, data acquisition, and peak integration. Peak area ratios, standard curve regression, and sample concentration / precision values ​​were calculated in Analyst® software version 1.6.3. Other results (e.g., mean statistics) were calculated in Excel® (Microsoft).

[0126] Pharmacokinetic and bioavailability data For PO administration of a first formulation containing approximately 3% bumetanide dibenzylamide, caprylocaproyl polyoxylglyceride (Labrasol ALF), propylene glycol, polyethylene glycol, and water, non-compartmental pharmacokinetic parameters for bumetanide dibenzylamide at the 30 mg / kg dose level showed higher concentrations in both males than females, suggesting good bioavailability. For NG (single oral gavage nasogastric administration) of the second formulation, which is a SEDDS / oral lymphatic targeting formulation, containing about 1.73 w / w% bumetanide dibenzylamide, about 32.4 w / w% polyoxyl 35 castor oil (Kolliphor EL), about 31.32 w / w% glyceryl monolinoleate (Maisine CC), about 31.32 w / w% soybean oil, and about 3.24 w / w% ethanol, the Cmax and AUCinf values ​​for the 30 mg / kg dose were much higher, with an 8-fold higher Cmax and 6-fold higher AUCinf. The concentration-time profile was different from that observed for the first formulation, as bumetanide dibenzylamide showed a later median Tmax and a shorter half-life. There were no obvious gender differences for the second formulation. Pharmacokinetic parameters for bumetanide dibenzylamide after IV bolus of the third formulation containing approximately 0.2% bumetanide dibenzylamide, ethanol, propylene glycol, 40% polyethylene glycol 400, and water administered at a dose level of 2 mg / kg were used to obtain absolute bioavailability estimates and true CL and Vz values ​​for bumetanide dibenzylamide after PO administration in monkeys. Absolute bioavailability (% Fabs) calculations for the PO formulation based on Cmax and AUCinf showed that the second formulation / SEDDS showed a 6-fold (2.5%-15%) increase in Fabs over the first formulation. There were limited numbers of measurable plasma samples containing bumetanide after PO or IV administration. There were no measurable concentrations of bumetanide after SL administration. A fourth formulation containing composition B listed in Table 54 was also administered to monkeys. Tables 30-33 summarize the plasma bumetanide dibenzylamide concentrations in monkeys after administration of the various formulations. [Table 30] [Table 31] [Table 32] [Table 33] EXAMPLES

[0127] Example 1: Synthesis of Bumetanide Dibenzylamide Bumetanide dibenzylamide was synthesized as described below. Bumetanide (960 mg, 2.6 mmol) was dissolved in dimethylformamide (DMF, 10 mL) and 1-ethyl-3-(3-dimethyl-aminopropyl)carbodiimide (EDC, 560 mg, 3.6 mmol) was added. After approximately 10 minutes, 1-hydroxybenzotriazole (HOBt, 392 mg, 2.9 mmol) was added and the solution was stirred for an additional 10 minutes. Dibenzylamine (1 mL, 5.2 mmol) was added and the reaction was stirred for 2 hours, at which point the reaction was complete by LC / MS. The reaction was poured into saturated ammonium chloride (20 mL) and extracted with ethyl acetate (2×100 mL). The ethyl acetate was washed with saturated sodium bicarbonate, water, and brine and dried over anhydrous magnesium sulfate. The ethyl acetate was removed under reduced pressure to give 1.0 g (75%) of N,N-dibenzyl 3-aminosulfonyl-5-butylamino-4-phenoxybenzamide (bumetanide dibenzylamide) as a white solid. Figure 12 shows the X-ray diffractogram analysis of bumetanide dibenzylamide. Figure 13 shows the DSC analysis of bumetanide dibenzylamide. Figure 14 shows the TGA analysis of bumetanide dibenzylamide. Figure 15 shows the DVS analysis of bumetanide dibenzylamide. Figure 16 shows the PSD analysis of bumetanide dibenzylamide. Figure 17 shows the form of bumetanide dibenzylamide under 40x magnification.

[0128] Example 2: Oral Capsules Solubility evaluation The development of an oral capsule formulation was carried out in two parts. First, the basic solubility of bumetanide dibenzylamide in various common solubilizers was determined. Then, the composition was constructed to obtain a self-emulsifying drug delivery system (SEDDS) using a mixture of medium-chain triglycerides, long-chain triglycerides, solubilizers, surfactants, and co-solvents.

[0129] The excipients listed in Table 34 are suggested based on their functional category and prior history of use. The ranges provided are estimates based on available data obtained during initial development, previous experience, and literature research. These ranges, with ratios adjusted to total 100% w / w, represent the space in which suitable self-emulsifying drug delivery systems may be obtained in combination with other excipients. [Table 34]

[0130] The solubility of bumetanide dibenzylamide at 50° C. was determined in multiple solubilizers by visual inspection in common SEDDS excipients. Bumetanide dibenzylamide was added stepwise to 2 grams of solubilizer, which was heated to 50° C. and stirred at 800 RPM on a stir plate until bumetanide dibenzylamide did not dissolve in a 10 minute period. The results are presented in Table 35. Bumetanide dibenzylamide had the highest solubility in lauroyl puroxyl-32 glyceride (Gelucire 44 / 14), caprylocaproyl polyoxyl glyceride (Labrasol ALF), sorbitan ester (Span® 80), and polyoxyl 35 castor oil (Kolliphor EL), and therefore were selected as candidate solubilizers in SEDDS development. [Table 35]

[0131] Capsule development and analysis A prototype capsule formulation was developed at a scale of less than 2 grams. The solubilizer / surfactant was heated up to 60°C while stirring at about 800 RPM using a magnetic stir bar and adding bumetanide dibenzylamide until it dissolved. The oil phase was then added to the formulation and stirred until the solution was clear. The solution was cooled to room temperature with stirring and then the co-solvent was added (if applicable). As illustrated in Tables 37 and 38, compositions containing increasing amounts of long chain triglycerides and ethanol as a co-solvent were investigated within the range (0-4.68% w / w) where the maximum solubility of bumetanide dibenzylamide was determined to be about 1.8% w / w. Comparative compositions are listed in Table 36. The minimum amount of ethanol required for complete solubilization of bumetanide dibenzylamide was determined to be about 3.24% (composition 6). [Table 36] [Table 37] [Table 38]

[0132] To test whether a composition resulted in a macro- or micro-dispersion, approximately 30 mg of formulation was added to 1.0 g of water and swirled gently. The resulting dispersions were visually characterized. SEDDS (macroemulsions) are typically characterized as opaque milky homogenous liquids, while SEDDS (microemulsions) are characterized by clear isotropic crystal-clear solutions with opalescence. Compositions 4-6 resulted in functional SEDDS for bumetanide dibenzylamide. Compositions 4 and 6 were selected for future development work, and the intermediate stability of those compositions was evaluated as described below.

[0133] intermediate stability To determine short term chemical stability, compositions 4 (Table 37) and 6 (Table 38) were scaled to 100 g batch sizes, encapsulated, and stored at 40° C. / 75% RH for 2 weeks. The antioxidant butylated hydroxytoluene (BHT) was added to each composition at 0.03% w / w.

[0134] Stability and storage analysis The capsules were manually packaged in HDPE bottles and heat sealed. As shown in Table 39, there was no significant change in the appearance of the capsules over the first two weeks of the stability study. [Table 39]

[0135] The results for the assay and related substances are illustrated in Table 40. From these results it is evident that both medical product lots: Compositions 4 and 6 do not produce significant amounts of decomposition products when stored at 40° C. / 75% RH conditions. [Table 40]

[0136] Based on this data, a capsule formulation of Composition 6 (shown in Table 38) containing about 3.24% ethanol was selected for use in the animal studies. As shown in Table 41, the bumetanide dibenzylamide concentration can be adjusted from about 0 to about 1.75% w / w with a corresponding adjustment in polyoxyl 35 castor oil (Kolliphor EL) % w / w while maintaining the proportions of all other excipients to 100% total weight. [Table 41]

[0137] Example 3: Nasal solution Solubility evaluation A study was conducted to evaluate the solubility of bumetanide dibenzylamide in various solvent / co-solvent systems (Table 43). The solvents were selected from the group consisting of caprylocaproyl polyoxylglyceride (Labrasol ALF), propylene glycol, PEG-400, Vitamin E TPGS, ethanol, water, and any combination thereof.

[0138] The excipients listed in Table 42 are suggested based on functional category and prior history of use. The ranges provided are estimates based on available data obtained during initial development, previous experience, and literature research. These ranges, with ratios adjusted to total 100% w / w, represent the space in which a solution suitable for nasal delivery may be obtained in combination with other excipients. [Table 42]

[0139] Based on the solubility data and chemical properties of bumetanide dibenzylamide, a low percentage of water is required to achieve reasonable solubility, therefore, PEG-400 was selected as the primary diluent. [Table 43]

[0140] A 50 g stock solution of each solvent system was prepared. 3.0 mL of each solvent, the active solution, was aliquoted into separate 8 mL clear glass vials. 30 mg ± 2 of bumetanide dibenzylamide was added to each vial and the samples mixed on a wrist action shaker for 8 hours. The solutions were checked every 30 minutes. If no visible bumetanide dibenzylamide was present, an additional 10 mg was added and mixing continued. This process was repeated until visible saturation of all solvent systems was achieved. Prior to analysis, samples were centrifuged at 5,000 RPM for 3 minutes and filtered through a 0.45 μm nylon syringe filter to remove excess solids. Samples were quantified using an HPLC method with UV absorbance detection. Sample measurements were performed in triplicate and the average results were used to determine the solubility of bumetanide dibenzylamide in each system.

[0141] Comparison of the results showed that the solubility of the drug substance can be significantly affected by the amount of water in the system (Table 44). Bumetanide dibenzylamide was readily soluble in caprylocaproyl polyoxylglycerides (Labrasol ALF) up to approximately 66 mg / mL (Composition 8), but in 50:50 caprylocaproyl polyoxylglycerides (Labrasol ALF) and water, the solubility was reduced slightly less than 10-fold. Solubility appears to decrease in correlation with each % w / w increase in water in Compositions 11-13. When sufficient solubility was achieved, the compositions were evaluated for use as nasal sprays. The solubility of bumetanide dibenzylamide in 100% propylene glycol (PEG 400) and 100% caprylocaproyl polyoxylglycerides (Labrasol ALF) (Composition 8) was also evaluated. [Table 44]

[0142] The saturation solubility of bumetanide dibenzylamide in the compositions set forth in Table 42 is in the range of about 0.6% to about 6.64%. The dose calculations included in Table 42 are based on 75% of the concentration at saturation. This is to reduce the risk of precipitation / crystallization due to environmental fluctuations. In addition, the two dose volumes (0.2 / 0.5 mL) were selected according to the standard range for nasal delivery. The total doses illustrated are based on an equivalent volume delivered to each nostril totaling 0.4-1.0 mL per dose.

[0143] A primary solvent system based on Composition-11 was selected for further evaluation. In order to maximize the amount of water in the formulation, an additional set of three samples was prepared based on this composition to evaluate the effect of water content from about 10% w / w to about 20% w / w.

[0144] Effect of moisture content The amount of water in a formulation can have a significant effect on the solubility of bumetanide dibenzylamide. For this reason, three additional small scale formulations (F1-F3) were prepared according to the compositions shown in Table 45. Increasing amounts of PVP and poloxamer were added to compositions F1-F3 to inhibit rapid precipitation upon dilution in water. [Table 45]

[0145] An excess of bumetanide dibenzylamide was added to each formulation with mixing at 40-45° C. The solutions were then cooled to ambient room temperature and mixed for approximately 4 hours before being filtered and evaluated by assay.

[0146] The solubility data for this evaluation was compared to the results obtained from Composition-11, which had a similar composition without PVP and poloxamer (Table 46). These results support the hypothesis that the solubility of bumetanide dibenzylamide decreases non-linearly as the water content increases or the water:organic solvent ratio is changed. [Table 46]

[0147] The solubility of bumetanide dibenzylamide was evaluated to identify a solvent or solvent system that would result in the highest possible concentration (mg / mL) of the composition in solution. The solutions were found to contain from about 20 mg / mL to about 40 mg / mL of bumetanide dibenzylamide. The results indicate that the optimal composition (bumetanide dibenzylamide concentration of at least 30 mg / mL) may contain water in the range of about 0% w / w to about 10% w / w. Two separate compositions were selected for short-term stability analysis.

[0148] intermediate stability Based on the results of the solubility study, short-term stability evaluation was performed on two proposed compositions of bumetanide dibenzylamide nasal solution. The formulation of the nasal solution compositions was based on the solubility evaluation.

[0149] The concentration of bumetanide dibenzylamide in the solution was approximately 30 mg / mL. Short-term stability evaluation was performed over 2 weeks of accelerated storage (40° C. / 75% RH). Testing was performed at time zero (T=0) and at 2 weeks. The composition summary is illustrated in Tables 47-48. [Table 47] [Table 48]

[0150] The prepared solutions were filtered through 0.45 μm nylon filters and packaged in clear glass vials. Samples were stored upright in glass serum vials at 40° C. / 75% RH for 2 weeks. Analysis was performed using an HPLC method with UV detection.

[0151] There were no observable changes in samples at the end of the study and no visible precipitates / particulates. The results (Table 49) demonstrated that the assay variation for the compositions was below the analytical precision (±2.0%). [Table 49]

[0152] Data for related compounds are reported as the percent area relative to the bumetanide dibenzylamide peak in the sample (Table 50).The results did not indicate any significant individual or total amounts of impurities at time 0 (T=0) or at the 2 week accelerated stability. [Table 50]

[0153] Both compositions demonstrated suitable short-term stability relative to appearance and related compounds. Based on these data, composition A was selected for use in the animal studies. For composition A, the bumetanide dibenzylamide concentration can be adjusted to about 20 mg / mL to about 40 mg / mL (2-4%) with a corresponding water content range of 8-10%, while maintaining the proportions of all other excipients to 100% total weight.

[0154] Example 5: Rectal gel and paste Two separate variations of the nasal solution vehicle system were prepared to produce a gel (primary formulation) and a paste (alternate formulation). The ranges for the excipients as shown in Table 51 are the same as for the nasal solution with additional gelling and thickening agents, and water is limited to about 20%. The rectal gel formulation contains about 20% water, so the maximum concentration of bumetanide dibenzylamide in the rectal gel is about 2.4%. The rectal paste formulation contains no water, so the maximum concentration of bumetanide dibenzylamide in the rectal paste is about 4.16%. [Table 51]

[0155] For the rectal gel (Table 52), a separate solution of sodium carboxymethylcellulose (CMC) was prepared and combined with the non-aqueous phase to produce a clear to slightly opaque viscous gel. The amount of CMC selected was based on previous experience, and it was concluded that the resulting gel was suitable to support the initial animal studies. [Table 52]

[0156] For the initial formulation of the rectal paste, a stock solution of the solvent phase (items 1-6 in Table 53) was prepared. PEG-3350 was added stepwise / quantitatively to this solution until a semi-solid paste of approximately 7.5% w / w was obtained. The amount of bumetanide dibenzylamide in the formulation was then adjusted to obtain the target concentration (6 mg / g). [Table 53]

[0157] intermediate stability The gel and paste formulations were then analyzed for short-term stability. A short-term stability evaluation was performed on the two proposed formulations of bumetanide dibenzylamide rectal dose 6 mg / mL. The study was conducted over a 2-week accelerated storage (40°C / 75% RH).

[0158] Each formulation batch was prepared by weight and approximately 50 g was packaged into five separate 4 ounce jars with PTFE lined caps for stability / storage.

[0159] Stability storage and analysis Samples were stored upright at 40°C / 75% RH for 2 weeks. Analysis was performed using an HPLC method with UV detection. The rectal gel appeared as a viscous, clear to opaque colorless gel. The rectal paste appeared as a viscous / flowing white to off-white opaque paste.

[0160] There was no observable change in the appearance of the samples (Table 54) at the end of the study, and no visible precipitation / particulates. Both compositions were determined to be close to 100% of the expected assay of (6 mg / g). However, at 2 weeks, there was a slight decrease in the assay of the rectal paste. The gel formulation also showed a significant decrease in the assay value. However, no increase in related compounds was observed. Therefore, it is possible that the assay change may be due to heterogeneity resulting from precipitation of bumetanide dibenzylamide. It is also possible that storage conditions are responsible for the significant decrease in the assay due to the hygroscopic nature of the preparation and absorbed water at high humidity. [Table 54]

[0161] There were no significant changes in related compounds between T=0 and the 2-week accelerated stability (Table 55). The only impurity detected above 0.10% with a relative retention time (RRT) of 0.86 was present in all samples and did not change over the course of the study, making this impurity unlikely to be a degradant. Based on the results of the short-term stability study, composition C was selected for use in the animal studies. [Table 55]

[0162] Example 6: Tablets - Buccal or Sublingual Administration Two tablet compositions were developed targeting a dose strength of up to about 30 mg of bumetanide dibenzylamide per tablet or capsule. In some cases, the dose strength is about 10 mg of bumetanide dibenzylamide per tablet. As previously described, solubility studies were performed similar to those performed for the oral capsule compositions. The solubility studies identified that both drug solubility and wettability were concerns in aqueous media. In addition, the oral cavity rarely contains more than about 2 ml of saliva available for solubilization / oral disintegration. These issues surrounding oral disintegration and solubilization were considered during the formulation process.

[0163] A conventional direct blend tablet was developed that was completed with a wetting agent and a solubilizer. Disintegration was assessed by continuous immersion of the tablet in approximately 700 ml of 37° C. water in a low form 1000 ml beaker with repeated vertical movements until complete disintegration was observed. [Table 56]

[0164] Dry Powder Blend Development The dry powder blend may be compressed into a tablet or filled into a capsule. In one embodiment, the dry powder is compressed into a tablet for sublingual administration. The tablet may also be used for buccal administration. The tablet may also be swallowed (via oral administration). In another embodiment, the dry powder filled capsule may be used for oral administration only. Table 56 lists common excipients for dry powders that may be used for compression into tablets or filled capsules. Table 57 illustrates the formulation utilized for tablet prototype batch A made by direct compression. All items were passed through a sieve screen and blended by appropriate means. [Table 57]

[0165] After the dry blend tablet formulation was successfully completed, an attempt was made to enhance the solubilization of the drug. Upon successful creation of tablet prototype batch A, tablet prototype batch B was developed in which bumetanide dibenzylamide solubilizer was incorporated directly into the dry blend tablet formulation. Visual solubility analysis provided knowledge that an approximate 1:2 ratio of bumetanide dibenzylamide to solubilizer was required to dissolve the desired amount of bumetanide dibenzylamide in 2 mL of water. A 1:1 ratio of lauroyl polyoxyl-32 glyceride (Gelucire 44 / 14) to sorbitan ester (Span® 80) was determined by a combination of melting point, taste, viscosity, and solubilization ability. This ratio provided a semi-solid that could be liquefied upon application of low heat. Utilizing a technique known as hot melt granulation, the surfactant was liquefied at 60° C., followed by the addition of the required amount of bumetanide dibenzylamide and poloxamer 407. The mixture was held under constant agitation to ensure complete uniform dispersion of the ingredients. Continuing under constant heating and mixing, Neusilin US2 (magnesium aluminometasilicate) was slowly added to adsorb the viscous mixture onto its coarse surface. Once fully adsorbed, the heat was removed with continued mixing until room temperature was reached. The cooled hot melt granulation was then sieved and blended with sieved Polyplasdone XL (super disintegrant), Cabosil M5P (fumed silica), and citric acid monohydrate, and magnesium stearate. Table 58 illustrates the formulation used for the sublingual tablet prototype batch B utilized in the dog study. [Table 58]

[0166] A comparison of density analysis of both batches is provided in Tables 59-60. Visual monitoring of the tableting process revealed that there were no weight variations or die filling issues. The Flowdex score of the 9 mm sublingual tablet prototype batch B revealed that the flow of this composition was better than that suggested by the density analysis data. In contrast to this is the Flowdex score of 26 mm recorded for the sublingual tablet prototype batch A, which indicates that the flow of the true dry blend may be worse than that suggested by the Carr Index or Hausner Ratio. This issue with flowability may be rectified upon reduction of the bumetanide dibenzylamide required for any human target dose strength (i.e., 10 mg dose). [Table 59] [Table 60]

[0167] Physical comparison of sublingual tablets Due to the relatively small size of the batches, they were not compressed by rotary tablet compression. Instead, a single station flexi-tab machine was used that utilizes a feed shoe that fills a single die by gravity. The tablets were intentionally made soft with the understanding that the packaging would ultimately consist of foil / foil blisters. Wetting refers to the time required for blue dyed water to completely penetrate the tablet. Disintegration refers to the time required for the tablet to become free of a hard core, as determined by inspection with a thin metal spatula. Table 61 lists the physical properties of the two formulations. [Table 61]

[0168] intermediate stability Two separate sublingual tablet formulations were monitored over a two week period by visual appearance, assays, and related compound data over a two week 40°C / 75%RH stability study. Details regarding tablet formulation composition and physical properties can be found below. Both compositions consisted of tablets containing bumetanide dibenzylamide at approximately 30 mg dose strength designed to be delivered to the sublingual region. The listed tables and procedures outline the compositions and preparations utilized in the production of both stability batches.

[0169] The items for preparing the sublingual tablet prototype batch B composition are outlined in Table 58. Items Nos. 2-4 were heated to 60° C. in a suitable sized container under constant agitation. Once items Nos. 2-4 were fully liquefied, item No. 1 was added to the container while maintaining constant temperature and mixing for 5 minutes. Item No. 5 was slowly added to the container while maintaining constant temperature and mixing. The heat was removed and the granulation was mixed until the items were reduced to room temperature. The granulation was sieved through a No. 40 mesh (420 micron) screen. Items Nos. 6-7 were sieved through a No. 40 mesh (420 micron) screen. Item No. 8 was sieved through a No. 20 mesh (840 micron) screen. The granulation and items Nos. 6-8 were added to a suitable sized container. The container was approximately 60% filled with material. Items Nos. 1-8 were blended for approximately 20 minutes using a 3D Shake mixer (turbula). Item No. 9 was sieved through a No. 40 mesh (420 micron) screen. Item No. 9 was added to the container containing items Nos. 1-8 and blended with a 3D Shake Mixer for approximately 5 minutes. 405 mg tablets were made using ½ inch standard concave tooling with a force of 3.5 kN.

[0170] The items for preparing the sublingual tablet prototype batch A composition are outlined in Table 57. Items 1-5 were sieved through a No. 40 mesh (420 micron) screen. Item 6 was sieved through a No. 20 mesh (840 micron) screen. Items 1-6 were added to an appropriately sized container. The container was approximately 60% filled with material. Item numbers 1-6 were blended for approximately 20 minutes using a 3D Shake mixer (turbula). Item number 7 was sieved through a No. 40 mesh (420 micron) screen. Item number 7 was added to the container containing items numbers 1-6 and blended for 5 minutes with the 3D Shake mixer. Item number 8 was sieved through a No. 40 mesh (420 micron) screen. Item number 8 was added to the container containing items numbers 1-7 and blended for approximately 5 minutes with the 3D Shake mixer. 200 mg tablets were made using 3 / 8 inch standard concave tooling with a force of 4 kN.

[0171] Stability Storage and Analysis The study was performed with tablets stored at 40°C / 75%RH. The tablets were stored in heat-sealed 60cc HDPE bottles at 30 counts per bottle with coils and 1g desiccant. The tablets were monitored for their physical appearance, assay values, and related compounds.

[0172] Samples were stored and tested as per Table 62. Analyses were performed at time zero (T=0) and at 2 weeks, with the compositions held at 40° C. / 75% RH. The target criteria was 90.0-110.0% of LC. [Table 62]

[0173] Results were recorded over the two week stability period monitored. The analysis was broken down into sections: visual appearance results, assay results, and related compound results. All tablets met appearance specifications and there was no significant change in tablet appearance for each batch over the first two weeks of the stability study. Appearance results are shown in Table 63. All time points analyzed were well within the stability criteria (Table 64). The assay values ​​appear to have decreased over the stability period. However, since there was no increase in related compounds over the same period, it can be concluded that the decrease in assay values ​​is highly unlikely to be caused by degradation. It is important to note that a minimal number of time points were analyzed so trends cannot be established. [Table 63] [Table 64]

[0174] Neither batch monitored over the two week stability period resulted in a significant increase in related compounds (Table 65). The only related compound recorded had negligible change over the time analyzed. This provides evidence that all processing methods utilized between both batches had little effect on the chemical stability of bumetanide dibenzylamide, providing confidence that the hot melt granulation technique can be implemented without extreme concerns of degradation. Thermodynamic results gathered from DSC analysis provide further confidence that temperature exposure up to 60°C is acceptable. [Table 65]

[0175] The results confirm that both formulations analyzed are stable and acceptable for animal studies within the time period monitored. The hot melt granulation did not completely solubilize all of the bumetanide dibenzylamide, instead forming a slurry or suspension. A slurry would have allowed many of these clumps to persist throughout processing, similar to the direct blend technique.

[0176] Solutions to these problems include increasing batch size and milling to obtain a more uniform particle size. Inherent in the hot melt granulation procedure, additional surfactants and solubilizers may be added to fully solubilize the bumetanide dibenzylamide. This provides additional dry substrate to absorb the increased liquid / semi-solid concentration, potentially resulting in a larger tablet suitable for oral administration. The maximum amount of bumetanide dibenzylamide in the dry powder formulation is based on its solubility in the solubilizer reduced by the amount of absorbent, and is approximately half the total weight of the dosage form. Sublingual tablet composition B Table 54 utilizes a 1:1 mixture of Gelucire 44 / 14 and Span® 80 as the dissolution agent and Neusilin US2 absorbent. The solubility of bumetanide dibenzylamide in a 1:1 mixture was determined to be about 500 mg / g, and the amount of Neusilin US2 absorbent required was about 15%, so the maximum dose for sublingual tablet composition B Table 54 is up to about 70 mg or about 17.5%. For sublingual administration, tablet size should be minimized, but larger tablets and capsules up to about 1 g are acceptable for oral administration. For oral administration, tablets or capsules can be formulated up to about 175 mg (17.5%) per dose. However, because of the known 3-fold reduction in dosage strength that occurs with human needs, such an increase in excipients may still likely result in a tablet formulation of less than about 250 mg per dose.

[0177] Example 7: Injectable formulations for SC, IM, IV bolus, and IV infusion The excipients listed in Table 66 are suggested based on functional category and prior history of use. The ranges provided are estimates based on available data obtained during treatment development, previous experience, and literature research. These ranges represent the space in which a solution suitable for injection can be obtained in combination with other excipients in ratios that adjust to a total of 100% w / w. [Table 66]

[0178] Sample preparation A study was conducted to evaluate the solubility of bumetanide dibenzylamide in various solvent / co-solvent systems. Multiple vehicle compositions were investigated that resulted in clear dosing solutions or suspensions upon preparation or immediately after preparation. The vehicles tested were 55% polyethylene glycol 400 (PEG-400) in water, 41% PEG-400, 12% ethanol, 47% water, 45% PEG-400, 10% DMSO, 45% water, 31% PEG-400, 31% tetraglyceride, 15% caprylocaproyl polyoxylglyceride (Labrasol ALF), 23% water, 30% PEG-400, 10% N-methylpyrrolidone, 10% DMSO, 50% water, 25% PEG-400, 10% DMSO, 20% tetraglycol, 45% water, 20% ethanol in water, 20% hydroxypropyl-β-cyclodextrin in water, 11% DMSO, 22% PEG-400, 22% tetraglycol, 44% water, 44% PEG-400, 0.4% poloxamer-188, 22% N-methylpyrrolidone, 33% water, and 20% PEG-400, 15% hydroxypropyl-β-cyclodextrin in water.

[0179] Multiple vehicle compositions were tested, and all compositions tested resulted in suspension samples either upon preparation or immediately after preparation. The final concentrations of bumetanide dibenzylamide obtained for the above vehicles were calculated at the point of precipitation and ranged from 1.25 to 5.56 mg / mL. Unexpectedly, a vehicle composition of 40% PEG-400, 20% propylene glycol, 5% ethanol, 35% water resulted in a clear solution for a period of at least about 3 hours at room temperature. After filtration through a 0.22 μm PVDF filter, the samples remained clear for up to 7 days. The compositions selected for the animal studies are listed in Tables 67 and 68. [Table 67] [Table 68]

[0180] For injectable compositions, the bumetanide dibenzylamide concentration may be adjusted to about 20 mg / mL to about 40 mg / mL (2-4%) with a corresponding water content range of 8-20%, while maintaining the proportions of all other excipients to 100% total weight. For injectable compositions with a water content greater than 20%, the bumetanide dibenzylamide concentration is limited to a maximum of about 2.5 mg / mL (0.25%).

[0181] Example 8: Oral Liquids (Solutions and Suspensions) The excipients listed in Table 69 are suggested based on functional category and prior history of use. The ranges provided are estimates based on available data obtained during initial development, previous experience, and literature research. These ranges, adjusted ratios totaling 100% w / w, represent the space in which solutions or suspensions suitable for oral delivery may be obtained in combination with other excipients. [Table 69]

[0182] Sample preparation The samples were prepared as previously described in Sample Development for Injection in Example 7. In addition, the compositions shown in Tables 47 and 48 (used for intranasal administration) are also oral solution formulations of bumetanide dibenzylamide.

[0183] The solution compositions selected for the animal studies are listed in Tables 70 and 71. [Table 70] [Table 71] [Table 72]

[0184] For oral solution compositions, the bumetanide dibenzylamide concentration may be adjusted to about 20 mg / mL to about 40 mg / mL (2-4%) with a corresponding water content range of 8-20%, while maintaining the proportion of all other excipients to 100% total weight. For compositions with a water content greater than 20%, the bumetanide dibenzylamide concentration is limited to a maximum of about 2.5 mg / mL (0.25%). For oral suspension compositions, the bumetanide dibenzylamide concentration may be adjusted with the addition of a wetting agent or surfactant up to about 40 mg / mL (4%). One embodiment of the oral suspension composition selected for animal studies is shown in Table 72. The suspension (intended for oral gavage) was carboxymethylcellulose (medium viscosity) 0.5% w / v in purified water.

[0185] Example 9: Permeability of test compounds in the Caco-2 assay The compounds of the present disclosure were tested in the gold standard permeability assay.Unexpectedly, the results demonstrate that the compounds tested are not expected to provide improved permeability.Table 73 shows the unpredictable nature of pharmaceutical development. [Table 73-1] [Table 73-2]

[0186] The signal response of bumetanide dibenzylamide in the receiver samples from A to B was undetectable. The signal response of bumetanide dibenzylamide SEDDS in one receiver sample from A to B was undetectable. For convenience of calculation, in these receiver samples, 1 / 300 of the measured peak area ratio (PAR) of the relevant TO sample was used as the PAR value. As can be seen, using the assumption of zero as the peak area for the above conditions, the solution recovery of bumetanide dibenzylamide SEDDS was greater than the acceptable cutoff value of 50.0, so the recovery of bumetanide dibenzylamide SEDDS was sufficient. The observed insufficient recovery (solution recovery % value less than 50.0) may complicate the results of bumetanide dibenzylamide, so the results generated in this study should be interpreted in conjunction with other in vitro and / or in vivo data presented herein. The observed elimination phenomenon (elimination ratio greater than 2.00) may complicate the prediction of permeability. Therefore, the permeability results of bumetanide morpholinoamide and bumetanide morpholinoamide SEDDS generated in this study should be interpreted in conjunction with the application conditions. The observed shedding phenomenon (shedding ratios > 2.00) may complicate the prediction of permeability. Therefore, the permeability results of bumetanide diethylamide and bumetanide diethylamide SEDDS generated in this study should be interpreted in conjunction with the application conditions. ND means not determined. Binning criteria: Low permeability: P app ≦0.500(×10 -6 cm / sec); Medium Permeability: 0.500 <P app <2.50(×10 -6 cm / sec); High permeability: P app ≧2.50(×10 -6cm / sec); and *Permeability binning criteria are suggested based on Creative Bioarray routine Caco-2 permeability assay conditions (2.00 μM dose concentration and 120 min incubation). Boundaries for low and high permeability binning correspond to 50% and 80% of "calculated Fa" in humans; Substrate potential**; High probability: ERa ≥ 2.00; Poor or absent: ERa < 2.00.

[0187] methodology Caco-2 culture Caco-2 cells purchased from ATCC were diluted to 1 × 10 5 cells / cm 2 The cells were seeded onto polyethylene membranes (PET) in 96-well Corning Insert plates at 60°C for confluent cell monolayer formation, and the medium was refreshed every 4-5 days until days 21-28. Table 74 lists the compound information. [Table 74-1] [Table 74-2]

[0188] Transportation-method The transport buffer in this study was HBSS with 10.0 mM HEPES at pH 7.40±0.05. Test compounds were tested in duplicate in both directions at 2.00 μM. Digoxin was tested in duplicate in both directions at 10.0 μM, while nadolol and metoprolol were tested in duplicate in the A to B direction at 2.00 μM. The final DMSO concentration was adjusted to less than 1%. The plates were incubated in a CO2 incubator at 37±1°C for 2 hours at 5% CO2 in saturated humidity without shaking. All samples after mixing with acetonitrile containing internal standards were also centrifuged at 3200×g for 10 minutes. For nadolol and metoprolol, 200 μL of the supernatant solution was diluted with 600 μL of ultrapure water for LC-MS / MS analysis. For digoxin and test compounds, 200 μL of the supernatant solution was diluted with 200 μL of ultrapure water for LC-MS / MS analysis. The concentrations of test and control compounds in the starting, donor, and receiver solutions were quantified by LC-MS / MS methodology using the peak area ratio of analyte / internal standard. After the transport assay, the Lucifer Yellow rejection assay was applied to determine the Caco-2 cell monolayer integrity.

[0189] Data analysis Apparent permeability coefficient P app (cm / sec) was calculated using the following equation: P app =(dC r / dt) × V r / (A×C0) In the formula, dC r / dt is the cumulative concentration of the compound in the receiver chamber as a function of time (µM / sec), and V r is the solution volume in the receiver chamber (0.075 mL apically and 0.25 mL basolaterally) and A is the surface area of ​​transport, i.e., 0.0804 cm for the area of ​​the monolayer. 2 and C0 is the initial concentration in the donor chamber (μM). The discharge ratio was calculated using the following equation: Emission ratio=P app (BA) / P app (AB)

[0190] Percent recovery was calculated using the following equation: Solution recovery % = 100 × [(V r ×C r )+(V d ×C d )] / (V d ×C0) In the formula, V d is the volume in the donor chamber (0.075 mL apically and 0.25 mL basolaterally), and C d and C r are the final concentrations of the transport compound in the donor and receiver chambers, respectively.

[0191] Figure 19 represents the tabular calculation of this Example 9. Figure 20 is a tabular representation of the LCMS data for the tested compounds. Figure 21 is a tabular representation of the Lucifer Yellow Rejection Assay for Monolayer Integrity. Figures 22A, 22B, and 22C also show (A) a tabular calculation of the permeability of the test compounds in the Caco-2 assay of Example 9, (B) a tabular representation of the LCMS data from the permeability of the test compounds in the Caco-2 assay of Example 9, and (C) a tabular representation of the Lucifer Yellow Rejection Assay for Monolayer Integrity Testing in relation to the permeability of the test compounds in the Caco-2 assay of Example 9.

[0192] Based on the results of this assay, which is a standard test for predicting intestinal drug permeability, there would have been no support for promoting the present disclosure of SEDDS formulations for the test compounds: bumetanide dibenzylamide and bumetanide morpholinoamide. Thus, this data supports the unexpected results of the present disclosure.

[0193] Example 10: SEDDS formulation enhances the bioavailability of bumetanide amide The above SEDDS formulations enhance the bioavailability of bumetanide amides, including but not limited to bumetanide morpholinoamide and bumetanide diethylamide.

[0194] methodology SEDDS formulated and non-formulated bumetanide morpholinoamide and bumetanide diethylamide were orally administered to rats. Experiments were performed as described above for bumetanide dibenzylamide. Three male and female rats were used at each time point for each SEDDS treatment and non-SEDDS treatment. Female rats did not show any concentration of drug at any formulation or time. This appeared to be experimental error, so all female rats were removed from the data.

[0195] Blood concentrations of SEDDS-formulated (black triangles) and unformulated (grey circles) bumetanide morpholinoamide at 2, 6, and 12 hours post-treatment are shown in Figure 23. An increase in the concentration of SEDDS-formulated bumetanide morpholinoamide was observed; however, there were no detectable concentrations in the blood by 24 hours (data not shown). Figure 24 shows an exponential fit to the data to predict what the blood concentration values ​​of formulated and unformulated bumetanide morpholinoamide might have been at the time point 2 hours prior.

[0196] The blood concentrations of formulated (black triangles) and unformulated (grey circles) bumetanide diethylamide at 2, 6, and 12 hours after treatment are shown in Figure 25. Based on the recorded data, the doses for both may have been subeffective. In addition, outliers were recorded. However, even with one outlier excluded, the mean blood concentration of formulated SEDD is still higher than that of unformulated bumetanide diethylamide at all time points.

[0197] Based on these observations, the SEDDS formulation can be considered an effective method of formulating and administering bumetanide amide.

[0198] Those skilled in the art to which this disclosure pertains may make modifications resulting in other embodiments employing the principles of the present disclosure without departing from its spirit or character, particularly in light of the foregoing teachings. The described embodiments are therefore to be considered in all respects merely illustrative and not restrictive, and the scope of the present disclosure is accordingly indicated by the appended claims rather than by the foregoing description or drawings. As a result, although the present disclosure has been described with reference to specific embodiments, modifications in structure, arrangement, materials, and the like that are obvious to those skilled in the art will still fall within the scope of the claims.

Claims

1. A pharmaceutical composition comprising bumetanide dibenzylamide and one or more solubilizing agents.

2. 10. The composition of claim 1, wherein the composition comprises from about 2.5 mg / mL to about 42 mg / mL of bumetanide dibenzylamide.

3. 10. The composition of claim 1, wherein the composition comprises about 0.25% w / w to about 15% w / w of bumetanide dibenzylamide.

4. 10. The composition of claim 1, wherein the composition comprises from about 0.1% w / w to about 99.75% w / w of one or more solubilizing agents.

5. 10. The composition of claim 1, wherein the one or more solubilizing agents are selected from the group consisting of short-chain triglycerides, long-chain triglycerides, and combinations thereof.

6. 10. The composition of claim 1, wherein the one or more solubilizing agents are selected from the group consisting of polyoxyl 35 castor oil, glyceryl monolinoleate, and any combination thereof.

7. 10. The composition of claim 1, wherein the one or more solubilizing agents are selected from the group consisting of caprylocaproyl polyoxylglyceride, phosphatidylcholine, caprylic / capric triglyceride, lauroylpurinoyl-32 glyceride, sorbitan esters, and any combination thereof.

8. 10. The composition of claim 1, wherein the one or more solubilizing agents are selected from the group consisting of ethanol, propylene glycol, polyethylene glycol 600, polyethylene glycol 3350, oleyl alcohol, and any combination thereof.

9. 10. The composition of claim 1, wherein the one or more solubilizing agents are selected from the group consisting of PEG-400, Vitamin E TPGS, and any combination thereof.

10. 10. The composition of claim 1, wherein at least one of the one or more solubilizing agents is soybean oil.

11. The composition of claim 1 , wherein the composition comprises water.

12. 2. The composition of claim 1, wherein the one or more solubilizing agents are selected from the group consisting of polyvinylpyrrolidone (K30), poloxamer 407 (P407), sodium carboxymethylcellulose (CMC), and any combination thereof.

13. The composition of claim 1 further comprising at least one superdisintegrant.

14. The composition of claim 1 further comprising at least one humectant.

15. The composition of claim 1 further comprising at least one surfactant.

16. 10. The composition of claim 1, wherein the composition comprises Ceolus KG (microcrystalline cellulose), Mannogem EZ (spray dried mannitol), Polyplasdone XL (super disintegrant), poloxamer 407, lauroyl polyoxyl-32 glyceride, sorbitan esters, Neusilin US2 (magnesium aluminometasilicate), citric acid monohydrate, Cabosil M5P (fumed silica), magnesium stearate, or any subcombination thereof.

17. 2. The pharmaceutical composition of claim 1, comprising about 1.79% w / w bumetanide dibenzylamide, about 33.48% w / w polyoxyl 35 castor oil, about 32.37% w / w glyceryl monolinoleate, and about 32.37% w / w soybean oil.

18. 2. The pharmaceutical composition of claim 1, comprising about 1.76% w / w bumetanide dibenzylamide, about 32.93% w / w polyoxyl 35 castor oil, about 31.83% w / w glyceryl monolinoleate, about 31.83% w / w soybean oil, and about 10.37% w / w ethanol.

19. 2. The pharmaceutical composition of claim 1, comprising about 1.59% w / w bumetanide dibenzylamide, about 22% w / w phosphatidylcholine, about 70% w / w caprylocaproyl polyoxylglyceride, and about 6.41% w / w caprylic / capric triglyceride.

20. 10. The pharmaceutical composition of claim 1, comprising about 1.98% w / w bumetanide dibenzylamide, about 19.39% w / w lauroylpurinoyl-32 glyceride, about 37.62% w / w sorbitan esters, and about 41.01% w / w soybean oil.

21. 2. The pharmaceutical composition of claim 1, comprising about 1.98% w / w bumetanide dibenzylamide, about 39.72% w / w caprylocaproyl polyoxylglyceride, about 25.94% w / w sorbitan ester, and about 49.78% w / w soybean oil.

22. 2. The pharmaceutical composition of claim 1, comprising about 1.73% w / w bumetanide dibenzylamide, about 32.40% w / w polyoxyl 35 castor oil, about 31.32% w / w glyceryl monolinoleate, about 31.32% w / w soybean oil, and about 3.24% w / w ethanol.

23. 2. The pharmaceutical composition of claim 1, comprising about 1.7% w / w bumetanide dibenzylamide, about 31.91% w / w polyoxyl 35 castor oil, about 30.85% w / w glyceryl monolinoleate, about 30.85% w / w soybean oil, and about 4.68% w / w ethanol.

24. 10. The pharmaceutical composition of claim 1, comprising about 10% w / w to about 100% w / w caprylocaproyl polyoxylglyceride.

25. 10. The pharmaceutical composition of claim 1, comprising about 12% w / w to about 20% w / w propylene glycol.

26. 10. The pharmaceutical composition of claim 1, comprising about 57% w / w to about 80% w / w PEG 400.

27. 10. The pharmaceutical composition of claim 1, comprising about 1% Vitamin E TPGS.

28. 2. The pharmaceutical composition of claim 1, comprising about 2.73% w / w bumetanide dibenzylamide, about 10% w / w caprylocaproyl polyoxylglyceride, about 12.05% w / w propylene glycol, about 67.22% w / w polyethylene glycol 400, and about 8% w / w water.

29. 2. The pharmaceutical composition of claim 1, comprising about 2.82% w / w bumetanide dibenzylamide, about 4.65% w / w caprylocaproyl polyoxylglyceride, about 13.01% w / w propylene glycol, about 67.97% w / w polyethylene glycol 400, about 0.92% w / w polyvinylpyrrolidone (K30), and about 10.62% w / w water.

30. 2. The pharmaceutical composition of claim 1, comprising about 0.6% w / w bumetanide dibenzylamide, about 10% w / w caprylocaproyl polyoxylglyceride, about 9.15% w / w propylene glycol, about 53.84% w / w polyethylene glycol 400, about 3.6% w / w polyvinylpyrrolidone (K30), about 2.4% w / w poloxamer 407 (P407), about 0.41% w / w sodium CMC, and about 20% w / w water.

31. 2. The pharmaceutical composition of claim 1, comprising about 0.6% w / w bumetanide dibenzylamide, about 10% w / w caprylocaproyl polyoxylglyceride, about 9.15% w / w propylene glycol, about 66.75% w / w polyethylene glycol 400, about 3.6% w / w polyvinylpyrrolidone (K30), about 2.4% w / w poloxamer 407 (P407), and about 7.5% w / w polyethylene glycol 3350.

32. 10. The pharmaceutical composition of claim 1, comprising about 15% w bumetanide dibenzylamide, about 20% w microcrystalline cellulose, about 51% w spray-dried mannitol, about 7% w Polyplasdone XL (super disintegrant), about 3% w poloxamer 407, about 1.5% w citric acid monohydrate, about 1.0% w Cabosil M5P, and about 1.5% w magnesium stearate.

33. 10. The pharmaceutical composition of claim 1, comprising about 7.4% w bumetanide dibenzylamide, about 9.9% w lauroylpurioxyl-32 glyceride, about 9.9% w sorbitan ester, about 54.3% w Polyplasdone XL (super disintegrant), about 0.5% w poloxamer 407, about 0.7% w citric acid monohydrate, about 2.0% w Cabosil M5P (fumed silica), about 14.8% w Neusilin US2 (magnesium aluminometasilicate), and about 0.5% w magnesium stearate.

34. The vehicle composition is 55% polyethylene glycol 400 (PEG-400) in water, or 41% PEG-400, 12% ethanol, 47% water, or 45% PEG-400, 10% DMSO, 45% water, or 31% PEG-400, 31% tetraglycol, 15% caprylocaproyl polyoxylglyceride, 23% water, or 30% PEG-400, 10% N-methylpyrrolidone, 10% DMSO, 50% water, or 25% PEG-400, 10% DMSO, 20% tetraglycol, 45% water, 20% ethanol in water, or 20% hydroxypropyl-β-cyclodextrin in water, or 11% DMSO, 22% PEG-400, 22% tetraglycol, 44% water, or 44% PEG-400, 0.4% poloxamer-188, 22% N-methylpyrrolidone, 33% water, or 20% PEG-400, 15% hydroxypropyl-β-cyclodextrin in water, or 40% PEG-400, 20% propylene glycol, 5% ethanol, and 35% water.

35. 10. The pharmaceutical composition of claim 1, comprising about 28 g of bumetanide dibenzylamide and about 3 ml of solvent, wherein the 50 g of solvent contains about 5 g of caprylocaproyl polyoxylglyceride, about 10 g of propylene glycol, about 28.5 g of PEG-400, about 0.5 g of Vitamin E TPGS, about 1 g of ethanol, and about 4.5 g of water.

36. 1. A pharmaceutical composition comprising bumetanide dibenzylamide and one or more solubilizing agents for treating a patient in need thereof, wherein the pharmaceutical composition is administered to the patient.

37. 37. The pharmaceutical composition of claim 36, wherein the pharmaceutical composition comprises from about 2.5 mg / mL to about 42 mg / mL of bumetanide dibenzylamide.

38. 37. The pharmaceutical composition of claim 36, wherein the pharmaceutical composition comprises about 0.25% w / w to about 15% w / w bumetanide dibenzylamide.

39. 37. The pharmaceutical composition of claim 36, wherein the one or more solubilizing agents comprise a short-chain triglyceride, a long-chain triglyceride, or a combination thereof.

40. 37. The pharmaceutical composition of claim 36, wherein the composition comprises from about 0.1% w / w to about 99.75% w / w of one or more solubilizing agents.

41. 37. The pharmaceutical composition of claim 36, wherein the one or more solubilizing agents comprise polyoxyl 35 castor oil, glyceryl monolinoleate, or any combination thereof.

42. 37. The pharmaceutical composition of claim 36, wherein the one or more solubilizing agents comprise caprylocaproyl polyoxylglyceride, phosphatidylcholine, caprylic / capric triglyceride, lauroylpuroyl-32 glyceride, sorbitan ester, and any combination thereof.

43. 37. The pharmaceutical composition of claim 36, wherein the one or more solubilizing agents comprise ethanol, propylene glycol, polyethylene glycol 600, polyethylene glycol 3350, oleyl alcohol, or any combination thereof.

44. 37. The pharmaceutical composition of claim 36, wherein the one or more solubilizing agents comprise PEG-400, Vitamin E TPGS, or any combination thereof.

45. 37. The pharmaceutical composition of claim 36, wherein the one or more solubilizing agents comprise soybean oil.

46. 37. The pharmaceutical composition of claim 36, wherein the one or more solubilizing agents comprise water.

47. 37. The pharmaceutical composition of claim 36, wherein the one or more solubilizing agents comprise polyvinylpyrrolidone (K30), poloxamer 407 (P407), sodium carboxymethylcellulose (CMC), or any combination thereof.

48. 37. The pharmaceutical composition of claim 36, wherein the one or more solubilizers comprises at least one superdisintegrant.

49. 37. The pharmaceutical composition of claim 36, wherein the one or more solubilizing agents comprises at least one wetting agent.

50. 37. The pharmaceutical composition of claim 36, wherein the one or more solubilizing agents comprises at least one surfactant.

51. 37. The pharmaceutical composition of claim 36, wherein the one or more solubilizing agents comprise Ceolus KG (microcrystalline cellulose), Mannogem EZ (spray dried mannitol), Polyplasdone XL (super disintegrant), poloxamer 407, lauroylpurioxyl-32 glyceride, sorbitan esters, Neusilin US2 (magnesium aluminometasilicate), citric acid monohydrate, Cabosil M5P (fumed silica), magnesium stearate, or any combination thereof.

52. 37. The pharmaceutical composition of claim 36, wherein the pharmaceutical composition comprises about 1.79% w / w bumetanide dibenzylamide, about 33.48% w / w polyoxyl 35 castor oil, about 32.37% w / w glyceryl monolinoleate, and about 32.37% w / w soybean oil.

53. 37. The pharmaceutical composition of claim 36, wherein the pharmaceutical composition comprises about 1.76% w / w bumetanide dibenzylamide, about 32.93% w / w polyoxyl 35 castor oil, about 31.83% w / w glyceryl monolinoleate, about 31.83% w / w soybean oil, and about 10.37% w / w ethanol.

54. 37. The pharmaceutical composition of claim 36, wherein the pharmaceutical composition comprises about 1.59% w / w bumetanide dibenzylamide, about 22% w / w phosphatidylcholine, about 70% w / w caprylocaproyl polyoxylglyceride, and about 6.41% w / w caprylic / capric triglyceride.

55. 37. The pharmaceutical composition of claim 36, wherein the pharmaceutical composition comprises about 1.98% w / w bumetanide dibenzylamide, about 19.39% w / w lauroylpurinoyl-32 glyceride, about 37.62% w / w sorbitan esters, and about 41.01% w / w soybean oil.

56. 37. The pharmaceutical composition of claim 36, wherein the pharmaceutical composition comprises about 1.98% w / w bumetanide dibenzylamide, about 39.72% w / w caprylocaproyl polyoxylglyceride, about 25.94% w / w sorbitan ester, and about 49.78% w / w soybean oil.

57. 37. The pharmaceutical composition of claim 36, wherein the pharmaceutical composition comprises about 1.73% w / w bumetanide dibenzylamide, about 32.40% w / w polyoxyl 35 castor oil, about 31.32% w / w glyceryl monolinoleate, about 31.32% w / w soybean oil, and about 3.24% w / w ethanol.

58. 37. The pharmaceutical composition of claim 36, wherein the pharmaceutical composition comprises about 1.7% w / w bumetanide dibenzylamide, about 31.91% w / w polyoxyl 35 castor oil, about 30.85% w / w glyceryl monolinoleate, about 30.85% w / w soybean oil, and about 4.68% w / w ethanol.

59. 37. The pharmaceutical composition of claim 36, wherein the pharmaceutical composition comprises from about 10% w / w to about 100% w / w caprylocaproyl polyoxylglyceride.

60. 37. The pharmaceutical composition of claim 36, wherein the pharmaceutical composition comprises about 12% w / w to about 20% w / w propylene glycol.

61. 37. The pharmaceutical composition of claim 36, wherein the pharmaceutical composition comprises about 57% w / w to about 80% w / w PEG 400.

62. 37. The pharmaceutical composition of claim 36, wherein the pharmaceutical composition comprises about 1% Vitamin E TPGS.

63. 37. The pharmaceutical composition of claim 36, wherein the pharmaceutical composition comprises about 2.73% w / w bumetanide dibenzylamide, about 10% w / w caprylocaproyl polyoxylglyceride, about 12.05% w / w propylene glycol, about 67.22% w / w polyethylene glycol 400, and about 8% w / w water.

64. 37. The pharmaceutical composition of claim 36, wherein the pharmaceutical composition comprises about 2.82% w / w bumetanide dibenzylamide, about 4.65% w / w caprylocaproyl polyoxylglyceride, about 13.01% w / w propylene glycol, about 67.97% w / w polyethylene glycol 400, about 0.92% w / w polyvinylpyrrolidone (K30), and about 10.62% w / w water.

65. 37. The pharmaceutical composition of claim 36, wherein the pharmaceutical composition comprises about 0.6% w / w bumetanide dibenzylamide, about 10% w / w caprylocaproyl polyoxylglyceride, about 9.15% w / w propylene glycol, about 53.84% w / w polyethylene glycol 400, about 3.6% w / w polyvinylpyrrolidone (K30), about 2.4% w / w poloxamer 407 (P407), about 0.41% w / w sodium CMC, and about 20% w / w water.

66. 37. The pharmaceutical composition of claim 36, wherein the pharmaceutical composition comprises about 0.6% w / w bumetanide dibenzylamide, about 10% w / w caprylocaproyl polyoxylglyceride, about 9.15% w / w propylene glycol, about 66.75% w / w polyethylene glycol 400, about 3.6% w / w polyvinylpyrrolidone (K30), about 2.4% w / w poloxamer 407 (P407), and about 7.5% w / w polyethylene glycol 3350.

67. 37. The pharmaceutical composition of claim 36, wherein the pharmaceutical composition comprises about 15% w bumetanide dibenzylamide, about 20% w microcrystalline cellulose, about 51% w spray-dried mannitol, about 7% w Polyplasdone XL (super disintegrant), about 3% w poloxamer 407, about 1.5% w citric acid monohydrate, about 1.0% w Cabosil M5P, and about 1.5% w magnesium stearate.

68. 37. The pharmaceutical composition of claim 36, wherein the pharmaceutical composition comprises a maximum of about 17.5% w bumetanide dibenzylamide, about 9.9% w lauroylpurioxyl-32 glyceride, about 9.9% w sorbitan ester, about 54.3% w Polyplasdone XL (super disintegrant), about 0.5% w poloxamer 407, about 0.7% w citric acid monohydrate, about 2.0% w Cabosil M5P (fumed silica), about 14.8% w Neusilin US2 (magnesium aluminometasilicate), and about 0.5% w magnesium stearate.

69. The pharmaceutical composition may be 55% polyethylene glycol 400 (PEG-400) in water, or 41% PEG-400, 12% ethanol, 47% water, or 45% PEG-400, 10% DMSO, 45% water, or 31% PEG-400, 31% tetraglycol, 15% caprylocaproyl polyoxylglyceride, 23% water, or 30% PEG-400, 10% N-methylpyrrolidone, 10% DMSO, 50% water, or 25% PEG-400, 10% DMSO, 20% tetraglycol, 45% water, or 20% PEG-400 in water.

37. The pharmaceutical composition of claim 36, comprising a vehicle composition comprising: 20% ethanol, or 20% hydroxypropyl-β-cyclodextrin in water, or 11% DMSO, 22% PEG-400, 22% tetraglycol, 44% water, or 44% PEG-400, 0.4% poloxamer-188, 22% N-methylpyrrolidone, 33% water, or 20% PEG-400, 15% hydroxypropyl-β-cyclodextrin in water, or 40% PEG-400, 20% propylene glycol, 5% ethanol, and 35% water.

70. 37. The pharmaceutical composition of claim 36, wherein the pharmaceutical composition comprises about 28 g of bumetanide dibenzylamide and about 3 ml of solvent, wherein the 50 g of solvent contains about 5 g of caprylocaproyl polyoxylglyceride, about 10 g of propylene glycol, about 28.5 g of PEG-400, about 0.5 g of Vitamin E TPGS, about 1 g of ethanol, and about 4.5 g of water.

71. 37. The pharmaceutical composition of claim 36, wherein the pharmaceutical composition is an oral capsule.

72. 37. The pharmaceutical composition of claim 36, wherein the pharmaceutical composition is a nasal solution.

73. 37. The pharmaceutical composition of claim 36, wherein the pharmaceutical composition is a rectal gel.

74. 37. The pharmaceutical composition of claim 36, wherein the pharmaceutical composition is a rectal paste.

75. 37. The pharmaceutical composition of claim 36, wherein the pharmaceutical composition is a sublingual tablet.

76. 37. The pharmaceutical composition of claim 36, wherein the pharmaceutical composition is an injectable composition.

77. 37. The pharmaceutical composition of claim 36, wherein administration of the patient with the pharmaceutical composition is oral.

78. 37. The pharmaceutical composition of claim 36, wherein administration of the patient with the pharmaceutical composition is performed intranasally.

79. 37. The pharmaceutical composition of claim 36, wherein administration of the patient with the pharmaceutical composition is performed rectally.

80. 37. The pharmaceutical composition of claim 36, wherein administration of the patient with the pharmaceutical composition is performed sublingually.

81. 37. The pharmaceutical composition of claim 36, wherein administration of the patient with the pharmaceutical composition is performed subcutaneously.

82. 37. The pharmaceutical composition of claim 36, wherein administration of the patient with the pharmaceutical composition is performed intramuscularly.

83. 10. The pharmaceutical composition of claim 1, comprising bumetanide dibenzylamide and one or more organic anion transport (OAT) inhibitors.

84. 84. The pharmaceutical composition of claim 83, wherein the one or more OAT inhibitors are competitive antagonists.

85. 84. The pharmaceutical composition of claim 83, wherein the bumetanide dibenzylamide and the one or more OAT inhibitors are formulated with different release profiles.

86. 86. The pharmaceutical composition of claim 85, wherein at least one OAT inhibitor is formulated to be released prior to the release of the bumetanide dibenzylamide.

87. At least one OAT inhibitor is selected from the group consisting of bumetanide dibenzylamide and bumetanide dibenzylamide. ｍａｘ 87. The pharmaceutical composition of claim 86, formulated to be released before reaching

88. 84. The pharmaceutical composition of claim 83, wherein the one or more OAT inhibitors are selected from the group consisting of probenecid, aspirin, ibuprofen, acetylsalicylic acid, diclofenac, aspartame, and valproic acid.

89. 10. The pharmaceutical composition of claim 1, comprising bumetanide dibenzylamide in a self-emulsifying drug delivery system (SEDDS).

90. 90. The pharmaceutical composition of claim 89, wherein the SEDDS further comprises an isotropic mixture of oil, solubilizer, surfactant, and co-solvent.

91. A pharmaceutical composition comprising bumetanide dibenzylamide in an oral lymphatic-targeted formulation.

92. Bumetanide dibenzylamide, Polyoxyl 35 castor oil (Kolliphor EL), Glyceryl monolinoleate (Maisine CC), Soybean oil and ethanol. The pharmaceutical composition of claim 1 .

93. 93. The composition of claim 92, comprising about 1-2% bumetanide dibenzylamide w / w, about 30-35% polyoxyl 35 castor oil (Kolliphor EL), about 30-35% glyceryl monolinoleate (Maisine CC), about 30-35% soybean oil w / w, and about 2.5-5% ethanol w / w.

94. 93. The composition of claim 92, comprising 1.7% bumetanide dibenzylamide (w / w), about 32.4% polyoxyl 35 castor oil (Kolliphor EL), about 31.3% glyceryl monolinoleate (Maisine CC), about 31.3% soybean oil, and about 3.2% ethanol (w / w).

95. 10. The pharmaceutical composition of claim 1, comprising a prodrug of bumetanide and one or more oral lymphatic-targeting excipients.

96. 96. The pharmaceutical composition of claim 95, wherein the prodrug of bumetanide is an amide prodrug.

97. 96. The pharmaceutical composition of claim 95, wherein the prodrug of bumetanide is one or more of bumetanide dibenzylamide, bumetanide diethylamide, and bumetanide morpholinoamide.

98. 96. The pharmaceutical composition of claim 95, comprising an alkoxylated castor oil.

99. 96. The pharmaceutical composition of claim 95, comprising polyoxyl 35 castor oil (Kolliphor EL).

100. 96. The pharmaceutical composition of claim 95, comprising one or more of a monoglyceride, a diglyceride, and a triglyceride.

101. 96. The pharmaceutical composition of claim 95, comprising glyceryl monolinoleate (Maisine CC).

102. 96. The pharmaceutical composition of claim 95, comprising a fixed oil.

103. 96. The pharmaceutical composition of claim 95, comprising soybean oil.

104. 96. The pharmaceutical composition of claim 95, comprising a water-soluble solvent.

105. 96. The pharmaceutical composition of claim 95, comprising ethanol.

106. 37. The pharmaceutical composition of claim 36, wherein the pharmaceutical composition comprises up to 17.5% w bumetanide dibenzylamide, about 20% w solubilizing agent, and about 15% w absorbing agent.

107. 90. The pharmaceutical composition of claim 89 for treating epilepsy in a patient in need thereof.

108. 90. The pharmaceutical composition of claim 89 for treating a seizure disorder in a patient in need thereof.

109. 90. The pharmaceutical composition of claim 89 for treating Alzheimer's disease in a patient in need thereof.