Palatable compositions containing sodium phenylbutyrate and uses thereof

Abstract

To provide a palatable sodium phenylbutyrate formulation for improving patient compliance, methods of making the same, and methods of treatment.SOLUTION: Palatable compositions comprising sodium phenylbutyrate and a taste-mask coating, and methods of treating congenital metabolic disorder (e.g., Maple syrup urine disease or urea cycle disorders), neurodegenerative disorders such as Parkinson's, spinal muscular atrophy, dystonia, or inclusion body myositis using such compositions are provided.SELECTED DRAWING: None

Description

[Technical Field]

[0001] [Background technology] Inborn errors of metabolism are a class of disorders resulting from inborn errors of metabolism. Many of these disorders are the result of defects in a single gene that encodes an enzyme important for the metabolism of a particular substrate. Reduced activity of that enzyme results in the accumulation of the substrate to toxic levels, which in turn leads to a variety of symptoms that depend on the substrate.

[0002] Uncontrolled branched-chain amino acid catabolism leads to an inborn error of metabolism known as maple syrup urine disease (MSUD). MSUD, also known as branched-chain ketoaciduria, is an autosomal recessive disorder that is usually diagnosed within the first 4–7 days of life and occurs in approximately 1 in 185,000 live births. MSUD is caused by mutations that result in deficiencies in the mitochondrial branched-chain ketoacid dehydrogenase complex (BCKDC), leading to the accumulation of BCAAs (leucine, valine, isoleucine) and their corresponding α-ketoacids (BCKAs) (α-ketoisocaproic acid, α-ketoisovaleric acid, and α-keto-β-methylvaleric acid) in cells and body fluids in MSUD patients. As described in International Patent Publication No. WO2011011781, incorporated herein by reference, sodium phenylbutyrate is useful for the treatment of MSUD. If left untreated, individuals with MSUD develop high levels of BCAAs and suffer from low IQ, psychiatric disorders (cognitive impairment), social impairment (executive impairment), and chronic and acute neurological damage, including metabolic decompensation (seizures and coma), central respiratory failure, and even death.

[0003] Urea cycle disorders (UCDs) are another disorder resulting from inborn errors of metabolism, occurring in approximately 1 in 30,000 births and characterized by the accumulation of toxic levels of nitrogen in the blood as ammonia and glutamate. In UCDs, mutations cause deficiencies in uric acid cycle enzymes (e.g., N-acetylglutamate synthase, carbamoylphosphate synthase I, ornithine transcarbamylase, argininosuccinate synthase, argininosuccinate lyase, or arginase), which can lead to life-threatening neurological complications. Treatment with phenylacetic acid (PA) or its prodrug, phenylbutyric acid (PB), removes excess nitrogen from the system as PA is acetylated to phenylacetylglutamine and excreted through the kidneys. An immediate-release formulation of sodium phenylbutyrate (BUPHENYL®) has been approved for the treatment of UCD, and a sustained-release form of phenylbutyric acid (RAVICTI®) has also been approved for the treatment of UCD.

[0004] Neuroinflammation and oxidative stress are underlying causes of various neurodegenerative disorders, including Parkinson's disease. Sodium phenylbutyrate has been shown to suppress both proinflammatory molecules and reactive oxygen species (ROS) in activated glial cells, indicating that sodium phenylbutyrate may be useful in the treatment of neurodegenerative disorders, including Parkinson's disease.

[0005] Spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disease characterized by degeneration of the anterior horn cells of the spinal cord. All forms of SMA are caused by homozygous loss of the functional survival motor neuron (SMN1) gene, which results in insufficient levels of SMN protein. Sodium phenylbutyrate has been found to be effective in increasing SMN protein levels and the number of SMN-containing nuclear structures. Therefore, sodium phenylbutyrate may be effective in treating SMA.

[0006] Dystonia is a neurological disorder involving sustained muscle contractions. Early-onset primary dystonia is the most common form of hereditary dystonia and is caused by a deletion of a glutamic acid residue near the carboxyl terminus of torsinA. Mutations in torsinA have been found to induce ER stress and inhibit the cyclic adenosine-3',5'-monophosphate (cAMP) response to the adenylate cyclase agonist forskolin. Both mechanisms have been shown to be corrected by 4-phenylbutyric acid, as described by Cho et al. PLoS One 2014, 9(11), p. e110086. These results suggest that sodium phenylbutyrate may be used in the treatment of dystonia.

[0007] Inclusion body myositis (IBM) is a degenerative muscle disease characterized by progressive weakness and atrophy of limb muscles. There are two common forms of IBM: sporadic and hereditary. As described by Nogalska et al. Neurobiol. Dis. 2014, 65, 93–101, sodium phenylbutyrate has been shown to reverse lysosomal dysfunction in an in vitro model of inclusion body myositis involving cultured human muscle fibers. Sodium phenylbutyrate has been shown to improve lysosomal activity, reduce Aβ42 and its oligomers, decrease γ-secretase activity, and prevent myofiber vacuolation. Therefore, sodium phenylbutyrate may be used to treat sporadic inclusion body myositis.

[0008] Commercially available formulations of immediate-release sodium phenylbutyrate (e.g., BUPHENYL®) are unpalatable due to a very unpleasant taste. Noncompliance due to poor taste can lead to inadequate dosing and suboptimal outcomes. The present invention addresses the need for improved patient compliance by providing a palatable sodium phenylbutyrate formulation that is biologically active and bioequivalent to BUPHENYL®. [Prior art documents] [Patent documents]

[0009] [Patent Document 1] International Patent Publication No. WO2011011781 [Non-patent literature]

[0010] [Non-Patent Document 1] Cho et al. PLoS One 2014, 9(11), p. e110086 [Non-patent document 2] Nogalska et al. Neurobiol. Dis. 2014, 65, pages 93-101 Summary of the Invention

[0011] The present invention relates to palatable pharmaceutical compositions comprising sodium phenylbutyrate and methods of treating inborn errors of metabolism (eg, MSUD or UCD) using such compositions.

[0012] Thus, the present invention relates to pharmaceutical compositions for oral administration comprising sodium phenylbutyrate and a taste-mask coating (e.g., the taste-mask coating is insoluble at the neutral pH of the mouth and soluble at the acidic pH of the stomach), methods for producing such compositions, and uses thereof. A non-limiting example of a taste-mask coating having these properties is a polymer formed from dimethylaminoethyl methacrylate, butyl methacrylate, and methyl methacrylate (e.g., a cationic polymer such as Eudragit EPO). In some embodiments, the composition may be in the form of a tablet containing a plurality of small particles each bearing a taste-mask coating. Given the high doses of sodium phenylbutyrate typically required to treat inborn errors of metabolism, such as UCD and MSUD, high drug-load formulations are desirable to minimize the amount of substance a patient must ingest.

[0013] In some embodiments, the compositions of the present invention are a plurality of spray-layered particles or beads for oral administration. In some embodiments, the spray-layered particles have a seed core or carrier over which a drug layer is coated, followed by a taste-masking coating layer. In addition to these coatings, the compositions may include other coatings (e.g., seal coats, barrier coats). In some embodiments, the compositions include particles containing at least 15% total weight of sodium phenylbutyrate. In some embodiments, the compositions include particles containing greater than 50% sodium phenylbutyrate. In some embodiments, the compositions include particles comprising at least 5% but not more than 50% of the total weight of the particles of a taste-masking coating.

[0014] In one aspect, the present invention relates to a taste-masked pharmaceutical composition (e.g., a taste-masked immediate-release composition) comprising sodium phenylbutyrate and a pharmaceutically acceptable carrier, wherein (i) less than 15% (e.g., less than 10%, less than 5%, less than 1%) of the sodium phenylbutyrate in the composition dissolves in 10 minutes at a neutral pH (e.g., pH 6-8, pH 6.5-7.5, a pH of about 6, a pH of about 7, a pH of about 8, a pH of about 6.8) in a transition dissolution test, and (ii) at least 95% (e.g., at least 96%, at least 97%, at least 98%, at least 99%) of the sodium phenylbutyrate in the composition dissolves in 60 minutes at an acidic pH (e.g., pH 1-5, pH 1-2, a pH of about 1, a pH of about 2, a pH of about 3, a pH of about 4, a pH of about 5, a pH of about 1.2) in a transition dissolution test.

[0015] In some embodiments, the composition comprises a taste mask coating comprising a coating that is insoluble at neutral pH (e.g., pH > 5) and soluble at acidic pH (e.g., pH < 2), such as a polymer formed from dimethylaminoethyl methacrylate, butyl methacrylate, and methyl methacrylate (e.g., Eudragit EPO). In some embodiments, the composition comprises 5-50% by total weight (e.g., 5-15%, 10-25%, 20-30%, 25-35%, 30-40%, 35-45%, or 40-50% by total weight, or at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, or at least 45% by total weight, or less than 10%, less than 15%, less than 20%, less than 25%, less than 30%, less than 35%, less than 40%, less than 45%, or less than 50% by total weight) of the taste mask coating.

[0016] In some embodiments, the composition comprises 15-60% by total weight sodium phenylbutyrate (e.g., 20-30%, 25-35%, 30-40%, 35-45%, 40-50%, 45-55%, or 50-60% by total weight, or at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, or at least 60% by total weight, or less than 20%, less than 25%, less than 30%, less than 35%, less than 40%, less than 45%, less than 50%, less than 55%, or less than 60% by total weight).

[0017] In some embodiments, the composition comprises 3-10% by total weight (e.g., 3-5%, 4-6%, 5-7%, 6-8%, 7-9%, or 8-10% by total weight, or at least 3%, at least 4%, at least 5%, at least 6%, at least 7%, at least 8%, at least 9%, or at least 10% by total weight, or less than 3%, less than 4%, less than 5%, less than 6%, less than 7%, less than 8%, less than 9%, or less than 10% by total weight) of a binder (e.g., hydroxypropyl methylcellulose such as HPMC E 5, hydroxypropyl cellulose, polyvinyl alcohol, polyvinylpyrrolidone).

[0018] In some embodiments, the composition comprises 0.1%-7% (e.g., 0.2-1%, 0.5-3%, 2-5%, 3-7%) of a plasticizer (e.g., polyethylene glycol, such as polyethylene glycol having a molecular weight of 5,000-7,000, such as PEG 6000, or triethyl citrate) by total weight. In some embodiments, the composition is free of plasticizers.

[0019] In some embodiments, the composition comprises 4-15% by total weight (e.g., 4-6%, 5-7%, 6-8%, 7-9%, or 8-10% by total weight, or at least 4%, at least 5%, at least 6%, at least 7%, at least 8%, or at least 9% by total weight, or less than 4%, less than 5%, less than 6%, less than 7%, less than 8%, less than 9%, or less than 10%) of hydrated magnesium silicate (e.g., talc).

[0020] In some embodiments, the composition comprises 1-5% by weight (e.g., 3-4%, 3.5-4.5%, 4-5% by weight, or at least 1%, at least 2%, at least 3%, or at least 4% by weight, or less than 2%, less than 3%, less than 4%, or less than 5% by weight) of a seal coat comprising a water-soluble polymer such as polyvinyl alcohol (e.g., Opadry, such as Opadry Clear). In some embodiments, the composition does not comprise a seal coat.

[0021] In some embodiments of any of the foregoing compositions, the composition is prepared as a taste mask coated tablet (e.g., a tablet coated with a taste mask coating comprising standard pharmaceutical excipients such as fillers, binders, glidants, lubricants, etc.; a polymer formed from dimethylaminoethyl methacrylate, butyl methacrylate, and methyl methacrylate, such as Eudragit EPO, produced using manufacturing methods such as blending, milling, dry granulation, wet granulation, pressing, etc.), a taste mask coated mini-tablet (e.g., a tablet having a diameter of less than 4 mm coated with a taste mask coating comprising standard pharmaceutical excipients such as fillers, binders, glidants, lubricants, etc.; a polymer formed from dimethylaminoethyl methacrylate, butyl methacrylate, and methyl methacrylate, such as Eudragit EPO, produced using manufacturing methods such as blending, milling, dry granulation, wet granulation, pressing, etc.), or a tablet prepared by spray-layering, extrusion spheronization, rotor granulation, or melt congealing. It is formulated as taste-masked coated beads produced by congealing methods.

[0022] In another aspect, the present invention provides a drug layer comprising 15-60% by total weight (e.g., 20-30%, 25-35%, 30-40%, 35-45%, 40-50%, 45-55%, or 50-60% by total weight, or at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, or at least 60% by total weight, or less than 20%, less than 25%, less than 30%, less than 35%, less than 40%, less than 45%, less than 50%, less than 55%, or less than 60% by total weight) sodium phenylbutyrate and a polymer formed from dimethylaminoethyl methacrylate, butyl methacrylate, and methyl methacrylate (e.g., Eudragit E The present invention relates to a pharmaceutical composition for oral administration of sodium phenylbutyrate, comprising a taste-masking coating of 5 to 50% by weight (e.g., 5 to 15%, 10 to 25%, 20 to 30%, 25 to 35%, 30 to 40%, 35 to 45%, or 40 to 50% by weight, or at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, or at least 45% by weight, or less than 10%, less than 15%, less than 20%, less than 25%, less than 30%, less than 35%, less than 40%, less than 45%, or less than 50% by weight), the taste-masking coating comprising a coating that is insoluble at neutral pH (e.g., pH > 5) but soluble at acidic pH (e.g., pH < 2), such as sodium phenylbutyrate (PO).

[0023] In some embodiments, the drug layer comprises 3-10% by total weight (e.g., 3-5%, 4-6%, 5-7%, 6-8%, 7-9%, or 8-10% by total weight, or at least 3%, at least 4%, at least 5%, at least 6%, at least 7%, at least 8%, at least 9%, or at least 10% by total weight, or less than 3%, less than 4%, less than 5%, less than 6%, less than 7%, less than 8%, less than 9%, or less than 10% by total weight) of a binder (e.g., HPMC E 5, such as hydroxypropyl methylcellulose, hydroxypropyl cellulose, polyvinyl alcohol, and polyvinylpyrrolidone).

[0024] In some embodiments, the drug layer further comprises 0.1-1% (e.g., 0.2-0.6% or about 0.5%) of a plasticizer (e.g., polyethylene glycol, such as polyethylene glycol having a molecular weight of 5,000-7,000, such as PEG 6000, or triethyl citrate) by total weight. In some embodiments, the drug layer does not comprise a plasticizer.

[0025] In some embodiments, the taste mask coating further comprises 1-9% by total weight (e.g., 3-5%, 4-6%, 5-7%, 6-8%, or 7-9% by total weight, or at least 3%, at least 4%, at least 5%, at least 6%, at least 7%, or at least 8% by total weight, or less than 3%, less than 4%, less than 5%, less than 6%, less than 7%, less than 8%, or less than 9% by total weight) of a plasticizer (e.g., polyethylene glycol, such as a polyethylene glycol having a molecular weight of 5,000-7,000, such as PEG 6000, or triethyl citrate).

[0026] In some embodiments, the taste mask coating further comprises 4-15% by total weight (e.g., 4-6%, 5-7%, 6-8%, 7-9%, or 8-10% by total weight, or at least 4%, at least 5%, at least 6%, at least 7%, at least 8%, or at least 9% by total weight, or less than 4%, less than 5%, less than 6%, less than 7%, less than 8%, less than 9%, or less than 10% by total weight) of hydrated magnesium silicate (e.g., talc).

[0027] In some embodiments, the taste mask coating comprises 5-30% by weight of a polymer formed from dimethylaminoethyl methacrylate, butyl methacrylate, and methyl methacrylate (e.g., Eudragit E PO). In some embodiments, the polymer formed from dimethylaminoethyl methacrylate, butyl methacrylate, and methyl methacrylate (e.g., Eudragit E PO) comprises 50-75% by weight of the taste mask coating.

[0028] In some embodiments, the composition further comprises 1-50% by weight (e.g., 1-10%, 5-15%, 10-20%, 15-25%, 20-30%, 25-35%, 30-40%, 35-45%, or 40-50% by weight, or at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, or at least 50% by weight, or less than 5%, less than 10%, less than 15%, less than 20%, less than 25%, less than 30%, less than 35%, less than 40%, less than 45%, or less than 50% by weight) of seed cores (e.g., microcrystalline cellulose, sugar spheres, starch spheres, or other inert spherical pharmaceutically acceptable material).

[0029] In some embodiments, the composition further comprises 1-5% by weight (3-4%, 3.5-4.5%, 4-5% by weight, or at least 1%, at least 2%, at least 3%, or at least 4% by weight, or less than 2%, less than 3%, less than 4%, or less than 5% by weight) of a seal coat comprising a water-soluble polymer such as polyvinyl alcohol (e.g., Opadry, such as Opadry Clear).

[0030] In some embodiments, the composition comprises 5-50% (eg, 5-35%, 15-35%, 15-50%) of the taste mask coating by total weight.

[0031] In some embodiments, the composition comprises 15-60% (eg, 15-35%, 15-25%) sodium phenylbutyrate by total weight.

[0032] In some embodiments, the pharmaceutical composition comprises 44-46% by total weight of cellulose pellets; 22-24% by total weight of sodium phenylbutyrate; 5-7% by total weight of HPMC E5; 3-4% by total weight of Opadry Clear; 4-6% by total weight of PEG 6000; 12-14% by total weight of a polymer formed from dimethylaminoethyl methacrylate, butyl methacrylate, and methyl methacrylate (e.g., Eudragit E PO); and 5-7% by total weight of talc.

[0033] In some embodiments, the pharmaceutical composition comprises about 45% by total weight cellulose pellets, about 23% by total weight sodium phenylbutyrate, about 6% by total weight HPMC E5, about 3% by total weight Opadry Clear, about 5% by total weight PEG 6000, about 13% by total weight polymer formed from dimethylaminoethyl methacrylate, butyl methacrylate, and methyl methacrylate (e.g., Eudragit E PO), and about 6% by total weight talc.

[0034] In another aspect, the invention features a pharmaceutical composition that includes: a. 38-40% by total weight of cellulose pellets; b. 8-20% by total weight of sodium phenylbutyrate; c. 5-7% by total weight of HPMC E5; d. 3-4% by total weight of Opadry Clear; e. 5-7% by total weight of PEG 6000; f. 17-19% by total weight of a polymer formed from dimethylaminoethyl methacrylate, butyl methacrylate, and methyl methacrylate (e.g., Eudragit E PO); and g. 8-10% by total weight of talc.

[0035] In another aspect, the invention features a pharmaceutical composition that includes: a. about 39% by total weight cellulose pellets; b. about 19% by total weight sodium phenylbutyrate; c. about 6% by total weight HPMC E5; d. about 3% by total weight Opadry Clear; e. about 6% by total weight PEG 6000; f. about 18% by total weight polymer formed from dimethylaminoethyl methacrylate, butyl methacrylate, and methyl methacrylate (e.g., Eudragit E PO); and g. about 9% by total weight talc.

[0036] In another aspect, the invention features a pharmaceutical composition that includes: a. 44-46% by total weight cellulose pellets; b. 22-24% by total weight sodium phenylbutyrate; c. 5-7% by total weight HPMC E5; d. 3-4% by total weight Opadry Clear; e. 4-6% by total weight PEG 6000; f. 12-14% by total weight polymer formed from dimethylaminoethyl methacrylate, butyl methacrylate, and methyl methacrylate (e.g., Eudragit E PO); and g. 5-7% by total weight talc.

[0037] In another aspect, the invention features a pharmaceutical composition that includes: a. about 45% by total weight cellulose pellets; b. about 23% by total weight sodium phenylbutyrate; c. about 6% by total weight HPMC E5; d. about 3% by total weight Opadry Clear; e. about 5% by total weight PEG 6000; f. about 13% by total weight polymer formed from dimethylaminoethyl methacrylate, butyl methacrylate, and methyl methacrylate (e.g., Eudragit E PO); and g. about 6% by total weight talc.

[0038] In some embodiments, the pharmaceutical composition comprises 44-46% by total weight of cellulose pellets; 22-24% by total weight of sodium phenylbutyrate; 5-7% by total weight of HPMC E5; 3-4% by total weight of Opadry Clear; 2-4% by total weight of PEG 6000; 14-16% by total weight of a polymer formed from dimethylaminoethyl methacrylate, butyl methacrylate, and methyl methacrylate (e.g., Eudragit E PO); and 7-9% by total weight of talc.

[0039] In some embodiments, the pharmaceutical composition comprises about 45% by total weight cellulose pellets, about 23% by total weight sodium phenylbutyrate, about 6% by total weight HPMC E5, about 3% by total weight Opadry Clear, about 3% by total weight PEG 6000, about 15% by total weight polymer formed from dimethylaminoethyl methacrylate, butyl methacrylate, and methyl methacrylate (e.g., Eudragit E PO), and about 8% by total weight talc.

[0040] In another aspect, the invention features a pharmaceutical composition that includes: a. 32-34% by total weight of cellulose pellets; b. 15-17% by total weight of sodium phenylbutyrate; c. 3-5% by total weight of HPMC E5; d. 2-3% by total weight of Opadry Clear; e. 3-4% by total weight of PEG 6000; f. 27-29% by total weight of a polymer formed from dimethylaminoethyl methacrylate, butyl methacrylate, and methyl methacrylate (e.g., Eudragit E PO); and g. 13-15% by total weight of talc.

[0041] In another aspect, the invention features a pharmaceutical composition that includes: a. about 33% by total weight cellulose pellets; b. about 16% by total weight sodium phenylbutyrate; c. about 4% by total weight HPMC E5; d. about 2% by total weight Opadry Clear; e. about 3% by total weight PEG 6000; f. about 28% by total weight polymer formed from dimethylaminoethyl methacrylate, butyl methacrylate, and methyl methacrylate (e.g., Eudragit E PO); and g. about 14% by total weight talc.

[0042] In another aspect, the invention features a pharmaceutical composition that includes: a. 15-17% by total weight of cellulose pellets; b. 45-50% by total weight of sodium phenylbutyrate; c. 4-6% by total weight of HPMC E5; e. 2-3% by total weight of PEG 6000; f. 20-22% by total weight of a polymer formed from dimethylaminoethyl methacrylate, butyl methacrylate, and methyl methacrylate (e.g., Eudragit E PO); and g. 7-9% by total weight of talc.

[0043] In another aspect, the present invention provides a composition comprising a. about 16% by total weight of cellulose pellets; b. about 48% by total weight of sodium phenylbutyrate; c. about 5% by total weight of HPMC E5; e. about 3% by total weight of PEG 6000; f. about 21% by total weight of a polymer formed from dimethylaminoethyl methacrylate, butyl methacrylate, and methyl methacrylate (e.g., Eudragit E PO); and g. about 8% talc by total weight.

[0044] In another aspect, the invention features a pharmaceutical composition that includes: a. 6-8% by total weight of cellulose pellets; b. 65-70% by total weight of sodium phenylbutyrate; c. 6-8% by total weight of HPMC E5; e. 1-3% by total weight of PEG 6000; f. 12-14% by total weight of a polymer formed from dimethylaminoethyl methacrylate, butyl methacrylate, and methyl methacrylate (e.g., Eudragit E PO); and g. 4-6% by total weight of talc.

[0045] In another aspect, the present invention provides a composition comprising a. about 7% by total weight of cellulose pellets; b. about 67% by total weight of sodium phenylbutyrate; c. about 7% by total weight of HPMC E5; e. about 2% by total weight of PEG 6000; f. about 13% by total weight of a polymer formed from dimethylaminoethyl methacrylate, butyl methacrylate, and methyl methacrylate (e.g., Eudragit E PO); and g. about 5% talc by total weight.

[0046] In another aspect, the invention features a pharmaceutical composition that includes: a. 4-6% by total weight of cellulose pellets; b. 45-50% by total weight of sodium phenylbutyrate; c. 4-6% by total weight of HPMC E5; e. 3-4% by total weight of PEG 6000; f. 28-30% by total weight of a polymer formed from dimethylaminoethyl methacrylate, butyl methacrylate, and methyl methacrylate (e.g., Eudragit E PO); and g. 11-13% by total weight of talc.

[0047] In another aspect, the present invention provides a composition comprising a. about 5% by total weight of cellulose pellets; b. about 47% by total weight of sodium phenylbutyrate; c. about 5% by total weight of HPMC E5; e. about 3% by total weight of PEG 6000; f. about 29% by total weight of a polymer formed from dimethylaminoethyl methacrylate, butyl methacrylate, and methyl methacrylate (e.g., Eudragit E PO); and g. about 12% talc by total weight.

[0048] In another aspect, the invention features a pharmaceutical composition that includes: a. 6-7% by total weight of cellulose pellets; b. 60-65% by total weight of sodium phenylbutyrate; c. 8-10% by total weight of HPMC E5; e. 2-3% by total weight of PEG 6000; f. 15-17% by total weight of a polymer formed from dimethylaminoethyl methacrylate, butyl methacrylate, and methyl methacrylate (e.g., Eudragit E PO); and g. 5-7% by total weight of talc.

[0049] In another aspect, the present invention provides a composition comprising a. about 7% by total weight of cellulose pellets; b. about 61% by total weight of sodium phenylbutyrate; c. about 9% by total weight of HPMC E5; e. about 3% by total weight of PEG 6000; f. about 16% by total weight of a polymer formed from dimethylaminoethyl methacrylate, butyl methacrylate, and methyl methacrylate (e.g., Eudragit E PO); and g. about 6% talc by total weight.

[0050] In another aspect, the invention features a pharmaceutical composition that includes: a. 4-6% by total weight of cellulose pellets; b. 42-47% by total weight of sodium phenylbutyrate; c. 6-8% by total weight of HPMC E5; e. 3-4% by total weight of PEG 6000; f. 28-30% by total weight of a polymer formed from dimethylaminoethyl methacrylate, butyl methacrylate, and methyl methacrylate (e.g., Eudragit E PO); and g. 11-13% by total weight of talc.

[0051] In another aspect, the present invention provides a composition comprising a. about 5% by total weight of cellulose pellets; b. about 45% by total weight of sodium phenylbutyrate; c. about 7% by total weight of HPMC E5; e. about 4% by total weight of PEG 6000; f. about 29% by total weight of a polymer formed from dimethylaminoethyl methacrylate, butyl methacrylate, and methyl methacrylate (e.g., Eudragit E PO); and g. about 12% talc by total weight.

[0052] In some embodiments of any of the foregoing compositions, the composition is formulated as spray-layered beads. In some embodiments of any of the foregoing compositions, the composition is formulated as taste-masked beads produced by extrusion / spheronization, rotor granulation, or melt-congealing methods.

[0053] In some embodiments, any of the foregoing compositions may be tested in an in vitro dissolution transfer test in which the composition is subjected to a neutral pH for a predetermined period of time and then transferred to an acidic pH for a predetermined period of time. The release of sodium phenylbutyrate is monitored at each pH to determine the dissolution rate of sodium phenylbutyrate from the composition.

[0054] In some embodiments of any of the aforementioned compositions, less than 15% (e.g., less than 10%, less than 5%, less than 1%) of the sodium phenylbutyrate in the composition dissolves in 10 minutes at neutral pH (e.g., pH 6-8, pH 6.5-7.5, a pH of about 6.8) in a transition dissolution test.

[0055] In some embodiments of any of the aforementioned compositions, at least 95% of the sodium phenylbutyrate in the composition dissolves in 60 minutes when transferred to an acidic pH (e.g., pH 1-5, pH 1-2, pH about 1.2) in a transition dissolution test.

[0056] In some embodiments of any of the aforementioned compositions, at least 95% of the sodium phenylbutyrate in the composition dissolves in 30 minutes at an acidic pH (e.g., pH 1-5, pH 1-2, pH about 1.2) in a transition dissolution test.

[0057] In some embodiments of any of the foregoing compositions, upon administration to a subject, the composition has equivalent distribution in plasma compared to BUPHENYL®. In some embodiments of any of the foregoing compositions, the composition is bioequivalent to BUPHENYL®.

[0058] In some embodiments of any of the foregoing compositions, upon administration to a subject, the composition has greater levels of sodium phenylbutyrate in the plasma at 30 minutes compared to a modified-release formulation of sodium phenylbutyrate (e.g., RAVICTI®).

[0059] In some embodiments of any of the foregoing compositions, the composition scores better in a taste test compared to BUPHENYL®.

[0060] The invention also features a method of making a pharmaceutical composition for oral administration containing sodium phenylbutyrate and a taste mask coating (e.g., the taste mask coating is insoluble at the neutral pH of the mouth and soluble at the acidic pH of the stomach).

[0061] In some embodiments of any of the aforementioned compositions, the taste-masked coated beads may be administered in a dosing vehicle having a viscosity of approximately 50 to 1750 centipoise (cP), for example, to aid in bead suspension and dosing. One type of suspending agent that can be used is modified cornstarch or a combination of modified food starch and maltodextrin (e.g., THICK-IT®). For example, any of the aforementioned compositions may be administered with approximately 1 to 4 teaspoons (tps) of THICK-IT® added per 120 mL of water to achieve this viscosity range. An appropriate amount of taste-masked beads can be added to the THICK-IT® water mixture immediately prior to administration and stirred to suspend the beads.

[0062] Other suspending agents may also be used as dosage vehicles. Exemplary suspending agents include agar, alginic acid, sodium carboxymethylcellulose, carrageenan, dextrin, gelatin, guar gum, hydroxyethyl cellulose, hydroxypropyl cellulose, hypromellose, methylcellulose, polyethylene glycol, povidone, tragacanth, xanthan gum, or other suspending agents known in the art.

[0063] Additionally, the dosage vehicle may further include flavor additives, flavorings, dyes (colorants), sweeteners, anticaking agents, glidants (flow enhancers), and lubricants.

[0064] In some embodiments of any of the foregoing compositions, the taste masked coated beads have a DV of 90% or less, such that 90% of the beads in the composition are smaller than about 500 μM. 90 The particle size distribution may be approximately 500 μm (eg, less than 500 μM, less than 400 μM, less than 300 μM) based on volume.

[0065] Accordingly, in another aspect, the present disclosure provides a method for producing a pharmaceutical composition comprising sodium phenylbutyrate by providing a core comprising cellulose pellets, applying a first layer comprising sodium phenylbutyrate, hydroxypropyl methylcellulose (e.g., HPMC E 5), and polyethylene glycol (e.g., PEG having a molecular weight of 5000-7000, such as PEG 6000), applying a second layer comprising polyvinyl alcohol (e.g., Opadry, such as Opadry Clear), and applying a third layer comprising a methacrylic acid derivative (e.g., a polymer formed from the copolymerization of dimethylaminoethyl methacrylate, butyl methacrylate, and methyl methacrylate, such as Eudragit E PO), polyethylene glycol (e.g., PEG having a molecular weight of 5000-7000, such as PEG 6000), and hydrated magnesium silicate (e.g., talc), thereby producing a pharmaceutical composition comprising sodium phenylbutyrate.

[0066] In some embodiments of the method, the final composition comprises 1-50% by total weight of cellulose pellets (e.g., 0-10%, 5-15%, 10-20%, 15-25%, 20-30%, 25-35%, 30-40%, 35-45%, or 40-50% by total weight, or at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, or at least 45% by total weight, or less than 5%, less than 10%, less than 15%, less than 20%, less than 25%, less than 30%, less than 35%, less than 40%, less than 45%, or less than 5% by total weight).

[0067] In some embodiments of the method, the final composition comprises 15-60% by total weight (e.g., 20-30%, 25-35%, 30-40%, 35-45%, 40-50%, 45-55%, or 50-60% by total weight, or at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, or less than 20% by total weight). less than 25%, less than 30%, less than 35%, less than 40%, less than 45%, less than 50%, less than 55%, or less than 60% sodium phenylbutyrate, 3-10% by weight (e.g., 3-5%, 4-6%, 5-7%, 6-8%, 7-9%, or 8-10% by weight, or at least 3%, at least 4%, at least 5%, at least 6%, at least 7%, at least 8%, or at least 9% by weight, or less than 3% by weight, less than 4%, less than 5%, less than 6%, less than 7%, less than 8%, less than 9%, or less than 10% of hydroxypropyl methylcellulose, less than 1% by total weight (e.g., 0.001-0.1%, 0.01%-0.2%, 0.1-0.3%, 0.2-0.5%, 0.4-0.6%, 0.5-0.7%, 0.6-0.8%, 0.7-0.9%, or 0.8-1.0% by total weight, or at least 0.001%, at least 0.01%, at least 0.001% by total weight, The first layer comprises polyethylene glycol (0.1%, at least 0.2%, at least 0.3%, at least 0.4%, at least 0.5%, at least 0.6%, at least 0.7%, at least 0.8%, or at least 0.9%, or less than 0.001%, less than 0.01%, less than 0.1%, less than 0.2%, less than 0.3%, less than 0.4%, less than 0.5%, less than 0.6%, less than 0.7%, less than 0.8%, less than 0.9%, or less than 1% by total weight).

[0068] In some embodiments of the method, the final composition comprises a second layer comprising 3-5% by total weight of polyvinyl alcohol (e.g., 3-4%, 3.5-4.5%, or 4-5% by total weight, or at least 3%, at least 3.5%, at least 4%, or at least 4.5% by total weight, or less than 3.5%, less than 4%, less than 4.5%, or less than 5% by total weight).

[0069] In some embodiments of the method, the final composition contains 10-15% by total weight (e.g., 10-12%, 11-13%, 12-15%, or 14-15% by total weight, or at least 10%, at least 11%, at least 12%, at least 13%, or at least 14% by total weight, or less than 10%, less than 11%, less than 12%, less than 13%, less than 14%, or less than 15% by total weight) of a polymer (e.g., Eudragit E) formed from dimethylaminoethyl methacrylate, butyl methacrylate, and methyl methacrylate. PO), 3 to 10% by total weight (e.g., 3 to 5%, 4 to 6%, 5 to 7%, 6 to 8%, 7 to 9, or 8 to 10% by total weight, or at least 3%, at least 4%, at least 5%, at least 6%, at least 7%, at least 8%, or at least 9% by total weight, or less than 3%, less than 4%, less than 5%, less than 6%, less than 7%, less than 8%, less than 9%, or less than 10% by total weight) polyethylene glycol, and 4 to 15% (e.g., 4 to 6%, 5 to 7%, 6 to 8%, 7 to 9%, or 8 to 10% by total weight, or at least 4%, at least 5%, at least 6%, at least 7%, at least 8%, or at least 9% by total weight, or less than 4%, less than 5%, less than 6%, less than 7%, at least 8%, or at least 9% by total weight, or less than 4%, less than 5%, less than 6%, less than 7%, less than 8%, less than 9%, or less than 10% by total weight) hydrated magnesium silicate.

[0070] In some embodiments of any of the foregoing methods, the first layer is applied in water.

[0071] In some embodiments of any of the foregoing methods, the second layer is applied in water.

[0072] In some embodiments of any of the foregoing methods, the third layer is applied in an organic solvent, such as a solution of acetone and isopropyl alcohol.

[0073] In another aspect, the invention features a pharmaceutical composition prepared by any of the aforementioned methods.

[0074] In another aspect, the invention features a method of treating an inborn error of metabolism (e.g., maple syrup urine disease or a urea cycle disorder) in a subject, comprising administering an effective amount of any of the aforementioned pharmaceutical compositions.

[0075] In another aspect, the invention features a method of treating a neurodegenerative disorder (e.g., Parkinson's disease) in a subject, comprising administering an effective amount of any of the aforementioned pharmaceutical compositions.

[0076] In another aspect, the invention features a method of treating spinal muscular atrophy in a subject, comprising administering an effective amount of any of the aforementioned pharmaceutical compositions.

[0077] In another aspect, the invention features a method of treating dystonia in a subject, comprising administering an effective amount of any of the aforementioned pharmaceutical compositions.

[0078] In another aspect, the invention features a method of treating inclusion body myositis in a subject, comprising administering an effective amount of any of the aforementioned pharmaceutical compositions.

[0079] In some embodiments of any of the aforementioned methods, the subject is a human.

[0080] In some embodiments of any of the aforementioned methods, the pharmaceutical composition is administered in a dosing vehicle having a viscosity of approximately 50 to 1750 centipoise (cP), e.g., to aid in suspension and dosing of the beads.

[0081] One type of suspending agent that can be used is modified cornstarch, or a combination of modified food starch and maltodextrin (e.g., THICK-IT®). For example, any of the foregoing compositions may be administered with approximately 1-4 teaspoons (tps) of THICK-IT® added per 120 mL of water to achieve this viscosity range. An appropriate amount of taste mask beads can be added to the THICK-IT® / water mixture immediately prior to administration and stirred to suspend the beads.

[0082] Other suspending agents may also be used as the dosage vehicle. Exemplary suspending agents include agar, alginic acid, sodium carboxymethylcellulose, carrageenan, dextrin, gelatin, guar gum, hydroxyethyl cellulose, hydroxypropyl cellulose, hypromellose, methylcellulose, polyethylene glycol, povidone, tragacanth, xanthan gum, or other suspending agents known in the art. In addition, the dosage vehicle may further include flavor additives, fragrances, dyes (coloring agents), sweeteners, anticaking agents, glidants (flow enhancers), and lubricants.

[0083] definition "About": As used herein, the term "about" when used in the context of the amount of a component of a composition means + / - 10% of the stated numerical value.

[0084] "Administered in combination": As used herein, the term "administered in combination" or "combined administration" means that two or more agents are administered to a subject simultaneously or within an interval such that the effects of each agent on the patient can overlap. In some embodiments, two or more agents are administered within about 60, 30, 15, 10, 5, or 1 minute of each other. In some embodiments, the administration of the agents is spaced sufficiently close together so that a combined (e.g., synergistic) effect is achieved.

[0085] "Animal": As used herein, the term "animal" refers to any member of the animal kingdom. In some, particularly therapeutic, embodiments, "animal" refers to humans at any stage of development. In some embodiments, "animal" refers to non-human animals at any stage of development. In certain embodiments, the non-human animal is a mammal (e.g., a rodent, mouse, rat, rabbit, monkey, dog, cat, sheep, cow, primate, or pig). In some embodiments, animals include, but are not limited to, mammals, birds, reptiles, amphibians, fish, and worms. In some embodiments, the animal is a transgenic animal, a genetically modified animal, or a clone.

[0086] "Approximately": As used herein, the term "approximately," when applied to one or more numerical values ​​of interest, refers to a numerical value that is similar to a stated reference value. In certain embodiments, unless otherwise stated or clear from the context, the term "approximately" refers to a numerical range that is within 25%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, or less than 1% in either direction (greater or lesser) of the stated reference value (except where such number exceeds 100% of the possible values).

[0087] "Binder": As used herein, the term "binder" refers to an excipient that holds ingredients together in a formulation or holds ingredients on a carrier (e.g., seed core). Binders ensure that tablets and granules can be formed with the necessary mechanical strength and provide bulk to low-active-dose tablets. Examples of binders include, but are not limited to, hydroxypropyl methylcellulose such as HPMC E 5, sugars and their derivatives, proteins such as gelatin, sugar alcohols such as xylitol, sorbitol, or maltitol, or synthetic polymers such as polyvinylpyrrolidone or polyethylene glycol.

[0088] "Bioequivalence": As used herein, the term "bioequivalent" refers to the absence of significant differences in the rate and extent to which the active ingredient or moiety in pharmaceutical equivalents or pharmaceutical substitutes becomes available at the site of drug action when administered at the same molar dose under similar conditions in a properly designed study. As will be appreciated by those skilled in the art, different types of evidence can be used to demonstrate bioequivalence for pharmaceutically equivalent drug products, including in vivo (e.g., Cmax and / or AUC data) or in vitro (e.g., dissolution rate) studies, or both. The choice of method used to demonstrate bioequivalence depends on the purpose of the study, available analytical methods, and the nature of the drug product. In some embodiments, bioequivalence can be demonstrated using any of the methods described herein, such as determining plasma levels of sodium phenylbutyrate in two different formulations at different time points in healthy subjects.

[0089] "Biologically active": As used herein, the phrase "biologically active" refers to the property of any substance that has activity in a biological system and / or organism. For example, a substance is considered to be biologically active if, when administered to an organism, it has a biological effect on the organism. In certain embodiments, a polynucleotide of the invention may be considered biologically active if even a portion of the polynucleotide mimics an activity that is considered biologically active or biologically relevant.

[0090] "By total weight": As used herein, the phrase "by total weight" refers to the amount of an ingredient in a composition as a percentage of the total weight of the entire composition, including all ingredients.

[0091] "Delivery": As used herein, "delivery" refers to the act or manner of delivering a compound, substance, entity, moiety, cargo, or payload.

[0092] "Dosage vehicle": As used herein, "dosage vehicle" refers to a pharmaceutically acceptable excipient (e.g., a thickening agent or suspending agent) or combination thereof that aids in the administration of a pharmaceutical formulation.

[0093] "Comparable distribution": As used herein, "comparable distribution" refers to a distribution of sodium phenylbutyrate from one formulation (e.g., as measured in plasma) that is substantially similar (e.g., within 10%, within 5%, within 2%, within 1%) to the distribution of another formulation.

[0094] "Modified-release formulation": As used herein, "modified-release formulation" refers to a formulation of sodium phenylbutyrate or a pharmaceutically acceptable salt thereof in which the sodium phenylbutyrate is released in a manner that results in a significantly different rate (e.g., significantly slower rate) and extent of absorption of the active pharmaceutical ingredient compared to BUPHENYL®. An approved modified-release formulation of sodium phenylbutyrate is glycerol phenylbutyrate, sold under the trademark RAVICTI® and approved for use in the treatment of UCD.

[0095] "Formulation": As used herein, a "formulation" includes at least sodium phenylbutyrate and a delivery agent.

[0096] "Greater Distribution": As used herein, the term "greater distribution" refers to a distribution of sodium phenylbutyrate (e.g., as measured in plasma) from one formulation that is greater than the distribution of another formulation (e.g., at least 5% greater, at least 10% greater, at least 20% greater, at least 50% greater).

[0097] "In vitro": As used herein, the term "in vitro" refers to phenomena that occur in an artificial environment (e.g., in a test tube or reaction vessel, in cell culture, in a Petri dish, etc.) rather than in a living organism (e.g., an animal, plant, or microorganism).

[0098] "In vivo": As used herein, the term "in vivo" refers to events that take place within an organism (e.g., an animal, plant, or microorganism, or cells or tissues thereof).

[0099] "Lubricant": As used herein, the term "lubricant" refers to a compound that prevents ingredients in a formulation from clumping together, prevents clumping of the finished composition (e.g., of spray-layered beads), or prevents ingredients from sticking to surfaces (e.g., equipment used to manufacture and / or process the composition).

[0100] "Organic solvent": As used herein, "organic solvent" refers to a carbon-based substance, other than water, that dissolves a solute (a chemically distinct liquid, solid, or gas), resulting in a solution.

[0101] "Pharmaceutically acceptable": The phrase "pharmaceutically acceptable" is used herein to refer to compounds, substances, compositions and / or dosage forms that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0102] "Pharmaceutically acceptable excipient": As used herein, the phrase "pharmaceutically acceptable excipient" or "pharmaceutically acceptable carrier" refers to any ingredient other than the compounds described herein (e.g., a vehicle capable of suspending or dissolving an active compound) that has the properties of being substantially non-toxic and non-inflammatory in a patient. Excipients may include, for example, anti-adherents, antioxidants, binders, coating agents, compression aids, disintegrants, dyes (colorants), emollients, emulsifiers, fillers (diluents), film-forming or coating agents, flavors, fragrances, glidants (flow enhancers), lubricants, preservatives, printing inks, adsorbents, suspending or dispersing agents, sweeteners, thickeners, and water for hydration. Exemplary excipients include, but are not limited to, butylated hydroxytoluene (BHT), calcium carbonate, calcium phosphate (dibasic), calcium stearate, croscarmellose, cross-linked polyvinylpyrrolidone, citric acid, crospovidone, cysteine, ethylcellulose, gelatin, hydroxypropyl cellulose, hydroxypropylmethylcellulose, lactose, magnesium stearate, maltitol, maltodextrin, mannitol, methionine, methylcellulose, methylparaben, microcrystalline cellulose, polyethylene glycol, polyvinylpyrrolidone, povidone, pregelatinized starch, propylparaben, retinyl palmitate, shellac, silicon dioxide, sodium carboxymethylcellulose, sodium citrate, sodium starch glycolate, sorbitol, starch (e.g., modified food starch or corn starch), stearic acid, sucrose, talc, titanium dioxide, vitamin A, vitamin E, vitamin C, and xylitol.

[0103] "Pharmaceutically acceptable salt": The present disclosure also includes pharmaceutically acceptable salts of the compounds described herein. As used herein, "pharmaceutically acceptable salt" refers to derivatives of the disclosed compounds in which the parent compound is modified by converting an existing acid or base moiety into its salt form (e.g., by reacting a free base group with a suitable organic acid). Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines, alkali or organic salts of acidic residues such as carboxylic acids, and the like. Representative acid addition salts include acetate, adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphosulfonate, citrate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, fumarate, glucoheptonate, glycerophosphate, hemisulfate, heptonate, hexanoate, hydrobromide, hydrochloride, hydroiodide, and 2-hydroxyethanesulfonate. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like, as well as non-toxic ammonium, quaternary ammonium, and amine cations, including, but not limited to, ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, and ethylamine. Pharmaceutically acceptable salts of the present disclosure include conventional non-toxic salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. The pharmaceutically acceptable salts of the present disclosure can be synthesized from the parent compound that contains a basic or acidic moiety by conventional chemical methods.Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or an organic solvent, or in a mixture of the two (generally, non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred). Lists of suitable salts can be found in Remington's The Science and Practice of Pharmacy, 21st Edition, AR Gennaro. (Lippincott, Williams & Wilkins, Baltimore, MD, 2006); Pharmaceutical Salts: Properties, Selection, and Use, PH Stahl and CG Wermuth (eds.), Wiley-VCH, 2008, and Berge et al., Journal of Pharmaceutical Science, 66, 1-19 (1977), each of which is incorporated herein by reference in its entirety.

[0104] "Pharmaceutically acceptable solvate": As used herein, the term "pharmaceutically acceptable solvate" refers to a compound of the present invention wherein molecules of a suitable solvent are incorporated into the crystal lattice. A suitable solvent is one that is physiologically acceptable at the administered dose. For example, solvates may be prepared by crystallization, recrystallization, or precipitation from a solution containing an organic solvent, water, or a mixture thereof. Examples of suitable solvents include ethanol, water (e.g., mono-, di-, and trihydrates), N-methylpyrrolidinone (NMP), dimethyl sulfoxide (DMSO), N,N'-dimethylformamide (DMF), N,N'-dimethylacetamide (DMAC), 1,3-dimethyl-2-imidazolidinone (DMEU), 1,3-dimethyl-3,4,5,6-tetrahydro-2-(1H)-pyrimidinone (DMPU), acetonitrile (ACN), propylene glycol, ethyl acetate, benzyl alcohol, 2-pyrrolidone, benzyl benzoate, and the like. When water is the solvent, the solvate is referred to as a "hydrate."

[0105] "Plasticizer": As used herein, the term "plasticizer" refers to an additive that increases the plasticity or flowability of a formulation. Plasticizers are used to modify the film formation process of coatings that are based on the physical drying of film-forming materials. Proper film formation is essential to meet the requirements for specific coating properties, such as dry film appearance, carrier adhesion, elasticity, etc., while simultaneously combining with a high level of hardness. Examples of plasticizers useful in the formulations and methods of the present invention include, but are not limited to, polyethylene glycols, such as PEG 6000 or triethyl citrate.

[0106] "Preventing": As used herein, the term "preventing" refers to partially or completely delaying the onset of an infection, disease, disorder, and / or condition; partially or completely delaying the onset of one or more symptoms, characteristics, or clinical manifestations of a particular infection, disease, disorder, and / or condition; partially or completely delaying the onset of one or more symptoms, characteristics, or manifestations of a particular infection, disease, disorder, and / or condition; partially or completely delaying the progression from an infection, a particular disease, disorder, and / or condition; and / or reducing the risk of developing pathology associated with an infection, disease, disorder, and / or condition.

[0107] "Sample": As used herein, the term "sample" or "biological sample" refers to a subset of tissues, cells, or components thereof (e.g., bodily fluids including, but not limited to, blood, mucus, lymph, synovial fluid, cerebrospinal fluid, saliva, amniotic fluid, amniotic cord blood (umbilical cord blood), urine, vaginal fluid, and semen). Samples may also include whole organisms, or a subset of their tissues, cells, or components, or a portion or part thereof, including, but not limited to, plasma, serum, spinal fluid, lymph, external portions of the skin, respiratory, intestinal, and genitourinary tracts, tears, saliva, milk, blood cells, tumors, organs. Samples also refer to media such as nutrient broth or gel, which may contain cellular components such as proteins or nucleic acid molecules.

[0108] "Scores well in a taste test": As used herein, the term "scores well in a taste test" refers to a formulation that scores higher in a taste test (e.g., any taste test known in the art) than another formulation. A variety of taste tests are known in the art, and any suitable taste test known in the art may be used to test a formulation for palatability, such as by a flavor profile test. The flavor profile method uses trained evaluators, such as a panel of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more experts, to identify, characterize, and quantify the perceived sensory attributes of a formulation. The attributes identified by this panel are basic tastes (sweet, sour, salty, bitter, umami), aroma (savory aromas and aromatic "off-notes"), sensory factors (coolness, numbing, bite / burn, etc.), and amplitude (perception of balance and fullness). The perceived strength or intensity of each of these attributes is measured and assigned an appropriate numerical value: 0 = none, 1 = slight, 2 = moderate, and 3 = strong. Chemical reference standards are used to establish the intensity scale for ongoing panelist calibration. In addition, all sensations remaining during the aftertaste are measured at selected intervals of 1, 5, 10, 15, or more than 15 minutes.

[0109] "Seal Coat": As used herein, the term "seal coat" refers to a layer of a compound that prevents direct contact between two layers of a composition. In some embodiments, the seal coat protects an ingredient in a formulation from degradation due to moisture in the air. In some embodiments, the seal coat protects an ingredient from degradation due to contact with an ingredient in another layer. Examples of compounds that may be used in the seal coat include, but are not limited to, Opadry, such as Opadry Clear, polyvinyl alcohol, hydroxypropyl cellulose, hydroxypropyl methylcellulose, or polyvinylpyrrolidone.

[0110] "Seed core": As used herein, the term "seed core" refers to a surface onto which components of a formulation may be applied. Examples of seed cores useful in the present invention include, but are not limited to, microcrystalline cellulose pellets, sugar spheres, starch spheres, or other inert, spherical, pharmaceutically acceptable materials. In some embodiments, the seed cores are about 100 μm to 1.5 mm in diameter.

[0111] "Significant" or "Significantly": As used herein, the terms "significant" or "significantly" are used synonymously with the term "substantially."

[0112] "Single unit dose": As used herein, a "single unit dose" is a dose of any therapeutic agent administered in one dose / one time / single route / single point of contact, i.e., a single administration event.

[0113] "Spray-layered beads": As used herein, the term "spray-layered beads" refers to spherical multiparticulates (e.g., 100-1500 μm in size) having one or more coating layers applied by fluidized bead coating techniques. A microcrystalline carrier such as sucrose or microcrystalline cellulose is typically used with a coating layer containing one or more drug substances. Extruded beads or lipid multiparticulates may also be spray-layer coated. In some embodiments, the multiparticulates comprise a compressed drug substance that is then coated with one or more layers (e.g., a taste-masking coating).

[0114] "Subject": As used herein, the term "subject" or "patient" refers to any organism to which a composition in accordance with the invention may be administered, e.g., for experimental, diagnostic, prophylactic, and / or therapeutic purposes. Typical subjects include animals (e.g., mammals such as mice, rats, rabbits, non-human primates, and humans).

[0115] "Substantially": As used herein, the term "substantially" refers to a qualitative state of exhibiting a complete or nearly complete degree or degree of a desired characteristic or property. Those skilled in the art of biology will understand that biological and chemical phenomena rarely, if ever, proceed toward and / or to completion or achieve or avoid an absolute result. Thus, the term "substantially" is used herein to capture the potential lack of completion that is inherent in many biological and chemical phenomena.

[0116] "Suffering from": An individual "suffering from" a disease, disorder, and / or condition has been diagnosed with or exhibits one or more symptoms of the disease, disorder, and / or condition.

[0117] "Susceptible to": An individual who is "susceptible to" a disease, disorder, and / or condition may not have been diagnosed with and / or may not exhibit symptoms of the disease, disorder, and / or condition, but has a tendency to develop the disease or its symptoms. In some embodiments, an individual who is susceptible to a disease, disorder, and / or condition (e.g., cancer) may be characterized by one or more of the following: (1) a genetic mutation associated with the development of the disease, disorder, and / or condition; (2) a genetic polymorphism associated with the development of the disease, disorder, and / or condition; (3) an increase and / or decrease in the expression and / or activity of proteins and / or nucleic acids associated with the disease, disorder, and / or condition; (4) habits and / or lifestyles associated with the development of the disease, disorder, and / or condition; (5) a family history of the disease, disorder, and / or condition; and (6) exposure to and / or infection with a microorganism associated with the development of the disease, disorder, and / or condition. In some embodiments, an individual who is susceptible to a disease, disorder, and / or condition will develop the disease, disorder, and / or condition. In some embodiments, an individual who is susceptible to a disease, disorder and / or condition does not develop the disease, disorder and / or condition.

[0118] "Taste mask coating": As used herein, the term "taste mask coating" refers to a layer of compounds that prevents the release of sodium phenylbutyrate in the oral cavity while allowing its release in the stomach in order to mask the unpleasant taste of sodium phenylbutyrate. In some embodiments, the taste mask coating refers to a layer of compounds that results in a formulation that scores well in a taste test. Examples of compounds useful in taste mask coatings for the formulations and methods of the present invention include, but are not limited to, polymers formed from dimethylaminoethyl methacrylate, butyl methacrylate, and methyl methacrylate (e.g., Eudragit E PO) and other coatings that are soluble at stomach pH but insoluble at mouth pH.

[0119] "Therapeutic Agent": The term "therapeutic agent" refers to any agent that has a therapeutic, diagnostic, and / or prophylactic effect and / or induces a desired biological and / or pharmacological effect when administered to a subject.

[0120] "Therapeutically effective amount": As used herein, a "therapeutically effective amount" refers to the amount of a compound that, when administered to a mammal for treating a condition, disorder, or pathology (e.g., an inborn error of metabolism, such as MSUD), is sufficient to effect such treatment. A "therapeutically effective amount" will vary depending on the compound, the disease and its severity, and the age, weight, physiological condition, and responsiveness of the mammal being treated. As used herein, the term "therapeutically effective amount" refers to an amount of a compound sufficient to prevent, inhibit, reduce, or eliminate one or more causes, symptoms, or complications of elevated plasma levels of branched-chain amino acids and / or branched-chain alpha-keto acids (e.g., levels in individuals with an inborn error of metabolism, such as MSUD) compared to plasma levels in subjects without an inborn error of metabolism (e.g., healthy subjects and / or subjects with normal levels of branched-chain amino acids and / or branched-chain alpha-keto acids). In some embodiments, the desired therapeutic effect is the achievement in an individual of target plasma levels of at least one branched-chain amino acid and / or branched-chain alpha-keto acid (e.g., 200-500 μmol / L leucine, 100-200 μmol / L isoleucine, and 100-300 μmol / L valine). In some embodiments, the desired therapeutic effect is the achievement of normal plasma levels of at least one branched-chain amino acid (e.g., 65-220 μmol / L leucine, 26-100 μmol / L isoleucine, and 90-300 μmol / L valine). In specific embodiments, the treatment is considered therapeutically effective when there is a particular degree of reduction in the plasma levels of one or more branched-chain amino acids and / or branched-chain alpha-keto acids.In some cases, a decrease of at least 5%, 7.5%, 10%, 12.5%, 15%, 17.5%, 20%, 22.5%, 25%, 27.5%, 30%, 32.5%, 35%, 37.5%, 40%, 42.5%, 45%, 47.5%, or 50% in plasma levels of one or more branched-chain amino acids and / or branched-chain alpha-keto acids, or one or more The treatment is considered therapeutically effective when there is at least about a 5%, 7.5%, 10%, 12.5%, 15%, 17.5%, 20%, 22.5%, 25%, 27.5%, 30%, 32.5%, 35%, 37.5%, 40%, 42.5%, 45%, 47.5%, or 50% decrease in plasma levels of branched-chain amino acids and / or branched-chain alpha-keto acids. Those skilled in the art will recognize that plasma levels can be measured by standard methods in the art, such as using plasma amino acid tests or urine amino acid tests by chromatography and / or mass spectrometry.

[0121] "Total daily dose": As used herein, the "total daily dose" is the amount given or prescribed in a 24-hour period. It may be administered as a single unit dose.

[0122] "Transition Dissolution Test": As used herein, the term "transition dissolution test" refers to an in vitro test of the release of sodium phenylbutyrate from a formulation. The dissolution of sodium phenylbutyrate may be determined using any method in the art. For example, the dissolution of sodium phenylbutyrate in a sodium phenylbutyrate formulation may be determined according to the dissolution assay protocol described below.

[0123] A pH 6.8 potassium phosphate buffer (USP) was prepared, and 700 mL of this solution was added to a Distek 2500 USP II (paddle) dissolution apparatus. The bath was heated to 37.5°C, and 1 gm of sodium phenylbutyrate multiparticulates was added with stirring at 100 RPM. Samples of the dissolution medium (1.5 mL) were collected at t = 5, 10, and 15 minutes. After the 15-minute sample was taken, 100 mL of 1 N hydrochloric acid solution was added to the dissolution vessel, and the volume was adjusted to 900 mL by adding pH 1.2, 0.1 N HCl solution (USP). The dissolution test continued for an additional 65 minutes, with 1.5 mL samples collected at t = 20, 30, 40, 50, 60, 70, and 80 minutes. After the 80-minute sample was taken, stirring was increased to 300 RPM for an additional 15 minutes, and a final 1.5 mL sample was collected at t = 95 minutes. A Shimadzu Prominence-I LC-2030C 3D HPLC system was used to measure drug release in all samples.

[0124] "Treating": As used herein, "treating" a condition, disorder, or pathological condition or "treatment" of a condition, disorder, or pathological condition includes (1) preventing or delaying the onset of clinical symptoms of the condition, disorder, or pathological condition in a mammal that may be afflicted with or predisposed to the condition, disorder, or pathological condition, but that has not yet experienced the condition, disorder, or pathological condition or does not display clinical or subclinical symptoms thereof; (2) inhibiting the condition, disorder, or pathological condition, i.e., arresting or reducing the disease or at least one clinical or subclinical symptom thereof; or (3) palliating the disease, i.e., causing regression of the condition, disorder, or pathological condition, or at least one clinical or subclinical symptom thereof. [Brief explanation of the drawings]

[0125] [Figure 1A] FIG. 1 is a schematic diagram of a taste masking particle having a seed core. [Figure 1B] FIG. 1 is a schematic diagram of a taste masking particle having a drug-containing core. [Figure 1C]FIG. 1 is a schematic diagram of a taste-masking tablet. [Figure 2] 1 is a graph illustrating drug release over time in a transitional dissolution test. [Figure 3] 1 is a graph illustrating drug release over time in a transitional dissolution test. [Figure 4] 1 is a graph illustrating drug release over time in a transitional dissolution test. [Figure 5] 1 is a graph illustrating drug release over time in a transitional dissolution test. [Figure 6] 1 is a graph illustrating drug release over time in a transitional dissolution test. [Figure 7] 1 is a graph illustrating drug release over time in a transitional dissolution test. [Figure 8] 1 is a graph illustrating drug release over time in a transitional dissolution test. DETAILED DESCRIPTION OF THE INVENTION

[0126] The invention described herein relates to taste-masked formulations of sodium phenylbutyrate and methods of using such formulations in the treatment of inborn errors of metabolism, such as MSUD and UCD, and neurodegenerative disorders, such as Parkinson's disease, spinal muscular atrophy, inclusion body myositis, or dystonia. The sodium phenylbutyrate formulations of the invention address the known problem of treatment non-compliance due to poor taste and the resulting under-dosing of commercially available formulations of sodium phenylbutyrate, such as BUPHENYL®. The formulations of the invention are taste-masked, pH-sensitive formulations with rapid distribution of the active ingredient, sodium phenylbutyrate, as measured, for example, in the subject's plasma. In some embodiments, the formulations contain a high drug load.

[0127] Method for Producing Taste Masking Compositions The taste-masking material may be prepared by first identifying suitable seed cores, such as cellulose pellets, and then preparing a solution containing sodium phenylbutyrate. The sodium phenylbutyrate-containing solution may be prepared by combining a solution of HPMC E 5 and PEG 6000 in purified water with a separate solution of sodium phenylbutyrate in purified water. The sodium phenylbutyrate-containing layer is then applied to the seed cores by spraying, followed by drying and storing the coated pellets.

[0128] The seal coat solution is prepared by mixing Opadry Clear in purified water and then applying it by spraying onto the dry drug-containing pellets. The pellets with the seal coat are then dried and stored.

[0129] A taste mask coating solution is then prepared in a 2:3 part acetone:IPA solution to which a polymer formed from dimethylaminoethyl methacrylate, butyl methacrylate, and methyl methacrylate (e.g., Eudragit E PO) is added. The solution containing the polymer formed from dimethylaminoethyl methacrylate, butyl methacrylate, and methyl methacrylate (e.g., Eudragit E PO) is then mixed with another solution containing homogenized talc and PEG 6000.

[0130] The taste mask coating solution is then applied to the seal-coated pellets by spraying. The pellets are then dried, resulting in the finished powder taste mask formulation. In some embodiments, the final composition (e.g., spray-layered beads) is mixed with a lubricant, such as silica, to prevent clumping of the composition, for example.

[0131] Prior to administration, the taste-masked formulation may be mixed with a dosage vehicle containing various pharmaceutically acceptable excipients, such as viscosity modifiers, suspending or dispersing agents, flavors, fragrances, dyes (colorants), sweeteners, anticaking agents, glidants (flow enhancers), and lubricants.

[0132] The dosing vehicle may be mixed with the taste mask formulation and added to the water and stirred, or the dosing vehicle may be added to the water first and mixed, after which the taste mask formulation may be added.

[0133] Other palatable liquids may be used in place of water, provided the liquid has a pH of ≥6.

[0134] Treatment method The present invention features pharmaceutical compositions containing a therapeutically effective amount of sodium phenylbutyrate in an orally acceptable formulation. In some embodiments, the pharmaceutical composition is a granular formulation dispersed in a pharmaceutically acceptable carrier; for example, the composition can be mixed in water and ingested by a patient (e.g., over 5-10 minutes). Suitable formulations for use in the present invention are described in Remington's Pharmaceutical Sciences, Mack Publishing Company, Philadelphia, PA 22222. nd ed., 2010. Except insofar as any conventional carrier is incompatible with the active ingredient, its use in pharmaceutical compositions is contemplated. Moreover, for animal (e.g., human) administration, it is understood that preparations should meet sterility, pyrogenicity, general safety and purity standards as required by the FDA Office of Biological Standards.

[0135] The actual dosage of the compositions of the present invention administered to a patient can be determined by physical and physiological factors such as body weight, severity of the condition, the type of disease being treated, previous or current therapeutic interventions, and the patient's idiopathic disease, as well as based on the route of administration. Depending on the dose and route of administration, the frequency of administration and / or effective amount of the preferred dose may vary depending on the subject's response. The practitioner responsible for administration will, in any event, determine the concentration of the active ingredient(s) of the composition and the appropriate dose for the individual subject.

[0136] Maple syrup urine disease For the treatment of MSUD, the actual dosage can be determined in part by measuring plasma branched-chain amino acid (BCAA) levels and adjusting the dose to reduce the plasma level of at least one BCAA to a range that is found to be non-toxic and supports optimal growth and development (Table 1).

[0137] [Table 1]

[0138] Urea cycle disorders Sodium phenylbutyrate is approved as an adjunctive therapy in the chronic management of patients with UCD. Sodium phenylbutyrate is indicated for all patients with neonatal-onset deficiency and for subjects with later-onset disease who have a history of hyperammonemic encephalopathy. Sodium phenylbutyrate is generally administered in combination with dietary protein restriction and often with essential amino acid supplementation.

[0139] The usual total daily dose of BUPHENYL® tablets and powder for patients with urea cycle disorders is 450 to 600 mg / kg / day for patients weighing less than 20 kg, or 9.9 to 13.0 g / m for patients weighing more. 2 / day. Tablets and powders are to be taken in equally divided amounts with each meal or diet (i.e., 3-6 times per day). In some embodiments, the pharmaceutical compositions of the present invention are bioequivalent to BUPHENYL®, and thus equivalent doses of sodium phenylbutyrate would likely be useful in treating UCD.

[0140] Spinal muscular atrophy Sodium phenylbutyrate has been studied as a treatment for infants with spinal muscular atrophy. The target dose of BUPHENYL® Powder for patients with spinal muscular atrophy is 450-600 mg / kg / day in four divided doses. In some embodiments, the pharmaceutical compositions of the invention are bioequivalent to BUPHENYL®, and therefore equivalent doses of sodium phenylbutyrate may be useful in treating spinal muscular atrophy.

[0141] Parkinson's disease For the treatment of Parkinson's disease, the actual dosage can be determined, in part, by measuring the level of a biomarker in the blood (e.g., the expression level of the gene DJ-1, as described in Zhou W. et al. J. Biol. Chem. 2011, 286(17), pp. 14941-14951) and adjusting the dose accordingly (e.g., to increase the expression level of DJ-1 without causing side effects).

[0142] Inclusion body myositis For the treatment of inclusion body myositis, the actual dosage can be determined by measuring the levels of biomarkers, for example, by measuring lysosomal activity, the amount of Aβ42 and its multimers, γ-secretase activity, and / or myofiber vacuolization, as described in Nogalska et al.

[0143] dystonia For the treatment of dystonia, the actual dosage can be determined by measuring the levels of biomarkers, for example, ER stress and / or cyclic adenosine-3',5'-monophosphate (cAMP) response to the adenylate cyclase agonist forskolin, as described in Cho et al.

[0144] dose The dosage of any composition described herein or identified using the methods described herein will depend on several factors, such as the method of administration, the disease being treated (e.g., MSUD, UCD, Parkinson's disease, spinal muscular atrophy, inclusion body myositis, or dystonia), the severity of the disease, and the age, weight, and health of the subject being treated.

[0145] It is not intended that the administration of the composition to a subject be limited to a particular dose or dosing frequency for the treatment methods of the present invention. The composition may be administered to a subject in a single dose or multiple doses. For example, the compositions described herein may be administered at least once daily (e.g., twice daily, three times daily, four times daily, or more). It should be understood that for any particular subject, specific dosing regimens should be adjusted over time according to the individual needs and the professional judgment of the person administering or supervising the administration of the composition. For example, if a lower dose does not provide sufficient activity in treating a disease or condition described herein (e.g., MSUD, UCD, Parkinson's disease, spinal muscular atrophy, inclusion body myositis, or dystonia), the dose of the composition can be increased. Conversely, if the disease (e.g., MSUD, UCD, Parkinson's disease, spinal muscular atrophy, inclusion body myositis, or dystonia) is diminishing, the dose of the composition can be decreased.

[0146] Although the attending physician will ultimately determine the appropriate amount and dosing regimen, a therapeutically effective amount of the compositions described herein may be, for example, in the range of approximately 450-600 mg / kg / day of sodium phenylbutyrate in a urea cycle disorder patient weighing less than 20 kg (e.g., a composition containing 50% by weight of sodium phenylbutyrate may require a dose of 900-1200 mg / kg / day to provide 450-600 mg / kg / day of sodium phenylbutyrate), or 9.9-13.0 g / m in a larger patient. 2 In some embodiments, the total daily dose is taken in equal amounts with each meal or diet (i.e., 3-6 times per day).

[0147] In some embodiments, a therapeutically effective amount of the compositions described herein is, for example, in the range of approximately 450-600 mg / kg / day of sodium phenylbutyrate in an MSUD patient weighing less than 20 kg (e.g., a composition comprising 50% by weight sodium phenylbutyrate may require a dose of 900-1200 mg / kg / day to provide 450-600 mg / kg / day of sodium phenylbutyrate), or 9.9-13.0 g / m in a larger patient. 2 In some embodiments, the total daily dose is taken in equal amounts with each meal or diet (i.e., 3-12 times per day).

[0148] solid dosage form for oral use Formulations for oral use include particles containing the active ingredient in a mixture with non-toxic pharmaceutically acceptable excipients, and such formulations are known to those skilled in the art (e.g., U.S. Patent Nos. 5,817,307, 5,824,300, 5,830,456, 5,846,526, 5,882,640, 5,910,304, 6,036,949, 6,036,949, 6,372,218, which are incorporated herein by reference).Some examples of solid dosage forms are shown in Figure 1. Excipients include, for example, inert diluents or fillers (e.g., sucrose, sorbitol, sugar, mannitol, microcrystalline cellulose, starch including potato starch, calcium carbonate, sodium chloride, lactose, calcium phosphate, calcium sulfate, or sodium phosphate); granulating and disintegrating agents (e.g., microcrystalline cellulose, starch including potato starch, croscarmellose sodium, alginates, or alginic acid); binders (e.g., sucrose, glucose, sorbitol, acacia, alginic acid, sodium alginate, gelatin, starch, pregelatinized starch, microcrystalline cellulose, magnesium aluminum silicate, sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, ethylcellulose, polyvinylpyrrolidone, or polyethylene glycol); lubricants, glidants, anti-adherents (e.g., magnesium stearate, zinc stearate, stearic acid, silica, hydrogenated vegetable oil, or talc). Other pharmaceutically acceptable excipients may be colorants, flavorings, plasticizers, humectants, and buffers. In some embodiments, the excipient (e.g., flavoring agent) is packaged with the composition. In some embodiments, the excipient (e.g., flavoring agent) is packaged separately from the composition (e.g., combined with the composition prior to administration).

[0149] The solid compositions of the present invention may include a coating adapted to protect the composition from unwanted chemical changes (e.g., chemical degradation prior to release of the active agent). Coatings may be applied to solid dosage forms in a manner similar to those described in the Encyclopedia of Pharmaceutical Technology, supra.

[0150] Powders and granules may be prepared using the above-mentioned ingredients in a conventional manner, for example using a mixer, fluidized bed equipment, melt-congeal equipment, rotor granulator, extruder / spheronizer or spray dryer.

[0151] Equivalents and Scope Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments in accordance with the invention described herein. The scope of the present invention is not intended to be limited to the above specification, but is instead set forth in the appended claims.

[0152] In the claims, articles such as "a," "an," and "the" may mean one or more unless indicated to the contrary or otherwise clear from the context. A claim or description including "or" between one or more elements of a group is considered satisfied when one, more than one, or all of the group elements are present in, employed in, or otherwise relevant to a given product or process, unless indicated to the contrary or otherwise clear from the context. The invention includes embodiments in which exactly one element of a group is present in, employed in, or otherwise relevant to a given product or process. The invention includes embodiments in which more than one, or all of the group elements are present in, employed in, or otherwise relevant to a given product or process.

[0153] It is also noted that the term "comprising" is intended to be open-ended, allowing for, but not requiring, the inclusion of additional elements or steps. Thus, when the term "comprising" is used herein, the term "consist of" is also included and disclosed.

[0154] Where ranges are given, the endpoints are included. Furthermore, unless otherwise indicated or otherwise apparent from the context and the understanding of one of ordinary skill in the art, numerical values ​​expressed as ranges can take any specific numerical value or subrange within the ranges described in different embodiments of the invention, down to 1 / 10 of the unit of the lower limit of that range, unless the context clearly dictates otherwise.

[0155] Furthermore, any particular embodiment of the present invention that falls within the prior art may be expressly excluded from any one or more claims. Because such embodiments are deemed to be known to those of skill in the art, such embodiments may be excluded even if the exclusion is not expressly stated herein. Any particular embodiment of the compositions of the present invention (e.g., any nucleic acid or protein encoded thereby; any method of production; any method of use; etc.) may be excluded from any one or more claims for any reason, whether or not related to the existence of prior art. [Example]

[0156] Example 1: Preparation of a taste-masked formulation of sodium phenylbutyrate The taste masking material may be prepared using the following methodology.

[0157] Drug Layering Solution A solution of HPMC E 5 and PEG 6000 in pure water is made. A separate solution of sodium phenylbutyrate in pure water is also prepared. The two solutions are then mixed to make the final drug layering solution of HPMC E 5, PEG 6000, and sodium phenylbutyrate in pure water.

[0158] Drug layer coating Cellulose pellets are preheated to 35+ / -2°C in a GPCG-1 fluid bed with a 6" Wurster insert and sprayed with the drug layering solution. The inlet air temperature is adjusted to maintain a product temperature of 35-45°C during coating. After spraying, the coated pellets are dried at 40°C for a minimum of 5 minutes. The product is passed through a 40#-70# screen and stored in a polyethylene bag until the next solution is prepared.

[0159] Seal Coat Solution The seal coat solution is prepared by mixing Opadry Clear in purified water for 30 minutes. While continuing to stir, pass the solution through a 40# screen.

[0160] Seal coat The drug-layered pellets are preheated to 35+ / -2°C in a GPCG-1 fluid bed with a 6" Wurster insert and sprayed with the seal coat solution. The inlet air temperature is adjusted to maintain a product temperature of 35-45°C during coating. After spraying, the coated pellets are dried at 40°C for a minimum of 5 minutes. The product is passed through a screen and stored in a polyethylene bag until the next solution is prepared.

[0161] Taste mask solution Prepare the taste mask coating. Mix 2:3 parts acetone:IPA solution and use half to make a solution of Eudragit E PO. Use the other half of the solution to homogenize the talc and PEG 6000 in a separate beaker. Both solutions are then mixed and then filtered through a 40# screen.

[0162] Taste Mask Covering The seal-coated pellets are preheated to 27 + / - 2°C in a GPCG-1 fluid bed and the taste mask coating is sprayed using a bottom spray. The inlet air temperature is adjusted to maintain a product temperature of 25-28°C during coating. After spraying, the pellets are dried at 40°C for a minimum of 10 minutes and stored in polyethylene bags. A formulation with 24 wt% taste mask coating and 22 wt% drug loading is shown in Table 2. [Table 2]

[0163] In vitro dissolution test A pH 6.8 potassium phosphate buffer (USP) was prepared, and 700 mL of this solution was added to a Distek 2500 USP II (paddle) dissolution apparatus. The bath was heated to 37.5°C, and 1 gm of sodium phenylbutyrate multiparticulates was added while stirring at 100 RPM. A sample of the dissolution medium (1.5 mL) was withdrawn and analyzed on a Shimadzu Prominence-I LC-2030C 3D HPLC system. After a 15-minute sample was taken, 100 mL of 1 N hydrochloric acid solution was added to the dissolution vessel, and the volume was adjusted to 900 mL by adding a pH 1.2, 0.1 N HCl solution (USP). The dissolution test continued for an additional 65 minutes, and the data are shown in Figure 2.

[0164] Example 2: Preparation of a taste-masked formulation of sodium phenylbutyrate The taste masking material was prepared using the methodology described in Example 1 to achieve a formulation with 44 wt% taste mask coating and 16 wt% drug loading. This formulation was subjected to dissolution testing as described in Example 1. Formulation details are provided in Table 3 and dissolution data is provided in Figure 3.

[0165] [Table 3]

[0166] Example 3: Preparation of a taste-masked formulation of sodium phenylbutyrate The taste masking material was prepared using the methodology described in Example 1, with the exception of the seal coat solution and coating process, to achieve a formulation with 31 wt% taste mask coating and 47 wt% drug loading. This formulation was subjected to dissolution testing as described in Example 1. Formulation details are provided in Table 4, and dissolution data is provided in Figure 4.

[0167] [Table 4]

[0168] Example 4: Preparation of a taste-masked formulation of sodium phenylbutyrate The taste masking material was prepared using the methodology described in Example 1, with the exception of the seal coat solution and coating process, to achieve a formulation with 18 wt% taste mask coating and 67 wt% drug loading. This formulation was subjected to dissolution testing as described in Example 1. Formulation details are provided in Table 5, and dissolution data is provided in Figure 5.

[0169] [Table 5]

[0170] Example 5: Preparation of a taste-masked formulation of sodium phenylbutyrate The taste masking material was prepared using the methodology described in Example 1, with the exception of the seal coat solution and coating process, to achieve a formulation with 43 wt% taste mask coating and 47 wt% drug loading. This formulation was subjected to dissolution testing as described in Example 1. Formulation details are provided in Table 6, and dissolution data is provided in Figure 6.

[0171] [Table 6]

[0172] Example 6: Preparation of a taste-masked formulation of sodium phenylbutyrate A taste mask material was prepared using the methodology described in Example 1, substituting the HPMC E 5 and PEG 6000 seal coat solution with Opadry seal coat solution. This modification to Example 1 was used to achieve a formulation with 23 wt% taste mask coating and 61 wt% drug loading. This formulation was subjected to dissolution testing as described in Example 1. Formulation details are provided in Table 7, and dissolution data is provided in Figure 7.

[0173] [Table 7]

[0174] Example 7: Preparation of a taste-masked formulation of sodium phenylbutyrate A taste mask material was prepared using the methodology described in Example 1, substituting the HPMC E 5 and PEG 6000 seal coat solution with Opadry seal coat solution. This modification to Example 1 was used to achieve a formulation with 43 wt% taste mask coating and 45 wt% drug loading. This formulation was subjected to dissolution testing as described in Example 1. Formulation details are provided in Table 8, and dissolution data is provided in Figure 8.

[0175] [Table 8]

[0176] Example 8: Reconstitution with Dosing Vehicle and Administration Sodium phenylbutyrate formulations, such as those prepared in Examples 1-7, may be suspensions in water using a dosing vehicle for oral administration. The dosing vehicle is first prepared by adding 2.5 tps of THICK-IT® to 120 ml of water and stirring. 10 g of the taste masking formulation is added to the dosing vehicle, the mixture is stirred to suspend the beads, and the patient swallows the entire prepared dose. An additional 120 mL of water is added, stirred to suspend any remaining formulation, and then swallowed. This process is repeated for a total of two rinses, rinsing the container twice to ensure all of the taste masking formulation is administered.

[0177] Example 9: Determination of Flavor Profile Sodium phenylbutyrate formulations, such as those prepared in Examples 1-7, can be tested for palatability using any suitable taste test known in the art, for example, by a flavor profile test. The flavor profile method uses trained evaluators, such as a panel of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more experts, to identify, characterize, and quantify the perceived sensory attributes of a formulation.

[0178] The attributes identified by this panel are basic tastes (sweet, sour, salty, bitter, umami), aroma (savory aromas and aromatic "off-notes"), sensory factors (cool, numbness, stinging / burning, etc.), and amplitude (perception of balance and fullness). The perceived strength or intensity of each of these attributes is measured and assigned an appropriate numerical value: 0 = none, 1 = slight, 2 = moderate, and 3 = strong. Chemical reference standards are used to establish the intensity scale for ongoing panelist calibration. In addition, all sensations remaining during the aftertaste are measured at selected intervals of 1 minute, 5 minutes, 10 minutes, 15 minutes, or longer.

[0179] Example 10: Determination of the distribution of sodium phenylbutyrate in plasma A designed Phase 1, single-center, single-dose, randomized, open-label, four-sequence, two-period, crossover study may be used to evaluate the bioequivalence of taste-masked sodium phenylbutyrate formulations to BUPHENYL® in healthy male and female volunteers under fed and fasted conditions. Male and female volunteers were randomized to one of four sequences to determine treatment for each study period. There was a minimum 12-hour washout period between periods. This washout period is considered adequate compared to the reported mean terminal half-life of 0.8 hours for sodium phenylbutyrate in healthy adults.

[0180] At least 64 volunteers will be enrolled in the study, with 16 randomly assigned to each of the study sequences. Informed consent forms will be signed before any study-related procedures are performed. Treatments will be balanced across male and female volunteers.

[0181] The four treatment sequences are as follows in Table 9:

[0182] [Table 9]

[0183] Volunteers will check in to the study facility at least 8 hours before Period 1 (Day 1) and remain at the study facility for two consecutive treatment periods, including a washout period between Periods 1 and 2 (Day 2). In the fasting sequence, volunteers will be required to fast for a minimum of 8 hours before starting treatment (administration of BUPHENYL® or a taste-masked formulation of sodium phenylbutyrate) during each period. In the fed sequence, volunteers will consume a U.S. Food and Drug Administration (FDA) standard high-calorie, high-fat breakfast beginning 30 minutes before administration of the composition before each period. Volunteers will receive an oral dose of a 500 mg taste-masked formulation (per the FDA Draft Guidance on Bioequivalence of Sodium Phenylbutyrate, May 2009). At each dosing period, the composition will be dissolved by gently mixing in 6 ounces of room-temperature tap water. Volunteers will be instructed to consume the solution immediately.

[0184] Each treatment period lasts one day. A blood sampling schedule facilitates the measurement of baseline and post-dose plasma phenylbutyric acid levels for each period, and the results are used to estimate non-compartmental pharmacokinetic (PK) parameters. Blood samples for measurement of plasma concentrations of phenylbutyric acid and phenylbutyric acid metabolites are obtained pre-dose and at 0.25, 0.5, 0.75, 1.0, 1.5, 2.0, 2.5, 3.0, 4.0, and 8.0 hours post-dose for each study period. Concentrations of phenylbutyric acid and phenylbutyric acid metabolites in the blood samples are measured using a validated liquid chromatography-tandem mass spectrometry (LC-MS / MS) method. Blood samples may be stored for PK analysis for up to 12 months after the end of the study.

[0185] Phenybutyric acid and phenylbutyric acid metabolites in volunteers given either the taste masked formulation or BUPHENYL® in fed (Sequences A and B) and fasted (Sequences C and D) states are compared to establish a 90% bioequivalence interval.

[0186] Safety will be assessed based on the occurrence of adverse events and clinically significant changes in laboratory results (chemistry, hematology, and urinalysis).

[0187] Other embodiments While the present disclosure has been described in conjunction with the detailed description of the invention of the present disclosure, it should be understood that the foregoing description is intended to illustrate, but not to limit, the scope of the present disclosure, which is defined by the appended claims. Other aspects, advantages, and modifications are within the scope of the following claims.

Claims

1. 1. A pharmaceutical composition for oral administration of sodium phenylbutyrate, comprising 15 to 65% by total weight of said sodium phenylbutyrate, and 5 to 50% by total weight of said taste masking coating comprising a polymer formed from dimethylaminoethyl methacrylate, butyl methacrylate, and methyl methacrylate.

2. 10. The pharmaceutical composition of claim 1, formulated as a plurality of spray-layered beads comprising a seed core, a drug layer comprising said sodium phenylbutyrate, and said taste mask coating.

3. 3. The pharmaceutical composition of claim 2, wherein the drug layer further comprises 3 to 10% by total weight of a binder.

4. 4. The pharmaceutical composition of claim 3, wherein the binder is HPMC E5.

5. The pharmaceutical composition according to any one of claims 2 to 4, wherein the drug layer further comprises 0.1% to 1% by total weight of a plasticizer.

6. 6. The pharmaceutical composition of claim 5, wherein the plasticizer is polyethylene glycol.

7. 7. The pharmaceutical composition of claim 6, wherein the polyethylene glycol is PEG6000.

8. 8. The pharmaceutical composition of any one of claims 1 to 7, wherein the taste mask coating further comprises 1 to 9% by total weight of a plasticizer.

9. 9. The pharmaceutical composition of claim 8, wherein the plasticizer is polyethylene glycol.

10. 10. The pharmaceutical composition of claim 9, wherein the polyethylene glycol is PEG6000.

11. 11. The pharmaceutical composition of any one of claims 1 to 10, wherein the taste mask coating further comprises 4-15% by total weight of hydrated magnesium silicate.

12. 12. The pharmaceutical composition of claim 11, wherein the hydrated magnesium silicate is talc.

13. 13. The pharmaceutical composition of any one of claims 1 to 12, wherein the taste mask coating comprises 5 to 30% by total weight of a polymer formed from dimethylaminoethyl methacrylate, butyl methacrylate and methyl methacrylate.

14. 14. The pharmaceutical composition according to any one of claims 2 to 13, comprising 1 to 50% of the seed cores by total weight.

15. 15. The pharmaceutical composition of claim 14, wherein the seed core comprises microcrystalline cellulose.

16. 16. The pharmaceutical composition according to any one of claims 1 to 15, further comprising a seal coat in an amount of 1 to 5% based on the total weight including polyvinyl alcohol.

17. 17. The pharmaceutical composition of claim 16, wherein the polyvinyl alcohol is Opadry.

18. 18. The pharmaceutical composition of claim 17, wherein the Opadry is Opadry Clear.

19. 19. The pharmaceutical composition of any one of claims 1 to 18, comprising 15 to 65% of said taste masking coating by total weight.

20. 20. The pharmaceutical composition according to any one of claims 1 to 19, comprising 15 to 35% sodium phenylbutyrate by total weight.

21. 21. The pharmaceutical composition according to any one of claims 1 to 20, comprising 15 to 25% sodium phenylbutyrate by total weight.

22. 22. The pharmaceutical composition of any one of claims 2 to 21, having a particle size distribution based on volume such that 90% of the sample is smaller than 500 μm.

23. A taste-masked pharmaceutical composition comprising sodium phenylbutyrate and a pharmaceutically acceptable carrier, wherein (i) less than 15% of the sodium phenylbutyrate in the pharmaceutical composition dissolves in 10 minutes at neutral pH in a transition dissolution test, and (ii) at least 95% of the sodium phenylbutyrate in the pharmaceutical composition dissolves in 60 minutes at acidic pH in a transition dissolution test.

24. 24. The pharmaceutical composition of claim 23, comprising a taste mask coating comprising a polymer formed from dimethylaminoethyl methacrylate, butyl methacrylate, and methyl methacrylate.

25. 25. The pharmaceutical composition of claim 23 or 24, comprising 50% by total weight of the taste masking coating.

26. 26. The pharmaceutical composition according to any one of claims 23 to 25, comprising 15 to 60% sodium phenylbutyrate by total weight.

27. 27. The pharmaceutical composition according to any one of claims 23 to 26, comprising 3 to 10% by total weight of a binder.

28. 28. The pharmaceutical composition according to any one of claims 23 to 27, comprising 0.1 to 7% by total weight of a plasticizer.

29. The pharmaceutical composition according to any one of claims 23 to 27, which is free of plasticizers.

30. 30. The pharmaceutical composition according to any one of claims 23 to 29, comprising 4 to 15% by total weight of hydrated magnesium silicate.

31. 31. The pharmaceutical composition according to any one of claims 23 to 30, comprising 1 to 5% of a seal coat based on the total weight including the water-soluble polymer.

32. 32. The pharmaceutical composition of any one of claims 23 to 31, formulated as a plurality of spray-layered beads.

33. 33. The pharmaceutical composition of any one of claims 23 to 32, having a particle size distribution based on volume such that 90% of the sample is smaller than approximately 500 μm.

34. 24. The pharmaceutical composition of any one of claims 1 to 23, wherein less than 15% of the sodium phenylbutyrate in the composition dissolves in 10 minutes at neutral pH in a transition dissolution test.

35. 35. The pharmaceutical composition of claim 34, wherein less than 10% of the sodium phenylbutyrate in the composition dissolves in 10 minutes at neutral pH in a transition dissolution test.

36. 24. The pharmaceutical composition of any one of claims 1 to 23, wherein at least 95% of the sodium phenylbutyrate in the composition dissolves in 60 minutes at acidic pH in a transition dissolution test.

37. 37. The pharmaceutical composition of claim 36, wherein at least 95% of the sodium phenylbutyrate in the composition dissolves in 30 minutes at acidic pH in a transition dissolution test.

38. 38. The pharmaceutical composition of any one of claims 1 to 37, wherein, upon administration to a subject, the composition has equivalent distribution in plasma compared to BUPHENYL®.

39. 39. The pharmaceutical composition of any one of claims 1 to 38, wherein upon administration to a subject, the composition has a greater concentration of sodium phenylbutyrate in plasma at 30 minutes compared to a modified release formulation of sodium phenylbutyrate.

40. 40. The pharmaceutical composition of any one of claims 1 to 39, wherein the composition scores better in taste tests compared to BUPHENYL®.

41. 1. A method for producing a pharmaceutical composition comprising sodium phenylbutyrate, comprising the steps of: a. providing a core comprising cellulose pellets; b. applying a first layer comprising sodium phenylbutyrate, hydroxypropyl methylcellulose, and polyethylene glycol; c. applying a second layer comprising polyvinyl alcohol; and d. applying a third layer comprising a polymer formed from dimethylaminoethyl methacrylate, butyl methacrylate, and methyl methacrylate, polyethylene glycol, and hydrated magnesium silicate. thereby producing a pharmaceutical composition comprising sodium phenylbutyrate.

42. 42. The method of claim 41, wherein the pharmaceutical composition comprises a core comprising 1 to 50% cellulose pellets by total weight.

43. 43. The method of claim 41 or 42, wherein the composition comprises 20-60% by total weight of sodium phenylbutyrate, 3-10% by total weight of hydroxypropyl methylcellulose, and less than 1% by total weight of polyethylene glycol.

44. 44. The method of any one of claims 41 to 43, wherein the composition comprises a second layer comprising 3 to 5% polyvinyl alcohol by total weight.

45. 45. The method of any one of claims 41 to 44, wherein the composition comprises a third layer comprising 10 to 15% by total weight of a polymer formed from dimethylaminoethyl methacrylate, butyl methacrylate, and methyl methacrylate, 3 to 10% by total weight of polyethylene glycol, and 4 to 15% by total weight of hydrated magnesium silicate.

46. 46. ​​The method of any one of claims 41 to 45, wherein the first layer is applied in water.

47. A method according to any one of claims 41 to 46, wherein the second layer is applied in water.

48. 48. The method of any one of claims 41 to 47, wherein the third layer is applied in an organic solvent.

49. 49. The method of claim 48, wherein the organic solvent is a solution of acetone and isopropyl alcohol.

50. 50. The method of any one of claims 41 to 49, wherein the hydroxypropyl methylcellulose is HPMC E 5.

51. 51. The method of any one of claims 41 to 50, wherein the polyvinyl alcohol is Opadry Clear.

52. 52. The method of any one of claims 41 to 51, wherein the polyethylene glycol is PEG6000.

53. 53. The method of any one of claims 41 to 52, wherein the hydrated magnesium silicate is talc.

54. A pharmaceutical composition prepared by the method of any one of claims 41 to 53.

55. 55. A method of treating an inborn error of metabolism in a subject, comprising administering an effective amount of the pharmaceutical composition of any one of claims 1 to 40 or 54.

56. 56. The method of claim 55, wherein the inborn error of metabolism is maple syrup urine disease.

57. 56. The method of claim 55, wherein the inborn error of metabolism is a urea cycle disorder.

58. 55. A method of treating a neurodegenerative disorder in a subject, comprising administering an effective amount of the pharmaceutical composition of any one of claims 1 to 40 or 54.

59. 59. The method of claim 58, wherein the neurodegenerative disorder is Parkinson's disease.

60. 55. A method of treating spinal muscular atrophy in a subject, comprising administering an effective amount of the pharmaceutical composition of any one of claims 1-40 or 54.

61. 55. A method of treating inclusion body myositis in a subject, comprising administering an effective amount of the pharmaceutical composition of any one of claims 1-40 or 54.

62. 55. A method of treating dystonia in a subject, comprising administering an effective amount of the pharmaceutical composition of any one of claims 1 to 40 or 54.

63. 63. The method of any one of claims 55 to 62, wherein the subject is a human.

64. 64. The method of any one of claims 55 to 63, wherein the composition is administered in combination with a dosing vehicle and a liquid such that the final viscosity is in the range of approximately 50 to 1750 cP.

65. 65. The method of claim 64, wherein the liquid is water.

66. 66. The method of claim 64 or 65, wherein the dosing vehicle is a combination of modified food starch and maltodextrin.

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