PALATABLE COMPOSITIONS INCLUDING SODIUM PHENYLBUTYRATE AND USES THEREOF

Abstract

The present invention features palatable pharmaceutical compositions including sodium phenylbutyrate and methods for the treatment of inborn errors of metabolism (e.g., Maple Syrup Urine Disease or Urea Cycle Disorders), neurodegenerative disorders such as Parkinson's disease, spinal muscular atrophy, dystonia, or inclusion-body myositis with such compositions.

Claims

1-30. (canceled)

31. A pharmaceutical composition for oral administration of sodium phenylbutyrate comprising a plurality of layered particles, wherein each layered particle comprises (i) a substrate; (ii) a drug layer comprising the sodium phenylbutyrate; and (iii) a taste-mask coating insoluble at a pH of greater than 5, wherein the pharmaceutical composition comprises greater than 60% by total weight sodium phenylbutyrate.

32. The pharmaceutical composition of claim 31, wherein each of the plurality of layered particles has a size from about 100 μm to 1,500 μm.

33. The pharmaceutical composition of claim 31, wherein the plurality of layered particles comprises a volume-based particle size distribution in which at least 90% of the layered particles in the plurality of layered particles are smaller than 500 μm.

34. The pharmaceutical composition of claim 31, wherein the substrate is a seed core.

35. The pharmaceutical composition of claim 31, further comprising a seal coating.

36. The pharmaceutical composition of claim 31, wherein the drug layer comprises the sodium phenylbutyrate, a binder, and a plasticizer.

37. The pharmaceutical composition of claim 31, wherein the taste-mask coating is insoluble at a pH of 6.5-7.5.

38. The pharmaceutical composition of claim 31, wherein the taste-mask coating is soluble at an acidic pH of less than 2.

39. The pharmaceutical composition of claim 31, wherein the pharmaceutical composition comprises at least 5% by total weight taste-mask coating.

40. The pharmaceutical composition of claim 31, wherein the taste-mask coating comprises a polymer.

41. The pharmaceutical composition of claim 31, wherein the taste-mask coating comprises a polymer formed from dimethylaminoethyl methacrylate, butyl methacrylate, and methyl methacrylate.

42. The pharmaceutical composition of claim 31, wherein the taste-mask coating further comprises a hydrated magnesium silicate and/or a plasticizer.

43. The pharmaceutical composition of claim 31, further comprising a glidant.

44. The pharmaceutical composition of claim 31, wherein the composition is a powder, granules, or a tablet.

45. The pharmaceutical composition of claim 31, wherein upon administration to a subject, said composition has an equivalent distribution in plasma compared to a sodium phenylbutyrate formulation that does not comprise a taste-mask coating.

46. The pharmaceutical composition of claim 31, wherein upon administration to a subject, said composition has greater sodium phenylbutyrate levels in the plasma at 30 minutes compared to a modified release formulation of sodium phenylbutyrate.

47. A method of treating an inborn error of metabolism in a subject, the method comprising orally administering the pharmaceutical composition of claim 31.

48. The method of claim 47, wherein the subject is human.

49. The method of claim 47, wherein (i) subjects under 20 kg are administered 450-600 mg/kg/day of sodium phenylbutyrate; and (ii) subjects over 20 kg are administered 9.9-13.0 g/m2/day of sodium phenylbutyrate.

50. The method of claim 47, wherein the inborn error of metabolism is a urea cycle disorder or maple syrup disease.

Description

BRIEF DESCRIPTION OF THE FIGURES

[0122] FIG. 1A is a schematic of a taste-masked particle with a seed core.

[0123] FIG. 1B is a schematic of a taste-masked particle with a drug containing core.

[0124] FIG. 1C is a schematic of a taste-masked tablet.

[0125] FIG. 2 is a graph illustrating drug release in a transfer dissolution test over time.

[0126] FIG. 3 is a graph illustrating drug release in a transfer dissolution test over time.

[0127] FIG. 4 is a graph illustrating drug release in a transfer dissolution test over time.

[0128] FIG. 5 is a graph illustrating drug release in a transfer dissolution test over time.

[0129] FIG. 6 is a graph illustrating drug release in a transfer dissolution test over time.

[0130] FIG. 7 is a graph illustrating drug release in a transfer dissolution test over time.

[0131] FIG. 8 is a graph illustrating drug release in a transfer dissolution test over time.

DETAILED DESCRIPTION OF THE INVENTION

[0132] The invention described herein features taste-masked formulations of sodium phenylbutyrate and methods of using the formulations in the treatment of inborn errors of metabolism such as MSUD and UCD, neurodegenerative disorders such as Parkinson's disease, spinal muscular atrophy, inclusion-body myositis, or dystonia. The formulations of sodium phenylbutyrate of the invention address known issues with treatment noncompliance, due to poor taste, and consequent insufficient dosing with 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, e.g., as measured in the plasma of a subject. In some embodiments, the formulations include a high drug load.

Methods of Producing Taste-Masked Compositions

[0133] Taste-masked materials may be prepared by first identifying a suitable seed core such as cellulose pellets, followed by preparation of a solution including sodium phenylbutyrate. The sodium phenylbutyrate containing solution may be prepared by combing in 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 than applied to the seed core by spraying, followed by drying and storage of the coated pellets.

[0134] A seal coat solution is prepared by mixing Opadry Clear in purified water, followed by application onto the dried drug-containing pellets by spraying. The pellets with the seal coat are then dried and stored.

[0135] A taste mask coating solution is then prepared in a 2:3 parts 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 a polymer formed from dimethylaminoethyl methacrylate, butyl methacrylate, and methyl methacrylate (e.g., Eudragit E PO) is then combined with another solution containing homogenized talc and PEG 6000.

[0136] The taste-mask coating solution is then applied to the seal coated pellets by spraying. Subsequent drying of the pellets results in the finished powder taste-masked formulation. In some embodiments, the final composition (e.g., spray-layered beads) is blended with a lubricant such as silica, e.g., to prevent agglomeration of the composition.

[0137] Prior to administration, the taste-masked formulation may be combined with a dosing vehicle that contains various pharmaceutically acceptable excipients such as viscosity modifiers, suspending or dispering agents, flavoring agents, fragrances, dyes (colors), sweeteners, anti-caking agents, glidants (flow enhancers), and lubricants.

[0138] The dosing vehicle may be mixed with the taste-masked formulation and added to water and stirred, or the dosing vehicle may be added first to the water and mixed before addition of the taste-masked formulation.

[0139] Other palatable liquids may be used instead of water provided that the pH of the liquid is ≥6.

Methods of Treatment

[0140] The present invention features pharmaceutical compositions in an orally tolerable formula that contains a therapeutically effective amount of sodium phenylbutyrate. In some embodiments the pharmaceutical composition is a granular formulation that is dispersed in a pharmaceutically acceptable carrier, for example the composition can be mixed into water and ingested by a patient (e.g., over the course of 5 to 10 minutes). Suitable formulations for use in the present invention are found in Remington's Pharmaceutical Sciences, Mack Publishing Company, Philadelphia, Pa. 22.sup.nd ed., 2010. Except insofar as any conventional carrier is incompatible with the active ingredient, its use in the pharmaceutical compositions is contemplated. Moreover, for animal (e.g., human) administration, it will be understood that preparations should meet sterility, pyrogenicity, general safety and purity standards as required by FDA Office of Biological Standards.

[0141] The actual dosage amount of a composition of the present invention administered to a patient can be determined by physical and physiological factors such as body weight, severity of condition, the type of disease being treated, previous or concurrent therapeutic interventions, idiopathy of the patient and on the route of administration. Depending upon the dosage and the route of administration, the number of administrations of a preferred dosage and/or an effective amount may vary according to the response of the subject. The practitioner responsible for administration will, in any event, determine the concentration of active ingredient(s) in a composition and appropriate dose(s) for the individual subject.

Maple Syrup Urine Disease

[0142] For the treatment of MSUD the actual dosage amount can be determined, in part, by measuring the levels of branched chain amino acids (BCAAs) in the plasma and adjusting dosage to decrease the plasma level of at least one BCAA to within a range that is accepted to be non-toxic and supports optimal growth and development (Table 1).

TABLE-US-00001 TABLE 1 Target Ranges for BCAAs Branched Chain Target Levels Normal Reference Range Amino Acid (μmol/L) (μmol/L) Leucine 200-500 65-220 Isoleucine 100-200 26-100 Valine 100-300 90-300

Urea Cycle Disorders

[0143] Sodium phenyl butyrate is approved as an adjunctive therapy in the chronic management of subjects with UCD. Sodium phenylbutyrate is indicated for all patients with neonatal-onset deficiency and subjects with late-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 acids supplementation.

[0144] The usual total daily dose of BUPHENYL® Tablets and Powder for patients with urea cycle disorders is 450-600 mg/kg/day in patients weighing less than 20 kg, or 9.9-13.0 g/m.sup.2/day in larger patients. The tablets and powder are to be taken in equally divided amounts with each meal or feeding (i.e., three to six times per day). In some embodiments, the pharmaceutical compositions of the present invention are bioequivalent to BUPHENYL® and, therefore, equivalent dosage of sodium phenylbutyrate would be likely be useful for the treatment of UCD.

Spinal Muscular Atrophy

[0145] Sodium phenyl butyrate has been investigated 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, divided into four doses. In some embodiments, the pharmaceutical compositions of the present invention are bioequivalent to BUPHENYL® and, therefore, equivalent dosage of sodium phenylbutyrate would be likely be useful for the treatment of spinal muscular atrophy.

Parkinson's Disease

[0146] For the treatment of Parkinson's disease the actual dosage amount can be determined, in part, by measuring the levels of biomarkers (e.g., the expression level of the gene DJ-1 as described in Zhou W. et al. J. Biol. Chem. 2011, 286(17), pages 14941-14951) in the blood and adjusting dosage accordingly (e.g., to increase the expression level of DJ-1 without resulting in side effects).

Inclusion-Body Myositis

[0147] For the treatment of inclusion-body myositis, the actual dosage amount can be determined by measuring the levels of biomarkers, e.g., by measuring the lysosomal activity, amount of Aβ42 and its oligomers, γ-secretase activity, and/or muscle-fiber vacuolization as described in Nogalska et al.

Dystonia

[0148] For the treatment of dystonia, the actual dosage amount can be determined by measuring the levels of biomarkers, e.g., by measuring ER stress and/or the cyclic adenosine-3′, 5′-monophosphate (cAMP) response to the adenylate cyclase agonist forskolin as described in Cho et al.

Dosages

[0149] The dosage of any composition described herein or identified using the methods described herein depends on several factors, including: the administration method, the disease (e.g., MSUD, UCD, Parkinson's disease, spinal muscular atrophy, inclusion-body myositis, or dystonia) to be treated, the severity of the disease, and the age, weight, and health of the subject to be treated.

[0150] With respect to the treatment methods of the invention, it is not intended that the administration of a composition to a subject be limited to a particular dosage, or frequency of dosing. The composition may be administered to the subject in a single dose or in multiple doses. For example, a composition described herein may be administered at least once a day (e.g., twice a day, three times a day, four times a day, or more). It is to be understood that, for any particular subject, specific dosage regimes should be adjusted over time according to the individual need and the professional judgment of the person administering or supervising the administration of the composition. For example, the dosage of a composition can be increased if the lower dose does not provide sufficient activity in the treatment of a disease or condition described herein (e.g., MSUD, UCD, Parkinson's disease, spinal muscular atrophy, inclusion-body myositis, or dystonia). Conversely, the dosage of the composition can be decreased if the disease (e.g., MSUD, UCD, Parkinson's disease, spinal muscular atrophy, inclusion-body myositis, or dystonia) is reduced.

[0151] While the attending physician ultimately will decide the appropriate amount and dosage regimen, a therapeutically effective amount of a composition described herein, may be, for example, in the range of approximately 450-600 mg/kg/day of sodium phenylbutyrate (e.g., a composition including 50% by weight sodium phenylbutyrate would require a dose of 900-1200 mg/kg/day to provide 450-600 mg/kg/day of sodium phenylbutyrate) for urea cycle disorder patients weighing less than 20 kg, or 9.9-13.0 g/m.sup.2/day in larger patients. In some embodiments the total daily dosage is to be taken in equally divided amounts with each meal or feeding (i.e., three to six times per day).

[0152] In some embodiments a therapeutically effective amount of a composition described herein, may be, for example, in the range of approximately 450-600 mg/kg/day of sodium phenylbutyrate (e.g., a composition including 50% by weight sodium phenylbutyrate would require a dose of 900-1200 mg/kg/day to provide 450-600 mg/kg/day of sodium phenylbutyrate) in MSUD patients weighing less than 20 kg, or 9.9-13.0 g/m.sup.2/day in larger patients. In some embodiments the total daily dosage is to be taken in equally divided amounts with each meal or feeding (i.e., three to twelve times per day).

Solid Dosage Forms for Oral Use

[0153] Formulations for oral use include particles containing the active ingredient(s) in a mixture with non-toxic pharmaceutically acceptable excipients, and such formulations are known to the skilled artisan (e.g., U.S. Pat. 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, hereby incorporated by reference). Some examples of solid dosage forms are shown in FIG. 1. Excipients may be, for example, inert diluents or fillers (e.g., sucrose, sorbitol, sugar, mannitol, microcrystalline cellulose, starches including potato starch, calcium carbonate, sodium chloride, lactose, calcium phosphate, calcium sulfate, or sodium phosphate); granulating and disintegrating agents (e.g., cellulose derivatives including microcrystalline cellulose, starches including potato starch, croscarmellose sodium, alginates, or alginic acid); binding agents (e.g., sucrose, glucose, sorbitol, acacia, alginic acid, sodium alginate, gelatin, starch, pregelatinized starch, microcrystalline cellulose, magnesium aluminum silicate, carboxymethylcellulose sodium, methylcellulose, hydroxypropyl methylcellulose, ethylcellulose, polyvinylpyrrolidone, or polyethylene glycol); and lubricating agents, glidants, and anti-adhesives (e.g., magnesium stearate, zinc stearate, stearic acid, silicas, hydrogenated vegetable oils, or talc). Other pharmaceutically acceptable excipients can be colorants, flavoring agents, plasticizers, humectants, and buffering agents. In some embodiments, excipients (e.g., flavoring agents) are packaged with the composition. In some embodiments, excipients (e.g., flavorings) are packaged separately from the composition (e.g., are combined with the composition prior to administration).

[0154] The solid compositions of the invention may include a coating adapted to protect the composition from unwanted chemical changes, (e.g., chemical degradation prior to the release of the active substances). The coating may be applied on the solid dosage form in a similar manner as that described in Encyclopedia of Pharmaceutical Technology, supra.

[0155] Powders and granulates may be prepared using the ingredients mentioned above in a conventional manner using, e.g., a mixer, a fluid bed apparatus, melt congeal apparatus, rotor granulator, extrusion/spheronizer, or spray drying equipment.

EQUIVALENTS AND SCOPE

[0156] 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 Description, but rather is as set forth in the appended claims.

[0157] In the claims, articles such as “a,” “an,” and “the” may mean one or more than one unless indicated to the contrary or otherwise evident from the context. Claims or descriptions that include “or” between one or more members of a group are considered satisfied if one, more than one, or all of the group members are present in, employed in, or otherwise relevant to a given product or process unless indicated to the contrary or otherwise evident from the context. The invention includes embodiments in which exactly one member of the 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 members are present in, employed in, or otherwise relevant to a given product or process.

[0158] It is also noted that the term “comprising” is intended to be open and permits but does not require the inclusion of additional elements or steps. When the term “comprising” is used herein, the term “consisting of” is thus also encompassed and disclosed.

[0159] Where ranges are given, endpoints are included. Furthermore, it is to be understood that unless otherwise indicated or otherwise evident from the context and understanding of one of ordinary skill in the art, values that are expressed as ranges can assume any specific value or subrange within the stated ranges in different embodiments of the invention, to the tenth of the unit of the lower limit of the range, unless the context clearly dictates otherwise.

[0160] In addition, it is to be understood that any particular embodiment of the present invention that falls within the prior art may be explicitly excluded from any one or more of the claims. Since such embodiments are deemed to be known to one of ordinary skill in the art, they may be excluded even if the exclusion is not set forth explicitly herein. Any particular embodiment of the compositions of the invention (e.g., any nucleic acid or protein encoded thereby; any method of production; any method of use; etc.) can be excluded from any one or more claims, for any reason, whether or not related to the existence of prior art.

EXAMPLES

Example 1. Preparation of Taste-Masked Formulations of Sodium Phenylbutyrate

[0161] Taste-masked materials may be prepared using the following methodology.

Drug Layering Solution

[0162] A solution of HPMC E 5 and PEG 6000 in purified water is made. A separate solution of sodium phenylbutyrate in purified water is also prepared. The two solutions are then combined to create the final drug layering solution of HPMC E 5, PEG 6000, and sodium phenylbutyrate in purified water.

Drug Layer Coating

[0163] Cellulose pellets are preheated to 35+/−2° C. in a GPCG-1 fluid bed with a 6″ Wurster insert, and the drug layering solution is sprayed. Inlet air temperature is adjusted to maintain product temperature at 35-45 C during coating. After spraying, the coated pellets are dried for a minimum of 5 minutes at 40° C. The product is passed through 40#-70#screen, and stored in a polyethylene bag until the next solution is prepared.

Seal Coat Solution

[0164] A seal coat solution is prepared by mixing Opadry Clear in purified water for 30 minutes. The solution is passed through a 40#screen while being continuously stirred.

Seal Coating

[0165] The drug layered pellets are preheated to 35+/−2° C. in the GPCG-1 fluid bed with a 6″ Wurster insert, and the seal coat solution is sprayed. Inlet air temperature is adjusted to maintain product temperature at 35-45° C. during coating. After spraying, the coated pellets are dried for a minimum of 5 minutes at 40° C. The product is passed through screen, and stored in a polyethylene bag until the next solution is prepared.

Taste-Mask Solution

[0166] A taste mask coating is prepared. A 2:3 parts acetone:IPA solution is mixed, and half is used to create a solution of Eudragit E PO. In a separate beaker the other half of solution is used to homogenize talc and PEG 6000. Both solutions are then combined before being filtered through a 40#screen.

Taste-Mask Coating

[0167] The seal coated pellets are preheated to 27+/−2° C. in the GPCG-1 fluid bed, and the taste mask coating is sprayed using bottom spray. Inlet air temperature is adjusted to maintain product temperature at 25-28° C. during coating. After spraying, the pellets are dried for a minimum of 10 minutes at 40° C., and stored in a polyethylene bag. A formulation with a 24 wt % taste-mask coat and 22 wt % drug load is presented in Table 2.

TABLE-US-00002 TABLE 2 Taste-mask coated formulation (24 wt % taste-mask coat, 22 wt % drug load) Layer Ingredient mg/g Seed core Microcrystalline cellulose pellets 443.6 Drug layer Sodium phenylbutyrate 221.8 HPMC E 5 55.5 PEG 6000 5.5 (H2O) — Seal coat Opadry Clear 31.1 (H2O) — Taste-mask coat Eudragit E PO 151.5 PEG 6000 15.5 Talc 75.8 (acetone) — (isopropyl alcohol) —

In Vitro Dissolution Testing

[0168] A pH 6.8 potassium phosphate buffer solution (USP) was prepared, and 700 mL of the 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 being agitated at 100 RPM. Samples of the dissolution media (1.5 mL) were collected and drug release was measured with a Shimadzu Prominence-I LC-2030C 3D HPLC system. 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 a pH 1.2 0.1 N HCl solution (USP). The dissolution test continued for another 65 minutes, and data is presented in FIG. 2.

Example 2. Preparation of a Taste-Masked Formulation of Sodium Phenylbutyrate

[0169] Taste-masked materials were prepared using the methodology described in Example 1 to achieve a formulation with a 44 wt % taste-mask coat and 16 wt % drug load. This formulation was dissolution tested as described in Example 1. The details of the formulation are presented in Table 3, and dissolution data is presented in FIG. 3.

TABLE-US-00003 TABLE 3 Taste-mask coated formulation (44 wt % taste-mask coat, 16 wt % drug load) Layer Ingredient mg/g Seed core Microcrystalline cellulose pellets 325.3 Drug layer Sodium phenylbutyrate 162.7 HPMC E 5 40.7 PEG 6000 4.1 (H2O) — Seal coat Opadry Clear 22.8 (H2O) — Taste-mask coat Eudragit E PO 277.8 PEG 6000 27.7 Talc 138.9 (acetone) — (isopropyl alcohol) —

Example 3. Preparation of a Taste-Masked Formulation of Sodium Phenylbutyrate

[0170] Taste-masked materials were prepared using the methodology described in Example 1, without the seal coat solution or coating steps, to achieve a formulation with a 31 wt % taste-mask coat and 47 wt % drug load. This formulation was dissolution tested as described in Example 1. The details of the formulation are presented in Table 4, and dissolution data is presented in FIG. 4.

TABLE-US-00004 TABLE 4 Taste-mask coated formulation (31 wt % taste-mask coat, 47 wt % drug load) Layer Ingredient mg/g Seed core Microcrystalline cellulose pellets 161.4 Drug layer Sodium phenylbutyrate 473.8 HPMC E 5 47.4 PEG 6000 7.1 (H2O) — Taste-mask coat Eudragit E PO 206.9 PEG 6000 20.6 Talc 82.8 (acetone) — (isopropyl alcohol) —

Example 4. Preparation of a Taste-Masked Formulation of Sodium Phenylbutyrate

[0171] Taste-masked materials were prepared using the methodology described in Example 1, without the seal coat solution or coating steps, to achieve a formulation with an 18 wt % taste-mask coat and 67 wt % drug load. This formulation was dissolution tested as described in Example 1. The details of the formulation are presented in Table 5, and dissolution data is presented in FIG. 5.

TABLE-US-00005 TABLE 5 Taste-mask coated formulation (18 wt % taste-mask coat, 67 wt % drug load) Layer Ingredient mg/g Seed core Microcrystalline cellulose pellets 73.2 Drug layer Sodium phenylbutyrate 669.5 HPMC E 5 67.0 PEG 6000 6.7 (H2O) — Taste-mask coat Eudragit E PO 122.5 PEG 6000 12.2 Talc 49.0 (acetone) — (isopropyl alcohol) —

Example 5. Preparation of a Taste-Masked Formulation of Sodium Phenylbutyrate

[0172] Taste-masked materials were prepared using the methodology described in Example 1, without the seal coat solution or coating steps, to achieve a formulation with a 43 wt % taste-mask coat and 47 wt % drug load. This formulation was dissolution tested as described in Example 1. The details of the formulation are presented in Table 6, and dissolution data is presented in FIG. 6.

TABLE-US-00006 TABLE 6 Taste-mask coated formulation (43 wt % taste-mask coat, 47 wt % drug load) Layer Ingredient mg/g Seed core Microcrystalline cellulose pellets 51.2 Drug layer Sodium phenylbutyrate 468.7 HPMC E 5 46.9 PEG 6000 4.7 (H2O) — Taste-mask coat Eudragit E PO 285.7 PEG 6000 28.5 Talc 114.3 (acetone) — (isopropyl alcohol) —

Example 6. Preparation of a Taste-Masked Formulation of Sodium Phenylbutyrate

[0173] Taste-masked materials were prepared using the methodology described in Example 1, substituting a HPMC E 5 and PEG 6000 seal coat solution with the Opadry seal coat solution. The change to Example 1 was used to achieve a formulation with a 23 wt % taste-mask coat and 61 wt % drug load. This formulation was dissolution tested as described in Example 1. The details of the formulation are presented in Table 7, and dissolution data is presented in FIG. 7.

TABLE-US-00007 TABLE 7 Taste-mask coated formulation (23 wt % taste-mask coat, 61 wt % drug load) Layer Ingredient mg/g Seed core Microcrystalline cellulose pellets 66.3 Drug layer Sodium phenylbutyrate 606.6 HPMC E 5 60.7 PEG 6000 6.0 (H2O) — Seal coat HPMC E 5 26.4 PEG 6000 3.2 (H2O) — Taste-mask coat Eudragit E PO 153.9 PEG 6000 15.4 Talc 61.5 (acetone) — (isopropyl alcohol) —

Example 7. Preparation of a Taste-Masked Formulation of Sodium Phenylbutyrate

[0174] Taste-masked materials were prepared using the methodology described in Example 1, substituting a HPMC E 5 and PEG 6000 seal coat solution with the Opadry seal coat solution. The change to Example 1 was used to achieve a formulation with an 43 wt % taste-mask coat and 45 wt % drug load. This formulation was dissolution tested as described in Example 1. The details of the formulation are presented in Table 8, and dissolution data is presented in FIG. 8.

TABLE-US-00008 TABLE 8 Taste-mask coated formulation (43 wt % taste-mask coat, 45 wt % drug load) Layer Ingredient mg/g Seed core Microcrystalline cellulose pellets 49.3 Drug layer Sodium phenylbutyrate 450.6 HPMC E 5 45.1 PEG 6000 4.5 (H2O) — Seal coat HPMC E 5 19.6 PEG 6000 2.4 (H2O) — Taste-mask coat Eudragit E PO 285.7 PEG 6000 28.5 Talc 114.3 (acetone) — (isopropyl alcohol) —

Example 8. Reconstitution with Dosing Vehicle and Administration

[0175] A formulation of sodium phenylbutyrate, e.g., the formulation prepared in Examples 1-7, can be suspension in water with the aid of a dosing vehicle for oral administration. The dosing vehicle is first prepared by adding 2.5 tsp of THICK-IT® to 120 mL of water and agitating. To this dosing vehicle are added 10 g of the taste-masked formulation, the mixture is agitated to suspend the beads, and the entire prepared dose is swallowed by the patient. The container is rinsed twice to ensure all of the taste-masked formulation is administered by adding an additional 120 mL of water, agitating to suspend any remaining formulation, and then swallowing; this process is repeated for a total of two rinses.

Example 9. Determination of Flavor Profile

[0176] A formulation of sodium phenylbutyrate, e.g., the formulation prepared in Examples 1-7, can be tested for palatability using any appropriate 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.

[0177] Attributes identified by the panel are basic tastes (sweet, sour, salty, bitter, umami), aromatics (flavoring aromatics and aromatic “off-notes”), feeling factors (cooling, numbing, bite/burn, etc.), and amplitude (perception of balance and fullness). The perceived strength or intensity of each of these attributes will be measured and assigned an appropriate value: 0 for none, 1 for slight, 2 for moderate, and 3 for strong. Chemical reference standards are used to establish the intensity scale for on-going panelist calibration. Additionally, all sensations remaining in the aftertaste are measured at selected intervals over 1, 5, 10, 15 or more minutes.

Example 10. Determination of Distribution of Sodium Phenylbutyrate in Plasma

[0178] A Phase 1, single-center, single-dose, randomized, open-label, 4-sequence, 2-period, crossover study designed may be used to evaluate the bioequivalence of a taste-masked sodium phenylbutyrate formulation to BUPHENYL® in healthy male and female volunteers in fed and fasted states. Male and female volunteers are randomized to one of the 4 sequences to determine treatment for each study period. There is a minimum 12-hour washout between periods. The washout duration is regarded as sufficient as compared with the 0.8 hour mean terminal half-life reported for sodium phenylbutyrate in healthy adults

[0179] At least 64 volunteers are enrolled in the study, with 16 randomized to each of the study sequences. An informed consent form is signed before any study-related procedures are performed. Treatments will be balanced for male and female volunteers.

The four treatment sequences are as follows in Table 9:

TABLE-US-00009 TABLE 9 Treatment Sequences for Bioequivalence Study Sequence Period 1 Period 2 A sodium phenylbutyrate fed Taste-masked fed B Taste-masked fed sodium phenylbutyrate fed C sodium phenylbutyrate fasted Taste-masked fasted D Taste-masked fasted sodium phenylbutyrate fasted

[0180] Volunteers check into the study center at least 8 hours prior to Period 1 (Day-1) and remain at the study center for the 2 consecutive treatment periods, including remaining at the study center during the washout between Period 1 and Period 2 (Day 2). For fasted sequences, volunteers are required to fast for a minimum of 8 hours prior to initiating treatment (BUPHENYL® or the taste-masked formulation of sodium phenylbutyrate administration) for each period. For fed sequences, volunteers consume a United States Food and Drug Administration (FDA) standard high calorie, high fat breakfast beginning 30 minutes prior to administration of a composition prior in each period.

[0181] Volunteers receive oral doses of 500 mg taste-masked formulation (per FDA Draft Guidance on Sodium Phenylbutyrate bioequivalence; May 2009). At each dosing time, the formulation is dissolved in 6 ounces of room temperature tap water by mixing gently. Volunteers are instructed to ingest the solution immediately.

[0182] Each treatment period lasts for 1 day. Blood draw schedules facilitate measurement of plasma phenylbutyrate levels at baseline and postdose for each period, and results are used to estimate the non-compartmental pharmacokinetic (PK) parameters. Blood samples for measurement of plasma concentrations of phenylbutyrate and phenylbutyrate metabolites are obtained in each study period at predose and at 0.25, 0.5, 0.75, 1.0, 1.5, 2.0, 2.5, 3.0, 4.0, and 8.0 hours postdose. The concentration of phenylbutyrate and phenylbutyrate metabolites in blood samples are measured using a validated liquid chromatography-tandem mass spectroscopy (LC-MS/MS) method. Blood samples may be stored for PK analyses for up to 12 months after the end of the study.

[0183] 90% bioequivalence intervals are built comparing phenylbutyrate and phenylbutyrate metabolites in volunteers receiving either the taste-masked formulation or BUPHENYL® in fed (Sequences A and B) and fasted (Sequences C and D) states.

[0184] Safety is evaluated on the basis of incidence of adverse events and clinically significant changes in laboratory test results (chemistry, hematology, and urinalysis).

OTHER EMBODIMENTS

[0185] It is to be understood that while the present disclosure has been described in conjunction with the detailed description thereof, the foregoing description is intended to illustrate and not limit the scope of the present disclosure, which is defined by the scope of the appended claims. Other aspects, advantages, and alterations are within the scope of the following claims.