WO2013109906A2 - Methods and formulations for treating sialic acid deficiencies - Google Patents

Methods and formulations for treating sialic acid deficiencies Download PDF

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Publication number
WO2013109906A2
WO2013109906A2 PCT/US2013/022167 US2013022167W WO2013109906A2 WO 2013109906 A2 WO2013109906 A2 WO 2013109906A2 US 2013022167 W US2013022167 W US 2013022167W WO 2013109906 A2 WO2013109906 A2 WO 2013109906A2
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Prior art keywords
sialic acid
extended release
release formulation
pharmaceutically acceptable
acceptable salt
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PCT/US2013/022167
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English (en)
French (fr)
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Emil D. Kakkis
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Ultragenyx Pharmaceutical Inc.
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Priority to BR112014017587A priority Critical patent/BR112014017587A8/pt
Priority to CN201380015020.XA priority patent/CN104271125A/zh
Priority to EP13739040.7A priority patent/EP2804600A4/en
Priority to JP2014553457A priority patent/JP2015504094A/ja
Priority to KR1020147022912A priority patent/KR20150000872A/ko
Priority to CA2862836A priority patent/CA2862836A1/en
Priority to AU2013209610A priority patent/AU2013209610B2/en
Publication of WO2013109906A2 publication Critical patent/WO2013109906A2/en
Priority to IL233225A priority patent/IL233225A0/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7012—Compounds having a free or esterified carboxyl group attached, directly or through a carbon chain, to a carbon atom of the saccharide radical, e.g. glucuronic acid, neuraminic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0002—Galenical forms characterised by the drug release technique; Application systems commanded by energy
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system

Definitions

  • Sialic acid is a sugar with a net negative charge, it is often present on terminating branches of N-glycans, O-glycans, and glvcosphmgolipids (gangliosides), and occasionally capping side chains of GPI anchors.
  • Sialic acid modification of cell surface molecules plays a role in many biological phenomena such as protein structure stability, regulation of cell adhesion, and signal transduction.
  • Sialic acid deficiency disorders such as Hereditary Inclusion Body Myopathy (HIBM or HIBM type 2), Nonaka myopathy, and Distal Myopathy with Rimmed Vacuoles (DMRV) are clinical diseases resulting from a reduction in sialic acid production.
  • HIBM or HIBM type 2 Hereditary Inclusion Body Myopathy
  • DMRV Distal Myopathy with Rimmed Vacuoles
  • HIBM is a rare autosomal recessive neuromuscular disorder caused by a biosyntheiic defect in the sialic acid synthesis pathway. Eisenberg et al., Nat. Genet. 29:83-87 (2001).
  • the disease usually manifests between the ages of 20 to 40 such as foot drop and slowly progressive muscle weakness and atrophy. Patients may suffer difficulties walking with foot drop, gripping, use of hands, and swallowing. The disease is progressive; most afflicted individuals become incapacitated and wheelchair-confined within two to three decades. No treatments are available.
  • FIG. 1 The biosynthesis steps and feedback regulation of GNE/MNK is depicted in Figure 1.
  • the production of sialic acid on glycocoiijugates requires the conversion of N- acetylglucosamine (conjugated to its carrier nucleotide sugar UDP) to sialic acid.
  • the sialic acid subsequently enters the nucleus where it is conjugated with its nucleotide sugar carrier CM P to make CMP-sialic acid, which is used as a donor sugar for glycosylation reactions in the cell.
  • CMP-sialic acid is a known regulator of GNE/MNK activity. Jay et al, Gene Reg. & Sys. Biol. 3 : 1 8 1 - 1 90 (2009) .
  • the present invention provides method for treating a sialic acid deficiency in an individual in need thereof comprising orally administering a sialic acid, or a pharmaceutically acceptable salt, solvate, or ester thereof, wherein the method provides a therapeutically effecti ve amount of sialic acid over a period of greater than about four hours.
  • the sialic acid, or a pharmaceutically acceptable salt, solvate, or ester thereof is in an extended release formulation. In some embodiments of the present invention, the sialic acid, or a pharmaceutically acceptable salt, solvate, or ester thereof, is in both an extended release formulation and an immediate release formulation.
  • the method provides a mean Cmm sialic acid of at least about 0. 1 1 mcg/ml at steady state during the dosing intervals. [0010] In some embodiments of the present invention, the method provides a mean plasma concentration of sialic acid of at least about 0.16 mcg/rnl at steady state during the dosing intervals.
  • the method provides a mean plasma concentration of sialic acid at steady state during the dosing intervals that is at least about 50% higher than the mean plasma concentration of sialic acid in the individual before the administration of the sialic acid, or a pharmaceutically acceptable salt, solvate, or ester thereof.
  • the method provides an improved absorption profile when the extended release formulation is administered under fed conditions than being administered under fasting conditions.
  • the sialic acid deficiency is a myopathy associated with sialic acid deficiency.
  • the sialic acid deficiency is a myopathy associated with sialic acid deficiency.
  • the myopathy associated with sialic acid deficiency is Hereditary Inclusion Body Myopathy (HIBM), Nonaka myopathy, and/or Distal Myopathy with Rimmed Vacuoles (DMRV).
  • HIBM Hereditary Inclusion Body Myopathy
  • DMRV Distal Myopathy with Rimmed Vacuoles
  • the extended release formulation is in a solid matrix form.
  • Figure 1 provides a diagram of intracellular sialic acid metabolism.
  • Figure 2 shows the particle size distribution for sialic acid.
  • Figure 3 shows the particle size distribution plot for ProCR sialic acid 250 mg final blends.
  • Figure 4 shows the dissolution plot of sialic acid 250 and 325 mg sustained release (SR) tablets by direct compression.
  • Figure 5 sho ws the dissolution profile of sialic acid 325 and 500 mg sustained release (SR) uncoated tablets.
  • Figure 6 shows the dissolution profile of sialic acid 325 and 500 mg sustained release (SR) coated tablets.
  • Figure 7 shows the dissolution profile of ManNAc 325 mg tablets.
  • Figure 8 shows the individual concentrations of sialic acid versus time in beagle dog serum following IV or oral administration, (A and B) concentration after administration of TA- 1 capsules; (C) concentration after administration of TA-2 tablets; (D) concentration after administration of TA-3 tablet; (E) concentration after administration of TA-4 tablets; (F) concentration after administration of TA-5 tablets; (G and H) concentration after intravenous administration of TA-6.
  • Figure 9 shows pharmacokinetic data for single doses of SA-E versus SA API in the canine - sialic acid in serum crossover study of orally administered SA-ER tablets.
  • Figure 10 shows results from repeated dosing of SA-ER in the dog: Day 0 to Day 7.
  • Figure 1 1 shows a comparison of urinary SA excretion in a crossover study of orally administered SA-ER in the dog - individual canine excretion levels over a 24 hour period. Three orally administered dose levels versus API versus the last day of 7 days of dosing.
  • Figure 12 shows a mean total urinary SA excretion comparison - total sialic acid in urine during 24 hours after/during dosing. Single doses, compared with API and with seventh day of repeat dosing.
  • Figure 13 shows the Study Scheme associated with the ER-SA. human clinical trial of Example 7.
  • Figure 14 shows pharmacokinetic data obtained for single dose ER-SA administration
  • Figure 15 shows pharmacokinetic data obtained for single dose ER-SA administration
  • Figure 16 shows pharmacokinetic data obtained for single dose ER-SA administration
  • Figure 17 shows pharmacokinetic data obtained for single dose ER-SA administration
  • Figure 18 shows pharmacokinetic data obtained for ER-SA repeated administration (650 x 3; 1,950 mg) for six different human patients. Open circles represent the first day in which baseline monitoring was conducted; closed circles represent data from the last day of 7 days of three times per day divided dosing. Free sialic acid concentration is in g/mL serum.
  • Figure 19 shows pharmacokinetic data obtained for ER-SA repeated administration (975 x 3; 2,925 mg) for five different human patients. Open circles represent the first day in which baseline monitoring was conducted; closed circles represent data from the last day of 7 days of three times per day divided dosing. Free sialic acid concentration is in ⁇ . serum.
  • Figure 20 is a schematic of the Phase I Interim Safety Study dosing schedule.
  • Figure 21 shows graphs depicting the mean free sialic acid concentrations at single dose levels (fasted and fed states).
  • the individual mean PK curves are shown for the 650 mg, 1950 mg, 2925 mg, 4875 mg and 6000 mg dose levels to compare fasted, fed and baseline SA levels.
  • Panels for 650 mg, 1950 mg, 2925 mg and 6000 mg have the same size y-axis but the 4875 mg panel has a larger y-axis due to the higher levels achieved.
  • Baseline curves for the subjects in each cohort are shown as open circles, fasted levels as black circles and fed curves as grey circles.
  • Baseline sialic acid levels for day 1 for a group of subjects are presented graphical!' on the same axis so that easy visual comparison can be made of before treatment to after treatment sialic acid levels.
  • the 6000 mg group was administered the 500 mg tablet whereas the rest of the dose groups were administered the 325 mg tablet.
  • Figure 22 is a graph depicting mean free sialic acid concentrations at different single dose levels (fasted state). The mean PK curves and standard deviations are shown for the 650 mg, 1950 mg, 2925 mg, 4875 mg and 6000 mg dose levels (Fasted state). The 6000 mg group was administered the 500 mg tablet whereas the rest of the dose groups were administered the 325 mg tablet.
  • Figure 23 is a graph depicting mean free sialic acid concentrations at different single dose levels (fed state). The mean PK curves and standard deviations are shown for the 650 mg, 1950 mg, 2925 mg, 4875 mg and 6000 mg dose levels (Fed state). The 6000 mg group was administered the 500 mg tablet whereas the rest of the dose groups were administered the 325 mg tablet. [0039] Figures 24A-F show graphs depicting free sialic acid concentrations in serum at different repeat dose levels.
  • Figure 25 shows a graph depicting free sialic acid concentrations in serum by 4 days of dosing sialic acid extended release formulation followed by 4 days of dosing sialic acid extended release formulation plus sialic acid immediate release formulation.
  • Figure 26 shows a graph depicting free sialic acid concentrations in serum by 4 days of dosing sialic acid extended release formulation followed by 4 days of dosing sialic acid extended release formulation plus sialic acid immediate release formulation.
  • the present application provides extended release pharmaceutical formulations comprising one or more compounds in the sialic acid biosynthetic pathway or derivative thereof and methods of treating and preventing sialic acid deficiencies utilizing the extended release pharmaceutical formulations.
  • This invention concerns designing an approach to substrate replacement that provides individuals with sialic acid deficiencies stable and stead)' day and nighttime replacement without high concentration spikes across a broad range of genotypes and in multiple tissues.
  • This invention can optimally achieve this substrate replacement and treatment benefit through the combination of using extended release formulations and one or more metabolites, including combinations of metabolites.
  • any of the extended release formulations detailed herein may comprise an effective amount of a therapeutic agent, such as an effective amount of sialic acid, or a pharmaceutically acceptable salt thereof.
  • oral administration and “oral ingestion” refer to all conventional forms for the oral delivery of a pharmaceutical composition to an individual and that result in the deposition of the pharmaceutical formulation into the gastrointestinal tract (including the gastro portion of the gastrointestinal tract, i.e., the stomach) of the patient. Accordingly, oral administration and oral ingestion include, by way of example, actual ingestion of a solid or liquid pharmaceutical composition, oral gavage, and the like.
  • treating and “treatment” as used herein refer to an approach for obtaining beneficial or desired results including clinical results.
  • beneficial or desired clinical results include, but are not limited to, one or more of the following: decreasing the severity and/or frequency one or more symptoms resulting from the disease, diminishing the extent of the disease, stabilizing the disease (e.g., preventing or delaying the worsening of the disease), delay or slowing the progression of the disease, ameliorating the disease state, increasing production of sialic acid, the sialylation precursor CMP-sialic acid (e.g., increasing intracellular production of sialic acid) and restoring the level of sialylation in muscle and other proteins, decreasing the dose of one or more other medications required to treat the disease, and/or increasing the quality of life.
  • "Treating" a patient with a formulation described herein includes management of an individual to inhibit or cause regression of a disease or condition.
  • Prophylaxis or “prophylactic treatment” “or preventive treatment” refers to prevention of the occurrence of symptoms and/or their underlying cause, for example, prevention of a disease or condition in a patient susceptible to developing a disease or condition (e.g., at a higher risk, as a result of genetic predisposition, environmental factors, predisposing diseases or disorders, or the like).
  • Prophylaxis includes HIBM myopathy in which chronic disease changes in the muscles are irreversible and for which animal model data suggests treatment benefit in prophylaxis.
  • delay means to defer, hinder, slow, retard, stabilize, and/or postpone development of the disease. This delay can be of varying lengths of time, depending on the history of the disease and/or individual being treated.
  • an "at risk” individual is an individual who is at risk of developing a sialic acid deficiency.
  • An individual “at risk” may or may not have detectable disease, and may or may not have displayed detectable disease prior to the treatment methods described herein.
  • At risk denotes that an individual has one or more so-called risk factors, which are measurable parameters that correlate with development of a sialic acid deficiency, which are described herein. An individual having one or more of these risk factors has a higher probability of developing a sialic acid deficiency than an individual without these risk factor(s).
  • an effective amount refers to the amount of one or more compounds in the sialic acid biosynthetic pathway in a sufficient amount to render a desired treatment outcome.
  • An effective amount may be comprised within one or more doses, i.e., a single dose or multiple doses may be required to achieve the desired treatment endpomt.
  • a “therapeutically effective amount” refers to an amount of one or more compounds in the sialic acid biosynthetic pathway sufficient to produce a desired therapeutic outcome (e.g., reduction of severity of a disease or condition). In one embodiment, the therapeutically effective amount refers to a therapeutically effective plasma concentration of sialic acid.
  • a “prophylactically effective amount” refers to an amount of a pharmaceutical formulation including one or more compounds in the sialic acid biosynthetic pathway sufficient to prevent or reduce severity of a future disease or condition when administered to an individual who is susceptible and/or who may develop a disease or condition.
  • extended release refers to a drug-containing formulation or fraction thereof, in which release of the drug is not immediate, i.e., with an “extended release” formulation, administration does not result in immediate release of the drug into an absorption pool.
  • extended release includes controlled release, sustained release, and delayed release formulations.
  • pharmaceutically acceptable is meant a material that is not biologically or otherwise undesirable, i.e., the material may be incorporated into a pharmaceutical composition administered to a patient without causing any significant undesirable biological effects or interacting in a deleterious manner with any of the other components of the composition in which it is contained.
  • pharmaceutically acceptable refers to a pharmaceutical carrier or excipient, it is implied that the carrier or excipient has met the required standards of toxicologicai and manufacturing testing or that it is included on the Inactive Ingredient Guide prepared by the U.S. Food and Drug administration.
  • disorder or “disease” used interchangeably herein, refers to any alteration in the state of the body or one of its organs and/or tissues, interrupting or disturbing the performance of organ function and/or tissue function (e.g., causes organ dysfunction) and/or causing a symptom such as discomfort, dysfunction, distress, or even death to a subject afflicted with the disease.
  • the term "individual” or “patient” refers to an animal, for example, a mammal and includes, but is not limited to, human, bovine, horse, feline, canine, rodent, or primate. Preferably, the individual is a human.
  • derivative as used herein includes derivatives, analogs, prodrugs, and unnatural precursors.
  • pharmaceutically acceptable salt refers to a salt which retains the biological effectiveness of the compound and which is not biologically or otherwise undesirable.
  • Pharmacokinetic parameters describe the in vivo characteristics of the active agent, i.e., the free sialic acid over time, such as plasma concentration (C), C max , C n , C 24 , T max , and AUC.
  • Cmax is the measured concentration of the active agent in the plasma at the point of maximum concentration.
  • C n is the measured concentration of an acti ve agent in the plasma at about n hours after administration.
  • C24 is the measured concentration of an active agent in the plasma at about 24 hours after administration.
  • TNase !iM refers to the time at which the measured concentration of an active agent in the plasma is the highest after administration of the active agent.
  • AUC is the area under the curve of a graph of the measured concentration of an active agent (typically plasma concentration) vs. time, measured from one time point to another time point.
  • AUC 0 .. t is the area under the curve of plasma concentration versus time from time 0 to time t.
  • the AUCo - ⁇ or AUC 0- i F is the calculated area under the curve of plasma concentration versus time from time 0 to time infinity.
  • extended release pharmaceutical formulations comprising as the therapeutic agent one or more compounds in the sialic acid biosynthetic pathway or a derivative thereof or a pharmaceutically acceptable salt of the foregoing.
  • the extended release pharmaceutical formulations comprise a therapeutic agent as detailed herein and a polymer.
  • An extended release formulation comprising a therapeutic agent and a polymer may further comprise one or more additional components, such as any one or more of a diluent, an excipient, an antioxidant, a lubricant, a colorant, a binder, a disintegrant, and the like.
  • extended release pharmaceutical formulations comprising one or more compounds in the sialic acid biosynthetic pathway or a derivative thereof below is exemplary and that this description applies equally to and includes extended release pharmaceutical formulations comprising any one or more compounds in the sialic acid hiosynthetic pathway
  • reference to and description of extended release plianiiaceutical formulations comprising any one or more derivatives of compounds in the sialic acid biosynthetie pathway below is exemplary and that this description applies equally to and includes extended release pharmaceutical formulations comprising any one or more derivatives, analogs, prodrugs, and/or unnatural precursor compounds in the sialic acid biosynthetie pathway.
  • the extended release formulation comprises sialic acid, or a pharmaceutically acceptable salt thereof, as the therapeutic agent.
  • the extended release formulation comprises MaNAc, or a pharmaceutically acceptable salt thereof, as the therapeutic agent.
  • the extended release formulation comprises sialic acid, or a pharmaceutically acceptable salt thereof and MaNAc, or a pharmaceutically acceptable salt thereof, as the therapeutic agents.
  • the extended release formulation comprises a prodrug of one or more compounds in the sialic acid biosynthetie pathway such as a prodrug of sialic acid, or a pharmaceutically acceptable salt thereof, as the therapeutic agent.
  • the extended release formulation comprises sialic acid, or a pharmaceutically acceptable salt thereof, as the therapeutic agent and further comprises a hydrocolloid polymer, an anionic, pH-dependent gel forming copolymer and a water swellable, pH independent polymer and optionally further comprises a lubricant and/or an excipient.
  • the extended release formulation comprises sialic acid, or a pharmaceutically acceptable salt thereof, carrageenan, sodium alginate and either hypromellose or polyethylene oxide.
  • the extended release formulation comprises sialic acid, or a pharmaceutically acceptable salt thereof, carrageenan, sodium alginate, either hypromellose or polyethylene oxide, magnesium stearate and microcrystalline cellulose and colloidal silicon dioxide.
  • the extended release formulation is a formulation of Table E. In yet another aspect, the extended release formulation is a formulation of Table 8. In yet another aspect, the extended release formulation is a formulation of Example 6. In yet another aspect, the extended release formulation is a formulation of Example 7.
  • sialic acid or a compound in the sialic acid biosynthetie pathway, or a derivative thereof, or a pharmaceutically acceptable salt of any of the foregoing may he administered as a therapeutic agent (e.g., as substrate replacement) to an individual who has or is suspected of having a sialic acid deficiency disorder.
  • Extended release formulations comprising such compounds, or pharmaceutically acceptable salts thereof, as the therapeutic agent are provided herein.
  • the sialic acid or a compound in the sialic acid biosynthetic pathway, or a derivative thereof, or a pharmaceutically acceptabie salt of any of the foregoing is sialic acid or a pharmaceutically acceptable salt thereof.
  • any of the extended release formulations detailed herein may comprise an effective amount of a therapeutic agent, such as an effective amount of sialic acid or a pharmaceutically acceptabie salt thereof.
  • a compound in the sialic acid biosynthetic pathway or a derivative thereof in one variation is a compound, or pharmaceutically acceptable salt thereof, that is at or downstream from ManNAc in the sialic acid biosynthetic pathway.
  • the therapeutic agent is a compound, or pharmaceutically acceptable salt thereof that is at or downstream from ManNAc in the sialic acid biosynthetic pathway and is depicted in Figure 1.
  • a compound in the sialic acid biosynthetic pathway or a derivati ve thereof in another variation is a compound, or a pharmaceutically acceptable salt thereof, that is at or upstream from CMP-sialic acid in the sialic acid biosynthetic pathway.
  • the therapeutic agent is a compound, or a pharmaceutically acceptable salt thereof, that is at or upstream from CMP-sialic acid in the sialic acid biosynthetic pathway and is depicted in Figure 1.
  • the compound in the sialic acid biosynthetic pathway or a derivative thereof does not include glucose or a pharmaceutically acceptable salt thereof.
  • the compound in the sialic acid biosynthetic pathway or a derivative thereof in one variation is a compound, or a pharmaceutically acceptable salt thereof, that is: (i) at or downstream from ManNAc in the sialic acid biosynthetic pathway, and (ii) is at or upstream from CMP-sialic acid in the sialic acid biosynthetic pathway.
  • the compound is a compound depicted in Figure 1 , or a pharmaceutically acceptable salt thereof.
  • a compound in the sialic acid biosynthetic pathway or derivative thereof includes, but is not limited to, mannosamine, N-acetyl mannosamine (ManNAc), ManNac-6-phosphate (ManNAc-6-P), UDP-GlcNAc, N-acetylneuraminic acid (NeuAc), NeuAc-9-phosphate (NeuAc-9-P), sialic acid (i.e., 5-N-acetylneuraminic acid), CMP-sialic acid, and/or derivatives thereof or pharmaceutically acceptable salts of the foregoing.
  • the one or more compounds in the sialic acid biosynthetic pathway or derivative thereof include N-acetylneuraminic acid (NeuAc) or a derivative thereof.
  • Structures of such NeuAc or derivatives thereof include, but are not limited to, those defined by the formula below:
  • R 4 is lower alkyl, lower alkanoyialkyl or lower alkyl alkanoyloxy.
  • the one or more compounds in the sialic acid biosynthetic pathway or derivative thereof include ManNAc or a derivative thereof. Structures of such ManNAc and derivatives thereof include, but are not limited to, those defined by the formula below:
  • each Ri , R 3 , R 4 , or R 5 is independently hydrogen, lower alkanovl, carboxvlate or lower alkyl; and R 2 is lower alkyl, lower alkanoyialkyl or lower alkyl alkanoyloxy.
  • lower alkyl refers to A.
  • lower alkyl includes methyl, ethyl, propyl, isopropyl, butyl, iso-butyl, sec-butyl, pentyl, 3-pentyl, hexyl as well as (C 3 - C6)cycioalkyl moieties (e.g., cyclopropyl, cyclobutyl, cyciopentyl, or cyclohexyl), (C 3 - C6)cycloalkyl(Ci-C6)alkyl (e.g., cyclopropyimethyl, cyclobutylmethyl, cyclopentylmethyi, cyclohexylmethyl, 2-cyclopropyiethyl, 2-cycloburylethyl, 2- cyclopentylethyi, or 2- cyclohexylethyl), (C 1 -C 6 )a3koxy (
  • R 2 is methyl, and each of R i, R. 3 , R4, and R 5 is hydrogen.
  • the ManNAc or derivative thereof is N-acetyl mannosamine (ManNAc).
  • the ManNAc or derivative thereof is N-levulinoylmannosamine (ManLev) or -azidoacetylmannosamine (ManNAz).
  • the one or more compounds in the sialic acid biosynthetic pathway or deri vative thereof is an ester of a compound in the sialic acid biosynthetic pathway.
  • the one or more compounds in the sialic acid biosynthetic pathway or derivative thereof is an ester of sialic acid or MaNAc.
  • the one or more compounds in the sialic acid biosynthetic pathway or derivative thereof is an ester of sialic acid.
  • the one or more compounds in the sialic acid biosynthetic pathway or derivative thereof is a prodrug of sialic acid.
  • a derivative of one or more compounds in the sialic acid biosynthetic pathway is an effective substrate replacement for sialic acid, such as in an individual who has or is suspected of having a sialic acid deficiency disorder.
  • a derivative of one or more compounds in the sialic acid biosynthetic pathway (e.g., a derivative of sialic acid or MaNAc), or an extended release formulation comprising a derivative of one or more compounds in the sialic acid biosynthetic pathway (e.g., a derivative of sialic acid or MaNAc) may exhibit any one or more of the following characteristics: (i) capable of delivering to an individual in need thereof a therapeutically effective amount of one or more compounds in the sialic acid pathway or derivatives thereof over a period of about or greater than about any of 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 hours; (ii) capable of delivering to an individual in need thereof a substantially constant therapeutically effective amount of one or more compounds in the sialic acid pathway or derivatives thereof over a period of about or greater than about any of 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 hours; (iii) capable of delivering to an individual in need thereof a therapeutically effective amount of one or more compounds in the sia
  • the one or more compounds in the sialic acid biosynthetic pathway or derivative thereof include sialic acid or a derivative thereof.
  • the sialic acid or derivative thereof is sialic acid.
  • the sialic acid or derivative thereof is a sialic acid analog such as N-levulmoyi sialic acid (SiaLev) or N-azidoacetyl sialic acid (SiaNAz).
  • the sialic acid is bound as a glycoconjugate.
  • the sialic acid or derivative thereof is an unnatural precursor such as siaiyiactose.
  • the extended release formulation comprises about any of one, two, three, or four compounds in the sialic acid biosynthetic pathway or a derivative thereof. In some embodiments, the extended release formulation comprises two compounds in the sialic acid biosynthetic pathway or a derivative thereof. Therefore, for example, the extended release formulation may include ManNAc or a derivative thereof and sialic acid or a derivative thereof More particularly, the extended release formulation may include ManNAc and sialic acid.
  • the amount of one or more compounds in the sialic acid biosynthetic pathway or derivative thereof in the extended release formulation is an amount effective to increase sialic acid production and/or increase sialylation ⁇ e.g., maximal restoration of sialylation).
  • the ratio of the two or more compounds in the sialic acid biosynthetic pathway or derivative thereof in some embodiments, is a ratio which minimizes feedback inhibition of the sialic acid biosynthetic pathway. In some embodiments, the ratio of the two or more compounds in the sialic acid biosynthetic pathway or derivative thereof is a ratio which allows efficient delivery of the two or more compounds in the sialic acid biosynthetic pathway or derivative thereof to muscle cells.
  • the ratio of the two or more compounds in the sialic acid biosynthetic pathway or derivative thereof is a ratio which minimizes feedback inhibition of the sialic acid biosynthetic pathway and aliow r s efficient delivery of the two or more compounds in the sialic acid biosynthetic pathway or derivative thereof to muscle cells.
  • the two or more compounds in the sialic acid biosynthetic pathway or derivative there of are ManNAc or a derivative thereof and sialic acid or a derivative thereof.
  • the ratio of ManNAc and sialic acid is a ratio which minimizes feedback inhibition of the sialic acid biosynthetic pathway and allows efficient deliver of ManNAc and/or sialic acid to muscle cells.
  • the combination may optimally spread out the replacement of intermediates, enhancing optimal distribution to all cell types with different metabolisms.
  • Methods of testing restoration of sialylation and determining the best ratio of the two or more compounds in the sialic acid biosynthetic pathway or derivative thereof using in vitro HIBM muscle cells are known in the art. See e.g., Noguchi 8. et al., J. Bio. Chem. 279(12): 11402-7 (2004).
  • NCAM neural cell adhesion molecule
  • the extended release formulation comprises two compounds in the sialic acid biosynthetic pathway or a derivative thereof
  • the two compounds in the extended release formulation may be present in a weight to weight percentage of between about any of 5%-95%:95%-5%, 5%-50%:95%-50%, or 10%-40%:90%-60%.
  • the two compounds in the extended release formulation may be present in a weight to weight percentage of about any of 90%: 10%, 80%:20%, 70%:30%, 60%:40%, 50%:50%, 40%:60%, 30%:70%, 20%:80%, or 10%:90%.
  • the two compounds in the extended release formulation are in a weight to weight percent of about 50%:50%.
  • the one or more compounds in the sialic acid pathway or derivatives thereof include ManNAc or a derivative thereof and/or sialic acid or a derivative thereof. Therefore, for example, the extended release formulation may include ManNAc and sialic acid wherein the weight to weight percentage of ManNAc to sialic acid is about any of 90%: 10%, 80%:20%, 70%:30%, 60%:40%, 50%:50%, 40%:60%, 30%:70%, 20%:80%, or 10%:90%.
  • the extended release formulations comprising one or more compounds in the sialic acid biosynthetic pathway or a derivative thereof as described herein may include one or more polymers.
  • the polymer may be a natural polymer (e.g., polysaccharide or protein), modified natural polymer, and/or synthetic polymer.
  • the polymer may be, for example, a hydrophobic polymer, hydrophilic polymer, hydrogel, soluble polymer, biodegradable polymer, nonbiodegradable polymer, and/or mucoadhesive polymer.
  • the polymer is a hydrophobic polymer.
  • hydrophobic polymers include polyethylene, polyvinyl chloride, ethyl cellulose or acryiate polymers and their copolymers.
  • the polymer is a hydrophilic polymer.
  • hydrophilic polymers include a) cellulose derivatives such as methyiceilulose (MC), hydroxyethyl- cellulose, hydroxypropyimethyl-cellulose (HPMC), or sodium carboxymethylcellulose, b) nonceilulose natural or semisynthetic polymers such as agar-agar, carob gum, alginates, molasses, polysaccharides of marmose and galactose, or chitosan. and modified starches and c) polymers of acrylic acid such as carbopoi polymers.
  • the polymer is a hydrogel.
  • hydrogeis include, but are not limited to, polyhydroxyethyle methylacrylate (PHEMA), polyvinyl alcohol (PVA), polyvinyl pyrrolidone (PVP), polyethylene oxide (PEG), or polyaerylamide (PA).
  • PHEMA polyhydroxyethyle methylacrylate
  • PVA polyvinyl alcohol
  • PVP polyvinyl pyrrolidone
  • PEG polyethylene oxide
  • PA polyaerylamide
  • the hydrogel is polyethylene oxide (e.g., PoiyoxTM water soluble resin, Dow Chemical Company, Mich., USA).
  • the polymer is a soluble polymer.
  • soluble polymers include, but are not limited to, polyethylene glycol (PEG), PVA, PVP, or HPMC.
  • the polymer is a biodegradable polymer.
  • biodegradable polymers include, but are not limited to, polylactic acid (PL A), polyglycoiic acid (PGA), poly(lactic/glycoIic acid) (PLGA), polycaprolactone (PCL), polyanhydrides, or polyorthoesters.
  • the polymer is a nonbiodegradable polymer.
  • nonbiodegradable polymers include, but are not limited to, polyethylene vinyl acetate, polydimethyl siloxane (PDS), polyether urethane (PEU), polyvinyl chloride (PVC), cellulose acetate (CA), or ethyl cellulose (EC).
  • the polymer is a mucoadhesive polymer.
  • mucoadhesive polymers include, but are not limited to, polycarbophil, sodium carboxymethyl cellulose, polyacrylic acid, tragacanth, methyl cellulose, pectin, natural gums, xanthan gum, guar gum, or karaya gum.
  • the extended release pharmaceutical, formulation includes two polymers.
  • the polymer is not polylactide.
  • the polymer is not a polylactide copolymer such as PLGA.
  • the extended release formulation comprises one or more polymers selected from the group consisting of a) a water-swellable, pH independent polymer, b) a anionic, pH-dependent, gel-forming copolymer, c) a cationic polymer, and d) a hydrocolloid polymer.
  • the extended release formulation comprises sialic acid, or a pharmaceutical ly acceptable salt thereof, as the therapeutic agent.
  • the extended release formulation comprises MaNAc, or a pharmaceutically acceptable salt thereof, as the therapeutic agent.
  • the extended release formulation comprises sialic acid, or a pharmaceutically acceptable salt thereof and MaNAc, or a pharmaceutically acceptable salt thereof!, as the therapeutic agents.
  • the extended release formulation comprises a prodmg of one or more compounds in the sialic acid biosynthetic pathway such as a prodrug of sialic acid, or a pharmaceutically acceptable salt thereof, as the therapeutic agent.
  • the extended release formulation comprises sialic acid, or a pharmaceutically acceptable salt thereof, as the therapeutic agent and further comprises a hydroeolloid polymer, an anionic, pH-dependent gel forming copolymer and a wafer swellabie, pH independent polymer and optionally further comprises a lubricant and/or an excipient.
  • the extended release formulation comprises sialic acid, or a pharmaceutically acceptable salt thereof, carrageenan, sodium alginate and either hypromellose or polyethylene oxide.
  • the extended release formulation comprises sialic acid, or a pharmaceutically acceptable salt thereof, carrageenan, sodium alginate, either hypromellose or polyethylene oxide, magnesium stearate and microcrystalline cellulose and colloidal silicon dioxide.
  • the extended release formulation is a formulation of Table E.
  • the extended release formulation is a formulation of Table 8.
  • the extended release formulation is a formulation of Example 6.
  • the extended release formulation is a formulation of Example 7.
  • Examples of a water-swellable, pH independent polymer include, but are not limited to, carbohydrate-based polymers such as, for example, hypromellose (formerly known as the family of hydroxypropyl methylcellulose), hydroxypropyl ethyl celluloses, hydroxypropyl cellulose, hydroxyethyl cellulose, methyl cellulose or other constituents Grades of these hypromellose copolymers typically used with the present invention include the E and K series such as for example, Dow Chemical Company's (Midland, Mich.
  • Grades of hydroxyethyl cellulose include, for example, Aqualon's Natrasol polymers HHX (mol. Wt. 1,300,000), HX (mol. wt. 1,000,000), H (mol. wt. 1 ,000,000), M (mol. wt. 720,000 and G (mol. wt. 1,150,000), and mixtures thereof.
  • Grades of hydroxypropyl cellulose include, for example, Aqualon's HPC polymers MF and MXF (mol. wt.
  • the water-swellable, pH independent polymer is hypromellose (e.g., hypromellose Type 2208).
  • the water-swellable, pH independent polymer is Methocel ⁇ (e.g., Methocel® l OOMPremium CR, Colorcon).
  • anionic, pH-dependent, gel-forming copolymer examples include, but are not limited to, mono-valent alginate salt such as sodium, potassium or ammonium alginate salts, or combinations thereof, and sodium carboxymetlivl cellulose and the like, or mixtures of one or more alginate salt and carboxymethyl cellulose and the like.
  • the anionic, pH ⁇ dependent, gel-forming copolymer is sodium alginate (e.g., Protanal ⁇ , FMC BioPolymer).
  • Examples of a cationic polymer include, for example, chitosan or a derivative thereof including, for example, trimethy!chitosan and quartermised chitosan, and chitosan-derived materials including, for example, those taught in U.S. Pat, No. 5,747,475.
  • Either high or low molecular weight chitosan products can be used in the pharmaceutical formulations of the present mvention and are readily available in pharmaceutical grade from suppliers located world-wide.
  • the hydrocoUoid polymer used in the formulations of the present invention can be carrageenan.
  • Carrageenans are available as iota, kappa and lambda carrageenans, with iota being used most frequently used and lambda being used least frequently.
  • Various salt forms of carrageenans are also available including, for example sodium carrageenan.
  • Typically used grades of iota carrageenan include, without limitation, carrageenan NF AEP brand colloids (Hadley, N.Y. USA) FD433 (1% viscosity; 300-400 cps) and FD384 (1% viscosity; about 100 cps).
  • Viscosity of other carrageenan products ranges from about 50 to about 4000 cps.
  • the carrageenan is lambda carrageenan (e.g., Viscarin GP-209, FMC BioPolymer).
  • the carrageenan has a viscosity of about 1500-2000 cPs. In some embodiments, the carrageenan has a viscosity of about 1600 cPs.
  • the extended release formulation comprises a water-swellable, pH independent polymer (e.g., hypromellose). In some embodiments, the extended release formulation further comprises an anionic, pH-dependent, gel-forming copolymer (e.g., an alginate salt). In some embodiments, the extended release formulation further comprises a hydrocoUoid polymer (e.g., carrageenan). In some embodiments, the extended release formulation comprises a water-swellable, pH independent polymer (e.g. hypromellose), an anionic, pH-dependent, gel-forming copolymer (e.g., an alginate salt) and a hydrocoUoid polymer (e.g., a carrageenan).
  • a water-swellable, pH independent polymer e.g. hypromellose
  • an anionic, pH-dependent, gel-forming copolymer e.g., an alginate salt
  • a hydrocoUoid polymer e.g.,
  • the extended release formulation comprises hypromellose (e.g. hypromellose Type 2208 or Methocel K100M), sodium alginate (e.g. Protanal) and a lambda carrageenan (e.g. Viscarin GP-209),
  • the extended release formulation comprises sialic acid, or a pharmaceutically acceptable salt thereof, as the therapeutic agent.
  • the extended release formulation comprises MaNAc, or a pharmaceutically acceptable salt thereof, as the therapeutic agent.
  • the extended release formulation comprises sialic acid, or a pharmaceutically acceptable salt thereof and MaNAc, or a pharmaceutically acceptable salt thereof, as the therapeutic agents.
  • the extended release formulation comprises a prodrug of one or more compounds in the sialic acid biosynthetic pathway such as a prodrug of sialic acid, or a pharmaceutically acceptable salt thereof, as the therapeutic agent.
  • the extended release formulation comprises sialic acid, or a pharmaceutically acceptable salt thereof, as the therapeutic agent and further comprises a hydrocolloid polymer, an anionic, pH-dependent gel forming co-polymer and a water swellable, pH independent polymer and optionally further comprises a lubricant and/or an exeipient.
  • the extended release formulation comprises sialic acid, or a pharmaceutically acceptable salt thereof, carrageenan, sodium alginate and either hypromeliose or polyethylene oxide.
  • the extended release formulation comprises sialic acid, or a pharmaceutically acceptable salt thereof, carrageenan, sodium alginate, either hypromeliose or polyethylene oxide, magnesium stearate and microcrystalline cellulose and colloidal silicon dioxide.
  • the extended release formulation is a formulation of Table E.
  • the extended release formulation is a formulation of Table 8.
  • the extended release formulation is a formulation of Example 6.
  • the extended release formulation is a formulation of Example 7.
  • the extended release formulation comprises a hydrogel (e.g., a polyethylene oxide).
  • the extended release formulation further comprises an anionic, pH-dependent, gel-forming copolymer (e.g. an alginate salt).
  • the extended release formulation further comprises a hydrocolloid polymer (e.g., carrageenan).
  • the extended release formulation comprises a hydrogel (e.g., a polyethylene oxide), an anionic, pH-dependent, gel-forming copolymer (e.g., an alginate salt) and a hydrocolloid polymer (e.g., a carrageenan).
  • the extended release formulation comprises polyethylene oxide (e.g.
  • the extended release formulation comprises sialic acid, or a pharmaceutically acceptable salt thereof, as the therapeutic agent.
  • the extended release formulation comprises MaNAc, or a pharmaceutically acceptable salt thereof, as the therapeutic agent.
  • the extended release formulation comprises sialic acid, or a pharmaceutically acceptable salt thereof and MaNAc, or a pharmaceutically acceptable salt thereof as the therapeutic agents.
  • the extended release formulation comprises a prodrug of one or more compounds in the sialic acid biosynthetic pathway such as a prodrug of sialic acid, or a pharmaceutically acceptable salt thereof, as the therapeutic agent.
  • the extended release formulation comprises sialic acid, or a pharmaceutically acceptable salt thereof, as the therapeutic agent and further comprises a hydrocoUoid. polymer, an anionic, pH-dependent gel forming co-polymer and a water swellable, pH independent polymer and optionally further comprises a lubricant and/or an excipient.
  • the extended release formulation comprises sialic acid, or a pharmaceutically acceptable salt thereof, carrageenan, sodium alginate and either hypromellose or polyethylene oxide.
  • the extended release formulation comprises sialic acid, or a pharmaceutically acceptable salt thereof, carrageenan, sodium alginate, either hypromellose or polyethylene oxide, magnesium stearate and microcrystalline cellulose and colloidal silicon dioxide.
  • the extended release formulation is a formulation of Table E.
  • the extended release formulation is a formulation of Table 8.
  • the extended release formulation is a formulation of Example 6.
  • the extended release formulation is a formulation of Example 7.
  • the extended release formulation comprises: (i) a hydrocoUoid polymer; (ii) an anionic, pH-dependent , gel forming co-polymer, and (iii) either a water- swellable, pH independent polymer or a hydrogel.
  • the extended release formulation comprises sialic acid, or a pharmaceutically acceptable salt thereof, as the therapeutic agent.
  • the extended release formulation comprises MaNAc, or a pharmaceutically acceptable salt thereof, as the therapeutic agent.
  • the extended release formulation comprises sialic acid, or a pharmaceutically acceptable salt thereof and MaN Ac, or a pharmaceutically acceptable salt thereof, as the therapeutic agents.
  • the extended release formulation comprises a prodrug of one or more compounds in the sialic acid biosynthetic pathway such as a prodrug of sialic acid, or a pharmaceutically acceptable salt thereof, as the therapeutic agent.
  • the extended release formulation comprises sialic acid, or a pharmaceutically acceptable salt thereof as the therapeutic agent and further comprises a hydrocoUoid polymer, an anionic, pH-dependent gel forming co-polymer and a water swellable, pH independent polymer and optionally further comprises a lubricant and/or an excipient.
  • the extended release formulation comprises sialic acid, or a pharmaceutically acceptable salt thereof, carrageenan, sodium alginate and either hypromeilose or polyethylene oxide.
  • the extended release formulation comprises sialic acid, or a pharmaceutically acceptable salt thereof carrageenan, sodium alginate, either hypromeilose or polyethylene oxide, magnesium stearate and macrocrystalline cellulose and colloidal silicon dioxide.
  • the extended release formulation is a formulation of Table E.
  • the extended release formulation is a formulation of Table 8.
  • the extended release formulation is a formulation of Example 6.
  • the extended release formulation is a formulation of Example 7.
  • An extended release formulation in one variation comprises a therapeutic agent as detailed herein (e.g., sialic acid) and (i) a hydrocolloid polymer; (ii) an anionic, pH-dependent, gel forming copolymer, and (iii) either a water-sweilab!e, pH independent polymer or a bydrogel.
  • a therapeutic agent as detailed herein (e.g., sialic acid) and (i) a hydrocolloid polymer; (ii) an anionic, pH-dependent, gel forming copolymer, and (iii) either a water-sweilab!e, pH independent polymer or a bydrogel.
  • exemplary extended release formulations include those listed in Table A, where it is understood that an extended release formulation may comprise any of the listed therapeutic agents in combination with at least one of any of polymers 1, 2, 3 A or 3B the same as if each and every combination of therapeutic agent and polymer or combination of polymers were specifically and individually listed.
  • an extended release formulation comprises a therapeutic agent of Table A, a polymer 1 of Table A, a polymer 2 of Table A and either a polymer 3A of Table A or a polymer 3B of Table A the same as if each and every combination of therapeutic agent and polymer combination were specifically and individually listed.
  • an extended release formulation comprises sialic acid, carrageenan (e.g., a lambda carrageenan such as Viscarin GP-209), an alginate salt (e.g., sodium alginate such as Protanal® LF 120M), and either (i) hypromeilose (e.g., hypromeilose Type 2208) or (ii) polyethylene oxide (e.g., Polyox), or a pharmaceutically acceptable salt of any of the foregoing.
  • carrageenan e.g., a lambda carrageenan such as Viscarin GP-209
  • an alginate salt e.g., sodium alginate such as Protanal® LF 120M
  • hypromeilose e.g., hypromeilose Type 2208
  • polyethylene oxide e.g., Polyox
  • Table A Exemplary Components for use in Extended Release Formulations.
  • Formulation Component Weigh t Percent of Component in Formulation Formulation Component Weight Percent of Component in Formulation
  • Therapeutic Agent mannosamine, N-acetyl mannosamine (ManNAc), ManNac-6- (A compound in the sialic phosphate (ManNAc-6-P), UDP-GlcNAc, N-acetylneuraminic acid biosynthetic pathway acid (NeuAc), euAc-9-phospbate ( euAc-9-P), sialic acid or derivative thereof or (i.e., 5-jV-acetylneuraminic acid), CMP-sialic acid, and/or salt of any of the derivatives thereof or pharmaceutically acceptable salts of the foregoing) foregoing.
  • ManNAc N-acetyl mannosamine
  • ManNac-6-P A compound in the sialic phosphate
  • UDP-GlcNAc N-acetylneuraminic acid biosynthetic pathway acid
  • NeAc N-acetylneuraminic acid biosynthetic pathway acid
  • Polymer 1 Carrageenan (e.g., iota, kappa or lambda carrageenan, or a salt
  • Hydrocolloid Polymer thereof, such as Viscarm GP-209, FMC BioPolymer
  • Polymer 2 Alginate or salt thereof (e.g., sodium, potassium or ammonium
  • gel forming polymer carboxymethyl cellulose or salt thereof (e.g., sodium
  • Polymer 3A Water- Hyprome!iose (e.g., hyprom.ell.ose Type 2208, E and K series swellable, pH independent such as for example, Dow Chemical Company's (Midland, polymer) Mich. USA) or Aqualon's (with a North American presence in
  • ethyl cellulose Ethocel polymers 7FP, 10FP and 100FP and Aqualon's polymers T10EC, N7, N10, N17, N22, N50, N100 and N200, and mixtures thereof
  • hydroxypropyl cellulose Aqualon's UPC polymers MF and MXF (moL wt. 580,000) and KF and HXF (moL wt.
  • hydroxyetbyl cellulose e.g., Aqualon's Natrasol polymers ffilxVmol, Wt. 1,300,000), HX (mol. wt. 1,000,000), H (mol. wt. 1,000,000), M (mol. wt. 720,000 and G (mol. wt. .1 ,150,000), and mixtures thereof); methyl cellulose..
  • Polymer 3B Hydrogel- Polyhydroxyetbyle methyl acrylate (PHEMA), polyvinyl alcohol forming polymer) (PVA), polyvinyl pyrrolidone (PVP), polyethylene oxide (PEO), polyacrylamide (PA), polyethylene oxide (e.g., PolyoxTM water soluble resin, Dow Chemical Company, Mich., USA),
  • PHEMA polyvinyl alcohol forming polymer
  • PVP polyvinyl pyrrolidone
  • PEO polyethylene oxide
  • PA polyacrylamide
  • polyethylene oxide e.g., PolyoxTM water soluble resin, Dow Chemical Company, Mich., USA
  • an extended release formulation comprises a therapeutic agent of Table A, a polymer 1 of Table A, a polymer 2 of Table A and either a polymer 3A or a polymer 3B of Table A, wherein the composition comprises the therapeutic agent and polymers in any one of the weight percent, ranges depicted in Table B.
  • Table B Exemplary Weight Percent of Certain Components for Use in Extended Release Formulations.
  • the extended release formulation comprises a therapeutic agent (a compound in the sialic acid biosynthetic pathway or derivative thereof or salt of any of the foregoing, such as any of the compounds detailed herein, including in Table A) and a polymer, wherein the polymer comprises: (i) a hydrocolloid polymer; (ii) an anionic, pH- dependent , gel forming co-polymer, and (Hi) either a water-swellable, pH independent polymer or a hydrogel, and wherein the weight percent ratio of polymers (i):(ii):(iii) is about 1 :5:5 or about 1 :5:6.
  • a therapeutic agent a compound in the sialic acid biosynthetic pathway or derivative thereof or salt of any of the foregoing, such as any of the compounds detailed herein, including in Table A
  • a polymer comprises: (i) a hydrocolloid polymer; (ii) an anionic, pH- dependent , gel forming co-polymer, and (Hi
  • weight percentages detailed herein refer to the weight percentages of a formulation blend (e.g., prior to formulation into a unit dosage amount such as a tablet, which may be further modified, e.g., by the addition of a tablet coating).
  • weight percentages detailed herein refer to the weight percentages of a unit dosage of a formulation, in which the formulation is in a form and/or packaged for administration to an individual (e.g., a tablet that has a coating).
  • the polymer may be present in the extended release formulation in an amount ranging from 5 to 40 parts by weight, from 10 to 20 parts by weight, relative to 100 parts by weight of the one or more compounds in the sialic acid pathway or derivatives thereof.
  • the one or more compounds in the sialic acid pathway or derivatives thereof in such formulations includes from about 0.1 to 99.9% by weight of the formulation.
  • the one or more compounds in the sialic acid pathway or derivatives thereof in such formulations includes about any of between 20%-30%, 30%-40%, 40%-50%, or 20%-50%.
  • the extend release formulation includes about any of between 40%-50%, 50%-60%, 60%-70%, or 50% to 70% by weight of polymer.
  • the drug load of the one or more compounds in the sialic acid pathway or derivatives thereof in the extended release formulation comprises about 20%s to 80%) w/w. In some embodiments, the drug load of the one or more compounds in the sialic acid pathway or derivatives thereof in the extended release formulation comprises about any ⁇ one of 20% to 60% w/w, 20% - 50% w/w, 20% - 40% w/w, 15% - 60% w/w, 15% - 50% w/w, 15% - 40% w/w, 25% - .60% w/w, 25% - 50% w/w, 25% - 40% w/w, 30% - 60% w/w, 30% - 50% w/w, 30%) - 45% w/w, 35% - 60%» w/w, 35% - 50% w/w, or 35%» - 45%» w/w.
  • the drug load of the one or more compounds in the sialic acid pathway or derivatives thereof in the extended release formulation comprises at least about any one of 25%> w/w, 3Q%> w/w, 35%> w/w, 4Q%> w/w, 45% w/w, or 5Q%> w/w. In some embodiments, the drug load of the one or more compounds in the sialic acid pathway or derivatives thereof in the extended release formulation comprises about 33%) w/w. In some embodiments, the drug load of the one or more compounds in the sialic acid pathway or derivatives thereof in the extended release formulation comprises about 43% w/w
  • the extended release formulation comprises about 20 to about 50 or about 20 to about 40 or about 20 to about 30% w/w of a water-sweliable, pH independent polymer (e.g., hypromellose). In some embodiments, the extended release formulation comprises about 25% w/w of a water-swellable, pH independent polymer (e.g., hypromellose). in some embodiments, the extended release formulation further comprises about 20-25% w/w of an anionic, pH-dependent, gel-forming copolymer (e.g., an alginate salt).
  • a water-sweliable, pH independent polymer e.g., hypromellose
  • the extended release formulation comprises about 25% w/w of a water-swellable, pH independent polymer (e.g., hypromellose).
  • the extended release formulation further comprises about 20-25% w/w of an anionic, pH-dependent, gel-forming copolymer (e.g., an alginate salt).
  • the extended release formulation further comprises about 21%w/w of an anionic, pH-dependent, gel-forming copolymer (e.g., an alginate salt). In some embodiments, the extended release formulation further comprises about 1-5% w/w of a hydrocolloid polymer (e.g., carrageenan). In some embodiments, the extended release formulation further comprises about 4% w/w of a hydrocolloid polymer (e.g., carrageenan). In some embodiments, the extended release formulation comprises about 20-30% w/w of a water-sweliable, pH independent polymer (e.g.
  • the extended release formulation comprises about 20-30% w/w hypromellose (e.g. hypromellose Type 2208 or Methocei 100M), about 20-25% w/w sodium alginate (e.g. Protanal) and about 1 -5% w/w lambda carrageenan (e.g. Viscarin GP-209).
  • an anionic, pH -dependent, gel-forming copolymer e.g., an alginate salt
  • a hydrocolloid polymer e.g., a carrageenan
  • the extended release formulation comprises about 20-30% w/w hypromellose (e.g. hypromellose Type 2208 or Methocei 100M), about 20-25% w/w sodium alginate (e.g. Protanal) and about 1 -5% w/w lambda carrageenan (e.g. Viscarin GP-209).
  • the extended release formulation comprises about 25%> w/w of a water-swellable, pH independent polymer (e.g. hypromellose), about 21% w/w of an anionic, pH-dependent, gel-forming copolymer (e.g., an alginate salt) and about 4% w/w of a hydrocolloid polymer (e.g., a carrageenan).
  • the extended release formulation comprises about 25% w/w hypromellose (e.g. hypromellose Type 2208 or Methocei 100M), about 21% w/w sodium alginate (e.g. Protanal) and about 4% w/w lambda carrageenan (e.g. Viscarin GP-209).
  • the extended release formulation comprises about 20 to about 50 or about 20 to about 40 or about 20 to about 2Q-30%> w/w of a hydrogel (e.g., a polyethylene oxide, Polvox WSR). In some embodiments, the extended release formulation comprises about 25% w/w of a hydrogel (e.g., a polyethylene oxide, Polyox WSR). In some embodiments, the extended release formulation further comprises about 20-25% w/w of an anionic, pH-dependent, gel-forming copolymer (e.g., an alginate salt).
  • a hydrogel e.g., a polyethylene oxide, Polvox WSR
  • the extended release formulation comprises about 25% w/w of a hydrogel (e.g., a polyethylene oxide, Polyox WSR). In some embodiments, the extended release formulation further comprises about 20-25% w/w of an anionic, pH-dependent, gel-forming copolymer (e.g., an alginate salt).
  • the extended release formulation further comprises about 21% w/w of an anionic, pH- dependent, gel-forming copolymer (e.g., an alginate salt). In some embodiments, the extended release formulation further comprises about 1-5% w/w of a hydrocolloid polymer (e.g., carrageenan). In some embodiments, the extended release formulation further comprises about 4% w/w of a hydrocolloid polymer (e.g., carrageenan).
  • the extended release formulation comprises about 20-30% w/w of a hydrogel (e.g., a polyethylene oxide), about 20-25% w/w of an anionic, pH-dependent, gel-forming copolymer (e.g., an alginate salt) and about 1-5% w/w of a hydrocolloid polymer (e.g., a carrageenan).
  • the extended release formulation comprises about 20- 30% w/w polyethylene oxide (e.g. Polyox WSR), about 20-25% w/w sodium alginate (e.g. Protanal) and about 1-5% w/w lambda carrageenan (e.g. Viscarin GP-209).
  • the extended release formulation comprises about 25% w/w of a hydrogel (e.g., a polyethylene oxide), about 21% w/w of an anionic, pH-dependent, gel-forming copolymer (e.g., an alginate salt) and about 4% w/w of a hydrocolloid polymer (e.g., a carrageenan).
  • the extended release formulation comprises about 25% w/w polyethylene oxide (e.g. Polyox WSR), about 21% w/w sodium alginate (e.g. Protanal) and about 4% w/w lambda carrageenan (e.g. Viscarin GP-209).
  • the extended release pharmaceutical formulations comprising one or more compounds in the sialic acid biosynthetic pathway or derivative thereof as described herein may further comprise a diluent, an excipient, an antioxidant, a lubricant, a colorant, a binder, a disintegrant, and the like.
  • any of the extended release formulations detailed herein may further comprise a diluent, an excipient, an antioxidant, a lubricant, a colorant, a binder, a disintegrant, and the like as detailed herein the same as if each and even' extended release formulation further comprising such a component were specifically and individually listed.
  • the extended release formulation comprises sialic acid, or a pharmaceutically acceptable salt thereof, as the therapeutic agent.
  • the extended release formulation comprises MaNAc, or a pharmaceutically acceptable salt thereof, as the therapeutic agent.
  • the extended release formulation comprises sialic acid, or a pharmaceutically acceptable salt thereof and MaNAc, or a pharmaceutically acceptabie salt thereof, as the therapeutic agents.
  • the extended release formulation comprises a prodrug of one or more compounds in the sialic acid biosynthetic pathway such as a prodrug of sialic acid, or a pharmaceutically acceptable salt thereof, as the therapeutic agent.
  • the extended release formulation comprises sialic acid, or a pharmaceutically acceptable salt thereof, as the therapeutic agent and further comprises a hydrocolloid polymer, an anionic, pH-dependent gel forming co-polymer and a water sweliable, pH independent polymer and optionally further comprises a lubricant and/or an excipient.
  • the extended release formulation comprises sialic acid, or a pharmaceutically acceptable salt thereof, carrageenan, sodium alginate and either hypromellose or polyethylene oxide.
  • the extended release formulation comprises sialic acid, or a pharmaceutically acceptable salt thereof, carrageenan, sodium alginate, either hypromellose or polyethylene oxide, magnesium stearate and microcrystalline cellulose and colloidal silicon dioxide.
  • the extended release formulation is a formulation of Table E. in yet another aspect, the extended release formulation is a formulation of Table 8. In yet another aspect, the extended release formulation is a formulation of Example 6. In yet another aspect, the extended release formulation is a formulation of Example 7.
  • the diluent is selected so as not to affect the biological activity of the combination.
  • examples of such diluents are distilled water, buffered w r ater, physiological saline, PBS, Ringer's solution, dextrose solution, and Hank's solution.
  • the pharmaceutical formulations can also include additional substances to approximate physiological conditions, such as pH adjusting and buffering agents, toxicity adjusting agents, wetting agents and detergents.
  • the phannaceutical formulations can also include any of a variety of stabilizing agents. Further guidance regarding pharmaceutical formulations that are suitable for various types of administration can be found in Remington: The Science and Practice of Phamiacy, 20th Edition. Baltimore, MD: Lippincott Williams & Wilkins, 2000.
  • the excipient may be selected from the group consisting of lactose, microcrystalline cellulose, corn starch, potato starch, wheat starch, sucrose, D-mannitol, precipitated calcium carbonate, dextrin, pre-gelatinized starch, and combinations thereof.
  • the excipient if present, may be contained in an amount of about 10 to about 90 parts by weight based on the total weight of the tablet.
  • the extend release formulation includes about any of between 40%-50%, 50%-60%, 60% ⁇ 70%, or 50% to 70% by weight of excipient.
  • the excipient is mieroerystalline cellulose.
  • the excipient is microcrystalline cellulose and colloidal silicon dioxide (e.g., ProSolv® SMCC HD90).
  • the extended release formulation comprises about 1-10% w/ ' w of microcrystalline cellulose and colloidal silicon dioxide (e.g., ProSolv® SMCC HD90).
  • the extended release formulation comprises about 5% w/w of mieroerystalline cellulose and colloidal silicon dioxide (e.g., ProSolv® SMCC HD90).
  • the binder may be selected from the group consisting of hydroxypropylcelluiose, direct tabletted macrocrystalline cel lulose, HP C, MC, hydroxyemylcelluiose, hydroxymethvlcellulose, carboxymethvl cellulose, and other cellulose derivative, PVP, PVA, paste, arable gum, dextrin, gelatin, alginates, and combinations thereof.
  • the binder if present, may be used in an amount of about 2 to about 60 parts by weight based on the total weight of the tablet.
  • the dismtegrant may be selected from the group consisting of sodium starch glycolate, crosspovidone, cross earmel!ose sodium, low-substituted hydroxypropylcelluiose, starch, carboxymethyleeilulose calcium, calcium carbonate, sodium bicarbonate, and combinations thereof.
  • the disintegrant if present, may be contained in an amount of about 0, 1 to about 32 parts by weight based on the total weight of the tablet composition.
  • the lubricant may be selected from the group consisting of magnesium stearate, calcium stearate, talc, light anhydrous silicic acid, and solid poiyethyl glycols and combinations thereof.
  • the lubricant if present, may be contained in an amount of about 0.1 to about 20 parts by weight based on the total weight of the tablet.
  • the lubricant is magnesium stearate (e.g., HyQual ⁇ ).
  • the extended release formulation comprises about 0.1-l%w/w magnesium stearate ⁇ e.g., HyQual ⁇ ).
  • the extended release formulation comprises about 0.5% w/w magnesium stearate (e.g., HyQual®).
  • an extended release formulation detailed herein further comprises an excipient.
  • the excipient comprises mieroerystalline cellulose.
  • the excipient comprises macrocrystalline cellulose and colloidal silicon dioxide.
  • the extended release formulation further comprising an excipient comprises the excipient in about 1 to about 20 or about 1 to about 15 or about 1 to about 10 or about 1 to about 5 or about 5 to about 20 or about 5 to about 15 or about 5 to about 10 or about any one of 1 , 2, 3, 4, 5, 6, 7, 8, 9 or 10 weight percent, in one variation, the extended release formulation comprises sialic acid, or a pharmaceutically acceptable salt thereof as the therapeutic agent. In another variation, the extended release formulation comprises Ma Ac, or a pharmaceutically acceptable salt thereof, as the therapeutic agent.
  • an excipient e.g., an excipient comprising mieroerystalline cellulose and colloidal silicon dioxide
  • the extended release formulation comprises sialic acid, or a pharmaceutically acceptable salt thereof as the therapeutic agent.
  • the extended release formulation comprises Ma Ac, or a pharmaceutically acceptable salt thereof, as the therapeutic agent.
  • the extended release formulation comprises sialic acid, or a pharmaceutically acceptable salt thereof and MaNAc, or a pharmaceutically acceptable salt thereof, as the therapeutic agents.
  • the extended release formulation comprises a prodrug of one or more compounds in the sialic acid biosynthetic pathway such as a prodrug of sialic acid, or a pharmaceutically acceptable salt thereof, as the therapeutic agent.
  • the extended release formulation comprises sialic acid, or a pharmaceutically acceptable salt thereof, as the therapeutic agent and further comprises a hydrocolloid polymer, an anionic, pH-dependent gel forming copolymer and a water swel lable, pH independent polymer and optionally further comprises a lubricant and/or an excipient.
  • the extended release formulation comprises sialic acid, or a pharmaceutically acceptable salt thereof, carrageenan, sodium alginate and either hypromellose or polyethylene oxide.
  • the extended release formulation comprises sialic acid, or a pharmaceutically acceptable salt thereof, carrageenan, sodium alginate, either hypromellose or polyethylene oxide, magnesium stearate and microcrystallme cellulose and colloidal silicon dioxide.
  • the extended release formulation is a formulation of Table E.
  • the extended release formulation is a formulation of Table 8.
  • the extended release formulation is a formulation of Example 6.
  • the extended release formulation is a formulation of Example 7.
  • an extended release formulation detailed herein (including but not limited to those listed under the heading "Extended Release Formulations” (e.g., any formulation of Tables A and B) further comprises a lubricant.
  • the lubricant comprises a stearate salt, such as magnesium stearate.
  • the extended release formulation further comprising a lubricant comprises the lubricant in about 0.1 to about 2 or about 0.1 to about 1 .5 or about 0.1 to about 1 .0 or about 0.01 to about 0.09-5 or about 0.1 to about 0.8 or about 0.1 to about 0.7 or about 0.1 to about 0.6 or about 0.1 to about 0.5 or about 0.2 to about 0.8 or about 0.3 to about 0.7 or about 0.4 to about 0.6 or about any one of 0.1 , 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9 or 1.0 weight percent.
  • a lubricant e.g., a stearate salt such as magnesium stearate
  • the extended release formulation comprises sialic acid, or a pharmaceutically acceptable salt thereof, as the therapeutic agent, in another variation, the extended release formulation comprises MaNAc, or a pharmaceutically acceptable salt thereof, as the therapeutic agent. In another variation, the extended release formulation comprises sialic acid, or a pharmaceutically acceptable salt thereof and MaNAc, or a pharmaceutically acceptable salt thereof as the therapeutic agents. In another variation, the extended release formulation comprises a prodrug of one or more compounds in the sialic acid biosynthetic pathway such as a prodrug of sialic acid, or a pharmaceutically acceptable salt thereof, as the therapeutic agent.
  • the extended release formulation comprises sialic acid, or a pharmaceutically acceptable salt thereof, as the therapeutic agent and further comprises a hydrocolloid polymer, an anionic, pH-dependent gel forming co-polymer and a water swellable, pH independent polymer and optionally further comprises a lubricant and/or an excipient.
  • the extended release formulation comprises sialic acid, or a pharmaceutically acceptable salt thereof, carrageenan, sodium alginate and either hypromellose or polyethylene oxide.
  • the extended release formulation comprises sialic acid, or a pharmaceutically acceptable salt thereof, carrageenan, sodium alginate, either hypromellose or polyethylene oxide, magnesium stearate and macrocrystalline cellulose and colloidal silicon dioxide.
  • the extended release formulation is a formulation of Table E.
  • the extended release formulation is a formulation of Table 8.
  • the extended release formulation is a formulation of Example 6.
  • the extended release formulation is a formulation of Example 7.
  • an extended release formulation detailed herein (including but not limited to those listed under the heading "Extended Release Formulations” (e.g., any formulation of Tables A and B) further comprises both an excipient and a lubricant.
  • the formulation further comprising both an excipient and a lubricant comprises the excipient (e.g., an excipient comprising macrocrystalline cellulose and colloidal silicon dioxide) in about 1 to about 20 or about 1 to about 15 or about 1 to about 10 or about 1 to about 5 or about 5 to about 20 or about 5 to about 15 or about 5 to about 10 or about any ⁇ one of 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 weight percent and comprises the lubricant (e.g., a stearate salt such as magnesium stearate) in about 0.1 to about 2 or about 0.1 to about 1.5 or about 0.1 to about 1.0 or about 0.01 to about 0.09-5 or about 0.1 to about 0.8 or about 0.1 to about 0.7 or about 0.1 to about 0.6 or about 0.1 to about 0.5 or about 0.2 to about 0.8 or about 0.3 to about 0.7 or about 0.4 to about 0.6 or about any one of 0.1 , 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.6,
  • the formulation further comprising both an excipient and a lubricant comprises the excipient (e.g., an excipient comprising microcrystalline cellulose and colloidal silicon dioxide) in a weight percent ratio to lubricant (e.g., a stearate salt such as magnesium stearate) of about any of 1 : 10 or 1 :11 or 1 : 9 or 1 : 10.5.
  • the extended release formulation comprises sialic acid, or a pharmaceutically acceptable salt thereof, as the therapeutic agent.
  • the extended release formulation comprises MaNAc, or a pharmaceutically acceptable salt thereof, as the therapeutic agent.
  • the extended release formulation comprises sialic acid, or a pharmaceutically acceptable salt thereof and MaNAc, or a pharmaceutically acceptable salt thereof, as the therapeutic agents.
  • the extended release formulation comprises a prodrug of one or more compounds in the sialic acid biosynthetic pathway such as a prodrug of sialic acid, or a pharmaceutically acceptable salt thereof as the therapeutic agent.
  • the extended release formulation comprises sialic acid, or a pharmaceutically acceptable salt thereof, as the therapeutic agent and further comprises a hydrocolloid polymer, an anionic, pH-dependent gel forming copolymer and a water swellable, pH independent polymer and optionally further comprises a lubricant and/or an excipient.
  • the extended release formulation comprises sialic acid, or a pharmaceutically acceptable salt thereof, carrageenan, sodium alginate and either hypromellose or polyethylene oxide.
  • the extended release formulation comprises sialic acid, or a pharmaceutically acceptable salt thereof, carrageenan, sodium alginate, either hypromellose or polyethylene oxide, magnesium stearate and microcrystalline cellulose and colloidal silicon dioxide.
  • the extended release formulation is a formulation of Table E.
  • the extended release formulation is a formulation of Table 8.
  • the extended release formulation is a formulation of Example 6.
  • the extended release formulation is a formulation of Exampl e 7.
  • compositions include those listed in Table C, where the compositions comprise a therapeutic agent, a polymer 1, a polymer 2, either a polymer 3A or a polymer 3B, an excipient and a lubricant, and it is understood that each and every combination of such components is intended the same as if each and every combination were specifically and individually listed.
  • Table C Exemplary Extended Release Formulation Compositions.
  • Formulation Component Exemplary Specific Components
  • Therapeutic Agent mannosamine, N-acetyl mannosamine (Man Ac), ManNac-6- (A compound in the phosphate (ManNAc-6-P), UDP-GIeNAc, N-aeetymeuraminic sialic acid biosynthetic acid ( euAc), NeuAe-9-phosphate (Ne Ac-9-P), sialic acid ⁇ i.e., pathway or derivative 5-N-acetylneuramimc acid), CMP-sialic acid, and/or derivatives thereof or salt of any of thereof or pharmaceutical ly acceptabl e salts of the foregoing. the foregoing)
  • Carrageenan e.g., iota, kappa or lambda carrageenan, or a salt
  • Hydrocolloid Polymer thereof such as Viscarin GP-209, FMC BioPolymer
  • Polymer 2 Alginate or salt thereof (e.g., sodium, potassium or ammonium
  • gel forming polymer carboxymethyl cellulose or salt thereof (e.g., sodium
  • Polymer 3A Water- Hypromeliose (e.g., hypromellose Type 2208, E and K series swellable, pH such as for example, Dow Chemical Company's (Midland, Mich. independent polymer) USA) or Aqualon's (with a North American presence in
  • hydroxyethyl cellulose e.g., Aqualon's atrasol polymers HHX (mol. Wt. 1,300,000), HX (mol. wt. 1,000,000), H (mol. wt. 1,000,000), M (mol. wt. 720,000 and G (mol. wt.
  • Polymer 3B (Hydrogel- Polyhydroxyethyle methylacrylate (PHEMA), polyvinyl alcohol forming polymer) (PVA), polyvinyl pyrrolidone (PVP), polyethylene oxide (PEO), polyaeryl amide (PA), polyethylene oxide ⁇ e.g., PolyoxTM water soluble resin, Dow Chemical Company, Mich., USA).
  • PHEMA polyvinyl- Polyhydroxyethyle methylacrylate
  • PVA polyvinyl alcohol forming polymer
  • PVP polyvinyl pyrrolidone
  • PEO polyethylene oxide
  • PA polyaeryl amide
  • polyethylene oxide ⁇ e.g., PolyoxTM water soluble resin Dow Chemical Company, Mich., USA.
  • Excipient lactose microcrystalline cellulose, corn starch, potato starch, wheat starch, sucrose, D-matmitol, precipitated calcium carbonate, dextrin, pre-gelatinized starch, mieroerystalline cellulose and colloidal silicon dioxide (e.g., ProSolv® SMCC HD90) and combinations thereof.
  • colloidal silicon dioxide e.g., ProSolv® SMCC HD90
  • Lubricant Stearate salt such as magnesium stearate ⁇ e.g., HyQual®) and calcium stearate
  • talc magnesium stearate ⁇ e.g., HyQual®
  • light anhydrous silicic acid e.g., talc
  • solid poly ethyl glycols and combinations thereof e.g., talc, light anhydrous silicic acid, and solid poly ethyl glycols and combinations thereof.
  • an extended release formulation is a composition as detailed in Table C, wherein the composition comprises the formulation components in any one of the weight percent ranges depicted in Table D. It is understood that each and every combination of such components and we; in percentages is intended the same as if each and every combination of component and weight percentage were specifically and individually listed. Table D. Exemplary Weight Percent of Certain Components for Use in Extended Release
  • hydroxyethyl cellulose e.g., hydroxyethyl cellulose
  • Polymer 3B Polyhydroxyethy 1 e me thy iacry late From about 20 to about 30;
  • PVA polyvinyl alcohol
  • PVP polyvinyl pyrrolidone
  • PEG polyethylene oxide
  • PA polyacrylamide
  • Polyethylene oxide about any of 20, 21 , 22, 23, 24, (e.g., PolyoxTM water soluble resin, Dow 25, 26, 27, 28, 29 and 30. Chemical Company, Mich., USA).
  • Excipient lactose macrocrystalline cellulose, com From about 1 to about 20 or starch, potato starch, wheat starch, about 1 to about 15 or about 1 sucrose, D-mannitoi, precipitated calcium to about 10 or about 1 to about carbonate, dextrin, pre-gelatinized starch, 5 or about 5 to about 20 or microcrystalline cellulose and colloidal about 5 to about 15 or about 5 silicon dioxide (e.g., ProSolv® S CC to about 10 or about any one of HD90) and combinations thereof. 1 , 2, 3, 4, 5, 6, 7, 8, 9 or 10 weight percent.
  • ProSolv® S CC to about 10 or about any one of HD90
  • Lubricant Stearate salt such as magnesium stearate From about 0.1 to about 2 or
  • HyQual® HyQual® and calcium stearate
  • about 0.1 to about 1.5 or about talc light anhydrous silicic acid
  • extended release formulations wherein the formulation comprises a therapeutic agent of Table C, a polymer 1 of Table C, a polymer 2 of Table C, a Polymer 3A or a polymer 3B of Table C, an excipient of Table C and a lubricant of Table C, wherein the components are present in the composition in the following weight percent ratios.
  • the weight percent ratio of Luhrican Poiymer l :ExcipientiPolymer 2iPolymer 3A or 3B:Therapeutie Agent is about 1 :8: 10:40:50:85 or about 1 :8.5 : 10.5 :42.5 :51 :86.5 or about 1 :8.4: 10.6:42.4:51 :86.6.
  • the therapeutic agent in any of the formulae detailed herein, including but not limited to the formulations in any of Tables A-D, in one aspect the therapeutic agent is sialic acid or ManNAc or a pharmaceutically acceptable salt thereof or a combination of sialic acid or ManNAc. In a particular aspect of any of the formulations detailed herein, including but not limited to the formulations in any of Tables A-D, the therapeutic agent is sialic acid, or a pharmaceutically acceptable salt thereof.
  • the components used to formulate the extended release pharmaceutical formulations are preferably of high purity and are substantially free of potentially harmful contaminants (e.g. , at least National Food (NF) grade, generally at least analytical grade, and more typically at least pharmaceutical grade).
  • pharmaceutical formulations intended for in vivo use are usually sterile. To the extent that a given compound must be synthesized prior to use, the resulting product is typically substantially free of any potentially toxic agents which may be present during the synthesis or purification process.
  • Compositions for parental administration are also sterile, substantially isotonic and made under GMP conditions.
  • the blends of the extended release formulation may have a particle size with a majority of particles being retained by a sieve size of 45 ⁇ . In some embodiments, the blends of the extended release formulation have a particle size with at least any one of 10%, 30%, 40%, 50% of particles retained by a sieve size of 45 ⁇ .
  • the extended release pharmaceutical formulations as described herein may be formulated into preparations in solid, semi-solid, liquid or gaseous forms, such as tablets, capsules, powders, granules, ointments, solutions, suppositories, injections, inhalants, gels, microspheres, and aerosols.
  • the extended release pharmaceutical formulations is formulated for administration by a variety of routes including oral, parenteral (including subcutaneous, intravenous, intramuscular and intraperitoneal), rectal, dermal, transdermal, intrathoracic, intrapulmonary and intranasal (respiratory) routes.
  • the extended release pharmaceutical formulation is formulated for oral administration.
  • any of the extended release formulations detailed herein may in one variation he formulated for oral administration.
  • any of the formulations provided under the heading "Extended Release Formulations,” including but not limited to any of the formulations set forth in Tables A-E, Example 6, or Example 7 may in one variation be a formulation that is suitable for oral administration.
  • a formulation that is suitable for oral administration may be formulated as a solid oral dosage form, such as a tablet or a capsule comprising the formulation as a powder
  • a solid oral dosage form of an extended release formulation is provided wherein the solid oral dosage form comprises any formulation provided herein (including but not limited to the formulations set forth in any one of Tables A-E, Example 6, or Example 7) in tablet form, wherein the tablet further comprises a coating (e.g., Opadr -II White).
  • the extended release formulation comprises sialic acid, or a pharmaceutically acceptable salt thereof, as the therapeutic agent.
  • the extended release formulation comprises MaNAc, or a pharmaceutically acceptable salt thereof, as the therapeutic agent.
  • the extended release formulation comprises sialic acid, or a pharmaceutically acceptable salt thereof and MaNAc, or a pharmaceutically acceptable salt thereof, as the therapeutic agents.
  • the extended release formulation comprises a prodrug of one or more compounds in the sialic acid biosynthetic pathway such as a prodrug of sialic acid, or a pharmaceutically acceptable salt thereof, as the therapeutic agent.
  • the extended release formulation comprises sialic acid, or a pharmaceutically acceptable salt thereof, as the therapeutic agent and further comprises a hydrocolloid polymer, an anionic, pH-dependent gel forming co-polymer and a water swellable, pH independent polymer and optionally further comprises a lubricant and/or an excipient.
  • the extended release formulation comprises sialic acid, or a pharmaceutically acceptable salt thereof, carrageenan, sodium alginate and either hypromellose or polyethylene oxide.
  • the extended release formulation comprises sialic acid, or a pharmaceutically acceptable salt thereof, carrageenan, sodium alginate, either hypromellose or polyethylene oxide, magnesium stearate and microcrystalline cellulose and colloidal silicon dioxide.
  • the extended release fommlation is a formulation of Table E.
  • the extended release formulation is a formulation of Table 8.
  • the extended release formulation is a formulation of Example 6.
  • the extended release formulation is a formulation of Example 7.
  • sialic acid biosynthetic pathway or derivative thereof as described herein can be administered in solid dosage forms, such as capsules, tablets, and powders, or in liquid dosage forms, such as elixirs, syrups, and suspensions.
  • the pharmaceutical formulations comprise an enteric- coating.
  • enteric- coatings Numerous types of acid-resistant enteric coatings are available. Examples of the acid-resistant coatings include cellulose acetate phthalate, polyvinyl acetate phthalate, shellac, an acrylic acid homopolymer or copolymer, a methacrylic acid homopolymer or copolymer, cellulose acetate trimellitate, hydroxypropyi methylcellulose phthalate or a combination of thereof.
  • a number of copolymers of methacrylic acid are known in the art and are commercially available.
  • the enteric coating comprises one or more of titanium dioxide, poly dextrose, hypromeliose, triacetin and macrogol/ ' PEG. In some embodiments, the enteric coating is Opadry® I I White.
  • the enteric coating (e.g., Opadry® II White) comprises about 1-5% w/w of the extended release formulation. In some embodiments, the enteric coating (e.g., Opadry® II White) comprises about 1-5% w/w of the extended release formulation.
  • An enteric coating can also be a time-release coating.
  • the time-release coatings are degraded away at a relatively constant rate until the coatings dissolve sufficiently for the time-release coatings to rupture.
  • the time required for the rupture of the enteric coatings is largely time-dependent ⁇ i.e., thickness), and largely pH independent.
  • time-release coating materials include cellulose acetate, cellulose acetate butyrate, cellulose acetate propionate, EC, and copolymers of aery late and methacrylates with quaternary ammonium groups such as Eudragit® RL and Eudragit® RS and Eudragit® NE30-D.
  • the extended release pharmaceutical formulations can be further subjected to a process of film coating.
  • an enteric or non-enteric film coating agent may be used, and the enteric film, coating agent can be cellulose acetate phthalate (CAP), polyvinyl acetate phthalate (PVAP), a methaerylate polymer (Eudragit L, S), or the like, while the non-enteric film coating agent can be hydroxypropylcellulose (HPC), MC, EC, HPMC, povidone, PVA, CA, shellac, or the like.
  • the process of coating can be performed by. for example, a pan coatmg method, a fluidized bed coating method, a compression coating method, or the like.
  • Coated tablets of the extended release formulation may be prepared in various sizes.
  • the coated tablets may have a length of about 16-20 mm, a width of about 7-12 mm and a thickness of about 5-8 mm, in some embodiments, the coated tablets have a length of about 17.7 mm, a width of about 9, 1 mm and a thickness of about 6.7 mm. In some embodiments, the coated tablets have a length of about 19.3 mm, a width of about 9,7 mm and a thickness of about 8.0 mm.
  • the extended release formulation comprises a drag load of about 30-60% (e.g., sialic acid and/or ManNAc), about 20-30% w/w of a water-swell able, pH independent polymer (e.g.
  • hypromellose about 20-25% w/w of an anionic, pH-dependent, gel-forming copolymer (e.g., an alginate salt), about 1-5 % w/w of a hydrocolloid polymer (e.g., a carrageenan), about 1-10% w/w of microcrystalline cellulose and colloidal silicon dioxide (e.g., Prosolv® SMCC D90), about 0.1-1% w/w/ magnesium stearate (e.g. HyQual®), and about 1-5% of an enteric coating (e.g. Qpadry® II White).
  • an anionic, pH-dependent, gel-forming copolymer e.g., an alginate salt
  • a hydrocolloid polymer e.g., a carrageenan
  • microcrystalline cellulose and colloidal silicon dioxide e.g., Prosolv® SMCC D90
  • 0.1-1% w/w/ magnesium stearate e.g. HyQual®
  • the extended release formulation comprises a drug load of about 30-60% (e.g., sialic acid and/or ManNAc), about 20-30%) w/w hypromellose (e.g. hypromellose Type 2208 or Methocel K100M), about 20-25% w/w sodium alginate (e.g. Protanal), about 1-5% w/w lambda carrageenan (e.g. Viscarin GP-209), about 1-10% w/w of microcrystalline cellulose and colloidal silicon dioxide (e.g., Prosolv® SMCC HD90), about 0.1 - 1% w/w/ magnesium stearate (e.g.
  • a drug load of about 30-60% (e.g., sialic acid and/or ManNAc), about 20-30%) w/w hypromellose (e.g. hypromellose Type 2208 or Methocel K100M), about 20-25% w/w sodium alginate (e.g. Protanal
  • the extended release formulation comprises a drug load of about 30-60%) (e.g., sialic acid and/or ManNAc), about 25% w/w of a water-swellable, pH independent polymer (e.g.
  • an anionic, pH-dependent, gel- forming copolymer e.g., an alginate salt
  • a hydrocolloid polymer e.g., a carrageenan
  • microcrystalline cellulose and colloidal silicon dioxide e.g., Prosolv® SMCC D90
  • w/w/ magnesium stearate e.g., HyQual®
  • enteric coating e.g., Qpadry® II White
  • the extended release formulation comprises a drug load of about 30-60% (e.g., sialic acid and/or ManNAc), about 25% w/w hypromellose (e.g., hypromellose Type 2208 or Methocel K100M), about 21% w/w sodium alginate (e.g. Protanal), about 4% w/w lambda carrageenan (e.g. Viscarin GP-209), about 5% w/w of microcrystalline cellulose and colloidal silicon dioxide (e.g., Prosolv ⁇ SMCC HD90), about 0.5% w/w/ magnesium stearate (e.g. HyQual®), and about 3.5% of an enteric coating (e.g. Opadry® II White).
  • a drug load of about 30-60% (e.g., sialic acid and/or ManNAc), about 25% w/w hypromellose (e.g., hypromellose Type 2208 or Methocel K100M), about 21%
  • the extended release formulation comprises a drug load of about 30-60% (e.g., sialic acid and/or ManNAc), about 20-30% w/w of a hydrogel (e.g. polyethylene oxide), about 20-25% w/w of an anionic, pH -dependent, gef- forming copolymer (e.g., an alginate salt), about 1-5 % w/w of a hydrocolloid polymer (e.g., a carrageenan), about 1-10% w/w of microcrystalfine cellulose and colloidal silicon dioxide (e.g., Prosolv® SMCC HD90), about 0.1-1% w/w/ magnesium stearate (e.g.
  • a drug load of about 30-60% (e.g., sialic acid and/or ManNAc), about 20-30% w/w of a hydrogel (e.g. polyethylene oxide), about 20-25% w/w of an anionic, pH -dependent, gef- forming copoly
  • the extended release formulation comprises a drug load of about 30-60% (e.g., sialic acid and/or ManNAc), about 20-30% w/w polyethylene oxide (e.g. Polyox WSR), about 20-25% w/w sodium alginate (e.g. Protanal), about 1-5% w/w lambda carrageenan (e.g. Viscarin GP-209), about 1-10% w/w of microcrystalline cellulose and colloidal silicon dioxide (e.g., Prosolv® SMCC i 11)90 ⁇ .
  • a drug load of about 30-60% (e.g., sialic acid and/or ManNAc), about 20-30% w/w polyethylene oxide (e.g. Polyox WSR), about 20-25% w/w sodium alginate (e.g. Protanal), about 1-5% w/w lambda carrageenan (e.g. Viscarin GP-209), about 1-10% w/w of microcrystalline cellulose and coll
  • the extended release formulation comprises a drug load of about 30-60% (e.g., sialic acid and/or ManNAc), about 25%) w/w of a hydrogel (e.g.
  • polyethylene oxide polyethylene oxide
  • an anionic, pH-dependent, gel-forming copolymer e.g., an alginate salt
  • a hydrocolloid polymer e.g., a carrageenan
  • microcrystalline cellulose and colloidal silicon dioxide e.g., Prosolv® SMCC HD90
  • microcrystalline cellulose and colloidal silicon dioxide e.g., Prosolv® SMCC HD90
  • w/w/ magnesium stearate e.g. HyQual®
  • an enteric coating e.g. Opadry® II White
  • the extended release formulation comprises a drug load of about 30-60% (e.g., sialic acid and/or ManNAc), about 25%) w/w polyethylene oxide (e.g. Polyos WSR), about 21% w/w sodium alginate (e.g. Protanal), about 4% w/w lambda carrageenan (e.g. Viscarin GP-209), about 5% w/w of microcrystalline cellulose and colloidal silicon dioxide (e.g., Prosolv® SMCC HD90), about 0.5% w/w,' magnesium stearate (e.g. HyQual®), and about 3.5% of an enteric coating (e.g. Opadry® II White).
  • a drug load of about 30-60% (e.g., sialic acid and/or ManNAc), about 25%) w/w polyethylene oxide (e.g. Polyos WSR), about 21% w/w sodium alginate (e.g. Protanal), about 4% w/w
  • the extended release formulation comprises about 25% to about 50% w/w of a sialic acid, or a pharmaceutically acceptable salt, solvate, or ester thereof; about 20% to about 40% w/w of one or more water-swellable, pH independent- polymers or one or more hydrogel- forming polymers; about 15% to about 30% w/w of one or more anionic, pH-dependent, gel-forming polymers; and about 3% to about 8% w/w of one or more hydrocoiloid polymers or one or more cationic polymers,
  • the extended release formulation comprises about 25% to about 50%) w/w of a sialic acid, or a pharmaceutically acceptable salt, solvate, or ester thereof; about 20% to about 30% w/w hypromeliose; about 3% to about 8% w/w carrageenan; and about 20% to about 25% w/w sodium alginate.
  • the extended release formulation comprises about 30% to about 45% w/w of a sialic acid.
  • the extended release formulation comprises about 22% to about 27% w/w hypromeliose.
  • the extended release formulation comprises about 4% to about 6%) w/w carrageenan.
  • the extended release formulation comprises about 20% to about 23% w/w carrageenan. In one embodiment, the extended release formulation further comprises about 1% to about 10% w/w of the mixture of microcrystalline cellulose and colloidal silicon dioxide; and about 0.1% to about 1% w/w magnesium stearate, [00133] In one embodiment, the extended release formulation comprises about 25%> to about 50% w/w of a sialic acid, or a pharmaceutically acceptable salt, solvate, or ester thereof; about 20% to about 30% w/w at least one of polyethylene glycol and polyethylene oxide; about 3% to about 8% w/w carrageenan; and about 20% to about 25% w/w sodium alginate.
  • the extended release formulation comprises about 30% to about 45% w/w of a sialic acid. In one embodiment, the extended release formulation comprises about 22% to about 27% w/w at least one of polyethylene glycol and polyethylene oxide. In one embodiment, the extended release formulation comprises about 4% to about 6% w/w carrageenan. In one embodiment, the extended release formulation comprises about 20% to about 23%) w/w carrageenan. In one embodiment, the extended release formulation further comprises about 1% to about 10% w/w of the mixture of microcrystalline cellulose and colloidal silicon dioxide; and about 0.1% to about 1% w/w magnesium stearate.
  • the extended release formulation comprises about
  • the extended release formulation is in 325 mg and 500 mg dosage form.
  • the present invention provides a method for treating a sialic acid deficiency in an individual in need thereof.
  • the method comprises orally administering a sialic acid, or a pharmaceutically acceptable salt, solvate, or ester thereof, and provides a therapeutically effective amount of sialic acid over a period of greater than about four hours.
  • the sialic acid, or a pharmaceutically acceptable salt, solvate, or ester thereof is in an extended release formulation, such as the ones described herein.
  • the sialic acid, or a pharmaceutically acceptable salt, solvate, or ester thereof is in both an extended release formulation, such as the ones described herein, and an immediate release formulation.
  • the extended release formulation and the immediate release formulation can be in separate dosage forms and be administered in a coordinated fashion.
  • an individual can take a dosage form of the extended release formation and a dosage form of the immediate release formulation concomitantly.
  • extended release formulation and the immediate release formulation can be formulated in a single dosage form.
  • a single dosage form of a sialic acid, or a pharmaceutical ly acceptable salt, solvate, or ester thereof can comprise an extended release component and an immediate relapse component.
  • the sialic acid, or a pharmaceutically acceptable salt, solvate, or ester thereof is administered on a regular dosing schedule having one or more dosing intervals per day.
  • the sialic acid, or a pharmaceutically acceptable salt, solvate, or ester thereof can be administered once, twice, three or four times per day.
  • sialic acid, or a pharmaceutically acceptable salt, solvate, or ester thereof! is administered three times per day (TID).
  • the present method provides a therapeutically effective amount of sialic acid over a period of greater than about eight hours per day. In some embodiments, the present method provides a therapeutically effective amount of sialic acid over a period of greater than about ten, twelve, fourteen, sixteen, or eighteen hours per day. For example, the present method provides a therapeutically effective amount of sialic acid over a period of about eight to about ten, about eight to about twelve, about eight to about fourteen, about eight to about sixteen, about ten to about fourteen, about twelve to about sixteen, or about sixteen to about twenty hours per day.
  • the present method provides a mean C m j n sialic acid of at least about 0.1 1 meg/ml at steady state during the dosing intervals. In some embodiments, the present method provides a mean C mm - sialic acid of at least about 0.12 mcg/ml, about 0.13 mcg/ml, about 0.14 mcg/ml, about 0.15 mcg/ml, about 0.16 mcg/ml, about 0.17 mcg/ml at steady state during the dosing intervals.
  • the present method provides a mean plasma concentration of sialic acid of at least about 0.16 mcg/ml at steady state during the dosing intervals. In some embodiments, the present method provides a mean plasma concentration of sialic acid of at least about 0.17 mcg/ml, about 0.18 mcg/ml, about 0.19 mcg/ml, about 0.20 mcg/ml, about 0.21 mcg/ml, about 0.22 mcg/ml, about 0.23 mcg/ml, about 0.24 mcg/ml at steady state during the dosing intervals.
  • the present method provides a mean plasma concentration of sialic acid at steady state during the dosing intervals that is at least about 50% higher than the mean plasma concentration of sialic acid in the mdividual before the administration of the sialic acid, or a pharmaceutically acceptable salt, solvate, or ester thereof.
  • the present method provides a mean plasma concentration of sialic acid at steady state during the dosing intervals that is at least about 60%, 70%, 80%, 90%, 100%, 110%, 120%, 130%, 140%, 150%, 160%, 170%, 180%, 190%, or 200%, higher than the mean plasma concentration of sialic acid in the individual before the administration of the sialic acid, or a pharmaceutically acceptable salt, solvate, or ester thereof.
  • the present method provides a plasma concentration profile of sialic acid at steady state such that the minimum plasma concentration of sialic acid during the dosing interval is at least about 35% of the maximum plasma concentration during the dosing interval. In some embodiments, the present method provides a plasma concentration profile of sialic acid at steady state such that the minimum plasma concentration of sialic acid during the dosing interval is at least about 40%, 45%, 50%, 55%, or 60% of the maximum plasma concentration during the dosing interval.
  • the present method provides an improved absorption profile when the extended release formulation is administered under fed conditions than being administered under fasting conditions.
  • the improved absorption profile includes that the mean C max determined at a fasted state is higher than the mean C max determined at a fed state.
  • the mean C max determined at a fasted state is about 10%, 15%, 20%, 25%, 30%, or 35% higher than the mean C max determined at a fed state.
  • the improved absorption profile includes that the mean T ma; ⁇ determined at a fed state is higher than the mean T max determined at a fasted state.
  • the ratio of the mean T max determined at a fed state and the mean T, tiax determined at a fasted state is about 1.2: 1 ; 13 : 1 ; 1 .4: 1 ; 1 .5 : 1 ; 1 .6: 1 ; 1 .7: 1 ; 1 .8: 1 ; 1 .9: 1 ; or 2: 1.
  • the extended release formulations detailed herein including but not limited to those detailed under the heading "Extended Release Formulation” and " ' Additional Formulation Components” (e.g., any of the formulations of Tables A-E, Example 6 or Example 7) may exhibit any of the characteristics detailed herein and belo w.
  • any of the extended release formulations detailed herein may exhibit any one or more of the following characteristics: (i) capable of delivering to an individual in need thereof a therapeutically effective amount of one or more compounds in the sialic acid pathway or derivatives thereof over a period of about or greater than about any of 8, 9, 10, 1 1 , 12, 13, 14, 15, 16, 17, 18, 19, or 20 hours; (ii) capable of delivering to an individual in need thereof a substantially constant therapeutically effective amount of one or more compounds in the sialic acid pathway or derivatives thereof over a period of about or greater than about any of 8, 9, 10, 1 1 , 12, 13, 14, 15, 16, 1 7, 18, 19, or 20 hours; (iii) capable of delivering to an individual in need thereof a therapeutically effective amount of one or more compounds in the sialic acid pathway or derivatives thereof with a T max of between about any of 2-6 hours, 2-5 hours, or 3-6 hours during each dosing interval; (iv) capable of delivering to an individual in need thereof a therapeutically effective amount of one or more compounds in
  • the extended release formulation comprises sialic acid, or a pharmaceutically acceptable salt thereof, as the therapeutic agent.
  • the extended release formulation comprises MaNAc, or a pharmaceutically acceptable salt thereof, as the therapeutic agent.
  • the extended release formulation comprises sialic acid, or a pharmaceutically acceptable salt thereof and MaNAc, or a pharmaceutically acceptable salt thereof as the therapeutic agents.
  • the extended release formulation comprises a prodrug of one or more compounds in the sialic acid biosynthetic pathway such as a prodrug of sialic acid, or a pharmaceutically acceptable salt thereof, as the therapeutic agent.
  • the extended release formulation comprises sialic acid, or a pharmaceutically acceptable salt thereof, as the therapeutic agent and further comprises a hydrocolloid polymer, an anionic, pH-dependent gel forming co-polymer and a water swellable, pH independent polymer and optionally further comprises a lubricant and/or an excipient.
  • the extended release formulation comprises sialic acid, or a pharmaceutically acceptable salt thereof, carrageen an, sodium alginate and either hypromellose or polyethylene oxide.
  • the extended release formulation comprises sialic acid, or a pharmaceutically acceptable salt thereof, carrageenan, sodium alginate, either hypromellose or polyethylene oxide, magnesium stearate and microcrystailine cellulose and colloidal silicon dioxide.
  • the extended release formulation is a formulation of Table E.
  • the extended release formulation is a formulation of Table 8.
  • the extended release formulation is a formulation of Example 6.
  • the extended release formulation is a formulation of Example 7.
  • the extended release formulation is capable of delivering to an individual in need thereof a therapeutically effective amount of one or more compounds in the sialic acid pathway or derivatives thereof over a period of greater than about any of 8, 9, 10, 1 1, 12, 13, 14, 15, 16, 17, 18, 19, or 20 hours. In some embodiments, the extended release formulation is capable of delivering to an individual in need thereof a therapeutically effective amount of one or more compounds in the sialic acid pathway or derivatives thereof over a period of greater than about 12 hours or greater than about 24 hours.
  • the extended release formulation is capable of delivering to an individual in need thereof a therapeutically effective amount of one or more compounds in the sialic acid pathway or derivatives thereof over a period of between about any of 6-10 hours, 8-12 hours, 10-16, or 12-20 hours, in embodiments of any of the extended release formulations, the extended release formulation is capable of delivering to an individual in need thereof a therapeutically effective amount of one or more compounds in the sialic acid pathway or derivatives thereof over a period of about any of 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 hours.
  • the extended release formulation is capable of delivering to an individual in need thereof a therapeutically effective amount of one or more compounds in the sialic acid pathway or derivatives thereof over a period of about 12 hours or about 24 hours.
  • the therapeutically effective amount is delivered to the bloodstream of the individual.
  • the therapeutically effective amount is delivered to muscle tissue of the individual.
  • the one or more compounds in the sialic acid pathway or derivatives thereof include MaiiNAc or a derivative thereof and/or sialic acid or a derivative thereof.
  • the extended release formulation is capable of delivering to an individual in need thereof a therapeutically effective amount of ManNAc and/or sialic acid to muscle tissue of the individual over a period of between about any of 6-10 hours, 8-12 hours, 10-16, or 12-20 hours.
  • the extended release formulation comprises sialic acid, or a pharmaceutically acceptable salt thereof, as the therapeutic agent.
  • the extended release formulation comprises MaNAc, or a pharmaceutically acceptable salt thereof, as the therapeutic agent.
  • the extended release formulation comprises sialic acid, or a pharmaceutically acceptable salt thereof and MaNAc, or a pharmaceutically acceptable salt thereof, as the therapeutic agents.
  • the extended release formulation is capable of delivering to an individual in need thereof a substantially constant (i.e., without large burst of drug availability and deficiencies in drug availability to the blood and/or tissues of interest (e.g., muscle tissue)) therapeutically effective amount of one or more compounds in the sialic acid pathway or derivatives thereof over a period of greater than about any of 8, 9, 10, 1 1, 12, 13, 14, 15, 16, 17, 18, 19, or 20 hours.
  • the extended release formulation is capable of delivering to an individual in need thereof a substantially constant therapeutically effective amount of one or more compounds in the sialic acid pathway or derivatives thereof over a period of between about any of 6-10 hours, 8-12 hours, or 10-16, or 12-20 hours. In embodiments of any of the extended release formulations, the extended release formulation is capable of delivering to an individual in need thereof a substantially constant therapeutically effective amount of one or more compounds in the sialic acid pathway or derivatives thereof over a period of about any of 8, 9, 10, 1 1, 12, 13, 14, 15, 16, 17, 18, 19, or 20 hours.
  • the one or more compoimds in the sialic acid pathway or derivatives thereof include ManNAc or a derivative thereof and/or sialic acid or a derivative thereof.
  • the extended release formulation is capable of delivering to an individual in need thereof a substantially constant therapeutically effective amount of ManNAc and/or sialic acid to muscle tissue of the individual over a period of between about any of 6-10 hours, 8-12 hours, or 10-16, 12-20 hours.
  • the extended release formulation comprises sialic acid, or a pharmaceutically acceptable salt thereof, as the therapeutic agent.
  • the extended release formulation comprises MaNAc, or a pharmaceutically acceptable salt thereof, as the therapeutic agent.
  • the extend ed release formulation comprises sialic acid, or a pharmaceutic ally ac ceptable salt thereof and MaNAc, or a pharmaceutical ly acceptable salt thereof, as the therapeutic agents.
  • the extended release formulation is capable of delivering to an individual in need thereof a therapeutically effective amount of one or more compounds in the sialic acid pathway or derivatives thereof with a Cmax of about 0.1-0.9 ,ug/mL, 0.1-100 ⁇ ig/mL, 0.2-0.3 ⁇ ig/mL, or 0.5-100 ⁇ ig/mL.
  • the extended release formulation is capable of delivering to an individual in need thereof a therapeutically effective amount of one or more compounds in the sialic acid pathway or derivatives thereof with a C max of about any one 0.5-80 ⁇ / ⁇ ,, 0.5-60 ⁇ ig/mL, 0.5 - 40 jig/mL or 0.5 - 20 ⁇ ig/mL. In some embodiments, the extended release formulation is capable of delivering to an individual in need thereof a therapeutically effective amount of one or more compounds in the sialic acid pathway or derivatives thereof with a Cmax of about 0.5 - 40 p.g/mL.
  • the extended release formulation is capable of delivering to an individual in need thereof a therapeutically effective amount of one or more compounds in the sialic acid pathway or derivatives thereof with a C max of about any one of 0.5 - 35 ⁇ ig/mL, 0.5 - 30 ⁇ ig/mL, 0.5 - 25 p,g/mL, 1- 40 ⁇ / ⁇ ⁇ _,, 2.5 - 40 p,g/mL, 5
  • - 40 ⁇ , 0.5 - 35 ⁇ g/mL, 1 - 35 pg/mL, 2.5 - 35 ⁇ g/mL, 5 - 35 ⁇ / ⁇ , 0.5 - 30 ⁇ / ⁇ 1,, 1 - 30 u mf .. 2.5 - 30 ug mi.. 5 - 30 uu ml .. 0.5 - 25 uu ml .. 0.1 - 0.3 im mi..
  • the extended release formulation is capable of delivering to an individual in need thereof a therapeutically effective amount of one or more compounds in the sialic acid pathway or derivatives thereof with a C max of about 0.5 - 20 ⁇ ./ ⁇ .. In some embodiments, the extended release formulation is capable of delivering to an individual in need thereof a therapeutically effective amount of one or more compounds in the sialic acid pathway or derivatives thereof with a C max of about 0.1 - 1 pg/mL.
  • the extended release formulation is capable of delivering to an individual in need thereof a therapeutically effective amount of one or more compounds in the sialic acid pathway or deri vatives thereof with a C max of about any one of 0.5 - 15 pg/mL, 0.5 - 10 pg/mL, 1 - 20 ⁇ / ⁇ , 2.5 - 20 ,ug/mL, 5 - 20 ⁇ g/mL, 0.5 - 15 ug/mL, 1 - 15 ⁇ ig/mL, 2.5 - 15 ⁇ ig/mL, 5 - 15 ⁇ ig/mL, 0.5 - 10 ⁇ ig/mL, 1 - 10 jig/mL, 2.5 - 10 jig/mL, or 5 - 10 Lig/mL.
  • the one or more compounds in the sialic acid pathway or derivatives thereof include ManNAc and/or sialic acid. In some embodiments, the one or more compounds in the sialic acid pathway or derivatives thereof include sialic acid.
  • the extended release formulation comprises sialic acid, or a pharmaceutically acceptable salt thereof, as the therapeutic agent. In another variation, the extended release formulation comprises MaNAc, or a pharmaceutically acceptable salt thereof as the therapeutic agent. In another variation, the extended release formulation comprises sialic acid, or a pharmaceutically acceptable salt thereof and MaNAc, or a pharmaceutically acceptable salt thereof, as the therapeutic agents.
  • the extended release formulation is capable of delivering to an individual in need thereof a therapeutically effective amount of one or more compounds in the sialic acid pathway or derivatives thereof with a trough level of about 0.05 - 0.2 _ug/mL, 0.05 - 0.3 ⁇ ig/mL, 0.1 - 0.3 ug/ L, or 0.1 - 20 pg/mL.
  • the extended release formulation is capable of delivering to an individual in need thereof a therapeutically effective amount of one or more compounds in the sialic acid pathway or derivatives thereof with a trough level of about any one of 0.05 - 0.2 ⁇ ig/mL, 0.05 - 0.3 ⁇ ig/mL, 0.1 - 0.2 ug/mL, 0.1 - 0.3 p,g/rnL, 0.2 - 0.3 pg/mL, 0.1 - 15 , ug/mL, 0.1 - 10 .iig/mL, 0.1 - 5 , ug/mL, 0.5 - 20, pg/mL, 0.5 - 15 ug/mL, 0.5 - 10 ⁇ ig/mL, 0.5 - 5 p,g/mL, 1 - 20 ⁇ ig/mL, 1 - 15 pg/mL, 1 - 10 ⁇ g/mL,
  • the extended release formulation is capable of delivering to an individual in need thereof a therapeutically effective amount of one or more compounds in the sialic acid pathway or derivatives thereof with a trough level of about 0.05-0.3 ig/mL.
  • the one or more compounds in the sialic acid pathway or derivatives thereof include ManNAc and/or sialic acid .
  • the one or more compounds in the sialic acid pathway or derivatives thereof include sialic acid.
  • the extended release formulation comprises sialic acid, or a pharmaceutically acceptable salt thereof, as the therapeutic agent.
  • the extended release formulation comprises Ma Ac, or a pharmaceutically acceptable salt thereof, as the therapeutic agent.
  • the extended release formulation comprises sialic acid, or a pharmaceutically acceptable salt thereof and MaNAc, or a pharmaceutically acceptable salt thereof, as the therapeutic agents.
  • the extended release formulation is administered three times a day (TID) to provide a therapeutic effect for throughout the day, i.e., about 24 hours.
  • TID three times a day
  • the extended release formulation can be taken by a patient approximately every 8 hours on a daily basis.
  • the extended release formulation provides a mean maximum plasma concentration of sialic acid from about 0.1 to about 1 p.g/mL from a mean of about 0.5 to about 6 hours after a first administration.
  • the extended release formulation provides a mean maximum plasma concentration of sialic acid from about 0, 15 to about 0.85 ⁇ g mL from a mean of about 1 to about 5.5 hours after a first administration.
  • the extended release formulation provides a mean maximum plasma concentration of sialic acid from about 0.2 to about 0.7 ⁇ / ⁇ _, from a mean of about 1.5 to about 5 hours after a first administration. In another embodiment, the extended release formulation provides a mean maximum plasma concentration of sialic acid from about 0.25 to about 0.55 ⁇ ig/mL from a mean of about 2 to about 4.5 hours after a first administration. In another embodiment, the extended release formulation provides mean a maximum plasma concentration of sialic acid from about 0.3 to about 0.5 g/mL from a mean of about 2.5 to about 4 hours after a first administration.
  • the extended release formulation provides a mean minimum plasma concentration of sialic acid from about 0.1 to about 0.5 ⁇ g mL from a mean of about 6 to about 8 hours after repeated administration approximately eve ' 8 hours through steady-state conditions.
  • the extended rel ease formulation provides a mean minimum plasma concentration of sialic acid from about 0.15 to about 0.45 ⁇ , from a mean of about 6 to about 8 hours after repeated administration approximately even' 8 hours through steady-state conditions.
  • the extended release formulation provides a mean minimum plasma concentration of sialic acid from about 0.2 to about 0,4 ⁇ g/mL from a mean of about 6 to about 8 hours after repeated administration approximately every 8 hours through steady-state conditions.
  • the extended release formulation provides a mean minimum plasma concentration of sialic acid from about 0.25 to about 0.35 ( ug/mL from a mean of about 6 to about 8 hours after repeated administration approximately every 8 hours through steady-state conditions,
  • the extended release formulation when administered to a patient on a regular dosing schedule, provides to the patient a therapeutic effect continuously over the period of the regular dosing schedule. That is, the therapeutic effect, once attained after the first administration, is constant during the period of the regular dosing schedule which includes multiple dosing intervals.
  • the regular schedule can be a dosing regimen provided by instructions accompanying the extended release formulation product.
  • such dosing regimen can be fixed or variable amount of the extended release formulation taken once per day, twice per day, three times per day, or four times per day.
  • a total amount of about 650 mg to about 6000 mg sialic acid, or a pharmaceutically acceptable salt, solvate, or ester thereof is administered to a patient per day on a regular dosing schedule.
  • a total amount of about 1950 mg to about 6000 mg sialic acid, or a pharmaceutically acceptable salt, solvate, or ester thereof is administered to a patient per day on a regular dosing schedule.
  • the regular dosing schedule refers to one or more administrations with approximately equal dosing intervals in each dosing cycle. For example, a three times per day (TID) dosing schedule denotes administration of the drug three times per day with approximately eight- hours dosing intervals.
  • about 650 mg of sialic acid, or a pharmaceutically acceptable salt, solvate, or ester thereof is administered to a patient once per day. In one embodiment, about 650 mg of sialic acid, or a pharmaceutically acceptable salt, solvate, or ester thereof is administered to a patient on a three times per day dosing schedule, in one embodiment, about 650 mg of sialic acid, or a pharmaceutically acceptable salt, solvate, or ester thereof, is administered to a patient on a three times per day dosing schedule.
  • about 650 mg of sialic acid, or a pharmaceutically acceptable salt, solvate, or ester thereof is administered to a patient on a three times per day dosing schedule (total amount of about 1950 mg per day). In one embodiment, about 975 mg of sialic acid, or a pharmaceutically acceptable salt, solvate, or ester thereof, is administered to a patient on a three times per day dosing schedule (total amount of about 2925 mg per day). In one embodiment, about 1000 mg of sialic acid, or a pharmaceutically acceptable salt, solvate, or ester thereof, is administered to a patient on a three times per day dosing schedule (total amount of about 3000 mg per day).
  • about 1500 mg of sialic acid, or a pharmaceutically acceptable salt, solvate, or ester thereof is administered to a patient on a three times per day dosing schedule (total amount of about 4500 mg per day).
  • about 1625 mg of sialic acid, or a pharmaceutically acceptable salt, solvate, or ester thereof is administered to a patient on a three times per day dosing schedule (total amount of about 4875 mg per day).
  • about 2000 mg of sialic acid, or a pharmaceutically acceptable salt, solvate, or ester thereof is administered to a patient on a three times per day dosing schedule (total amount of about 6000 mg per day).
  • about 4000 mg of sialic acid, or a pharmaceutically acceptable salt, solvate, or ester thereof is administered to a patient on a three times per day dosing schedule (total amount of about 12000 mg per day).
  • about 2000 mg of sialic acid, or a pharmaceutically acceptable salt, solvate, or ester thereof, in extended release formulaion and about 2000 mg of sialic acid, or a pharmaceutically acceptable salt, solvate, or ester thereof, in immediate release formulaion are administered to a patient in combination on a three times per day dosing schedule (total amount of about 12000 mg per day).
  • the extended release formulation when admmistered to a patient on a regular dosing schedule, provides a relatively flat plasma concentration profile of sialic acid at steady state, wherein there are no substantial peak or trough in the relatively flat plasma concentration profile and the minimum plasma concentration of sialic acid in the relatively flat plasma concentration profile is sufficient to provide a therapeutic effect to the patient.
  • the extended release formulation when administered to a patient on a regular dosing schedule, provides a relatively flat plasma concentration profile of sialic acid at steady state such that a mean C m j n /C, court a x sialic acid ratio during the dosing interval is about 0.40 to about 1.0, about 0.45 to about 1.0, about 0.5 to about 1.0, about 0.55 to about 1.0, about 0.6 to about 1.0, or about 0.65 to about 1.0, or about 0.7 to about 1.0, or about 0.75 to about 1.0, or about 0.8 to about 1.0, or about 0.85 to about 1.0, or about 0.9 to about 1.0, or about 0.95 to about 1.0 and the C, t ,j hail is sufficient to provide a therapeutic effect.
  • the extended release formulation when admmistered to a patient a three times a day (TDD), provides a mean Cg/Cmax sialic acid ratio of about 0.40 to about 1.0, about 0.45 to about 1.0, about 0.5 to about 1.0, about 0.55 to about 1.0, about 0.6 to about 1.0, or about 0.65 to about 1.0, or about 0.7 to about 1.0, or about 0.75 to about 1.0, or about 0.8 to about 1.0, or about 0.85 to about 1.0, or about 0.9 to about 1.0, or about 0.95 to about 1.0 at steady state after administration to the patient,
  • the extended release formulation which is in a three times a day (TID) dosage form, provides to a patient a therapeutic effect for about 8 hours and a relatively flat plasma concentration profile of sialic acid at steady state such that the minimum plasma concentration of sialic acid during the dosing interval is about 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95% of the maximum plasma concentration during the dosing interval.
  • TID three times a day
  • the extended release formulation which is in a three times a day (TID) dosage form, provides to a patient a therapeutic effect for about 8 hours and a relatively flat plasma concentration profile of sialic acid at steady state such that the maximum plasma concentration of sialic acid during the dosing interval is about 155%, 150%, 145%, 140%, 135%, 130%, 125%», 120%, 115%, 110%, or 105% of the minimum plasma concentration during the dosing interval.
  • TID three times a day
  • the extended release formulation is capable of delivering to an individual in need thereof a therapeutically effective amount of one or more compounds in the sialic acid pathway or derivatives thereof with less than about any of 10%, 20%, 30%, 40%, 50%, 60%, or 70% excreted after one hour. In embodiments of any of the extended release formulations, the extended release formulation is capable of delivering to an individual in need thereof a therapeutically effective amount of one or more compounds in the sialic acid pathway or derivatives thereof with less than about any of 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90% excreted after four hours.
  • the extended release formulation is capable of delivering to an individual in need thereof a therapeutically effective amount of one or more compounds in the sialic acid pathway or derivatives thereof with less than about any one of 2, 3, 4, or 5% excreted after 12 hours.
  • the one or more compounds in the sialic acid pathway or derivatives thereof include ManN Acer a derivative thereof and/or sialic acid or a derivative thereof, in some embodiments, the one or more compounds in the sialic acid pathway or derivatives thereof include Man Ac and/or sialic acid. In some embodiments, the one or more compounds in the sialic acid pathway or derivatives thereof include sialic acid.
  • the extended release formulation comprises sialic acid, or a pharmaceutically acceptable salt thereof, as the therapeutic agent.
  • the extended release formulation comprises MaNAc, or a pharmaceutically acceptable salt thereof, as the therapeutic agent.
  • the extended release formulation comprises sialic acid, or a pharmaceutically acceptable salt thereof and MaNAc, or a pharmaceutical ly acceptable salt thereof, as the therapeutic agents.
  • the extended release formulation is capable of delivering to an individual in need thereof between about any of 0.1-50 g/day, 0.5-25 g/day, 1-15 g/day, 1-10 g/day, or 2-5 g/day of one or more compounds in the sialic acid pathway or derivatives thereof. In some embodiments, the extended release formulation is capable of delivering to an individual in need thereof between about 2 g/day and 5 g/day of one or more compounds in the sialic acid pathway or derivatives thereof.
  • the extended release formulation is capable of delivering to an individual in need thereof between about any of 0.01-750 mg kg, 0,5-500 mg/kg, 1-250 mg/kg, 2.5-100 mg/kg, or 5-50 mg/kg of one or more compounds in the sialic acid pathway or derivatives thereof. In some embodiments, the extended release formulation is capable of delivering to an individual in need thereof between about 5 mg/kg and 50 mg/kg of one or more compounds in the sialic acid pathway or derivatives thereof. In some embodiments, the one or more compounds in the sialic acid pathway or derivatives thereof include ManNAc or a derivative thereof and/or sialic acid or a derivative thereof.
  • the extended release formulation is capable of delivering to an individual in need thereof between about 5 mg/kg and 50 mg/kg of ManN Ac and/or sialic acid.
  • the extended release formulation comprises sialic acid, or a pharmaceutically acceptable salt thereof, as the therapeutic agent.
  • the extended release formulation comprises MaNAc, or a pharmaceutically acceptable salt thereof, as the therapeutic agent.
  • the extended release formulation comprises sialic acid, or a pharmaceutically acceptable salt thereof and MaNAc, or a pharmaceutically acceptable salt thereof, as the therapeutic agents.
  • the extended release formulation is capable of delivering to an individual in need thereof between about any of 0.01-750 mg/kg/day, 0.5-500 mg/kg/day, 1-250 mg/kg/day, 2.5-100 mg/kg/day, or 5-50 mg/kg/day of one or more compounds in the sialic acid pathway or derivatives thereof. In some embodiments, the extended release formulation is capable of delivering to an individual in need thereof between about 5 mg kg/day and 50 mg/kg/day of one or more compounds in the sialic acid pathway or derivatives thereof. In some embodiments, the one or more compounds in the sialic acid pathway or derivatives thereof include ManNAc or a derivative thereof and/or sialic acid or a derivative thereof.
  • the extended release formulation is capable of delivering to an individual in need thereof between about 5 mg/kg/day and 50 mg/kg/day of ManNAc and/or sialic acid.
  • the extended release formulation comprises sialic acid, or a pharmaceutically acceptable salt thereof, as the therapeutic agent.
  • the extended release formulation comprises MaNAc, or a pharmaceutically acceptable salt thereof, as the therapeutic agent.
  • the extended release formulation comprises sialic acid, or a pharmaceutically acceptable salt thereof and MaNAc, or a pharmaceutically acceptable salt thereof, as the therapeutic agents.
  • the extended release formulation has an absolute bioavailability of about 1-50%. In some embodiments, the extended release formulation has an absolute bioavailability of about any one of 1-45%, 1 ⁇ 40%, 1-35%, 1-30%, 1-20%, 1-10%. In some embodiments the extended release formulation has an absolute bioavailability of about 1 - 25%. In some embodiments, the extended release formulation has an absolute bioavailability of about any one of 5, 10, 15, 20, 25 or 50%. In some embodiments, the one or more compounds in the sialic acid pathway or derivatives thereof include ManNAc or a derivative thereof and/or sialic acid or a derivative thereof.
  • the one or more compounds in the sialic acid pathway or derivatives thereof include sialic acid or a derivative thereof.
  • the extended release formulation comprises sialic acid, or a pharmaceutically acceptable salt thereof, as the therapeutic agent.
  • the extended release formulation comprises MaNAc, or a pharmaceutically acceptable salt thereof, as the therapeutic agent.
  • the extended release formulation comprises sialic acid, or a pharmaceutically acceptable salt thereof and MaNAc, or a pharmaceutically acceptable salt thereof, as the therapeutic agents.
  • the extended release formulation has a bioavailability based on sialic acid levels in the urine of about 0.5-100%). In some embodiments, the extended release formulation has a bioavailability based on sialic acid levels in the urine of about any one of 0.5-2.5%, 1-2.5 %, 2 - 8%, 2 - 12%, 2.5-20%), 2.5-40%, 2.5- 80%, 2.5 - 100%.
  • the extended release formulation comprises sialic acid, or a pharmaceutically acceptable salt thereof, as the therapeutic agent.
  • the extended release formulation comprises MaNAc, or a pharmaceutically acceptable salt thereof, as the therapeutic agent.
  • the extended release formulation comprises sialic acid, or a pharmaceutically acceptable salt thereof and MaNAc, or a pharmaceutically acceptable salt thereof, as the therapeutic agents.
  • the extended release formulation has a mean residence time (MR! ' ) of at least about 3.5 hours. In some embodiments, the extended release formulation has a MRT of at least about any one of 3, 4, 4.5, 5, 5.5 or 6 hours.
  • the one or more compounds in the sialic acid pathway or derivatives thereof include MaiiNAc or a derivative thereof and/or sialic acid or a derivative thereof. In some embodiments, the one or more compounds in the sialic acid pathway or derivatives thereof include sialic acid or a derivative thereof.
  • the extended release formulation comprises sialic acid, or a pharmaceutically acceptable salt thereof, as the therapeutic agent.
  • the extended release formulation comprises MaNAc, or a pharmaceutically acceptable salt thereof, as the therapeutic agent.
  • the extended release formulation comprises sialic acid, or a pharmaceutically acceptable salt thereof and MaNAc, or a pharmaceutically acceptable salt thereof, as the therapeutic agents.
  • the extended release formulations and/or the combination of the extended release formulation and immediate release formulation as described herein can be a sialic acid Reference Drug.
  • the term "Reference Drug” is defined in the U.S. Federal Food and Drug Administration's (FDA) Orange Book, Approved Drug Products with. Therapeutic Equivalence Evaluations.
  • the present invention includes any bioequivalence of the extended release formulations and/or the combination of the extended release formulation and immediate release formulation as a reference drug.
  • Bioequivalence denotes the absence of a significant difference in the rate and extent to which the active agent or surrogate marker for the active agent in pharmaceutical equivalents or pharmaceutical alternatives becomes available at the site of action when administered in an appropriately designed study.
  • bioequivalence is any definition thereof as promulgated by the U.S. Food and Drag Admmistration or any successor agency thereof.
  • bioequivalence is determined according to the Federal Drag Administration's guidelines and criteria, including "GUIDANCE FOR INDUSTRY BIOAVAI LABI LITY AND BIQEQUVALENCE STUDIES FOR ORALLY ADMINISTERED DRUG PRODUCTS GE N ERA L CONSIDERATIONS '" available from the U.S.
  • DHHS Department of Health and Human Sendees
  • FDA Food and Drug Administration
  • CDER Center for Drag Evaluation and Research
  • GUIDANCE FOR INDUSTRY STATISTICAL APPROACHES TO ESTABLISHING BIOEQLWALENCE DHHS, FDA, CDER, January 2001, both of which are incorporated herein in their entirety.
  • bioequivalence is determined according to the European Medicines Agency (EMEA) document “Note for Guidance on the Investigation of Bioavailability and Bioequivaience", issued July 26, 2001, available from EMEA.
  • the present invention provides a formulation of sialic acid, or a pharmaceutically acceptable salt, solvate, or ester thereof wherein the formulation exhibits a ratio of a geometric mean of logarithmic transformed AUC 0 .. E of the formulation to a geometric mean of logarithmic transformed AUCo- t of the sialic acid Reference Drug from about 0.80 to about 1.25.
  • the present invention provides a formulation of sialic acid, or a pharmaceutically acceptable salt, solvate, or ester thereof wherein the formulation exhibits a ratio of a geometric mean of logarithmic transformed AUCo- ⁇ of the formulation to a geometric mean of logarithmic transformed AUCo - ⁇ of the sialic acid Reference Drag from about 0.80 to about 1.25.
  • the present invention provides a formulation of sialic acid, or a pharmaceutically acceptable salt, solvate, or ester thereof!, wherein the formulation exhibits a ratio of a geometric mean of logarithmic transformed C max of the formulation to a geometric mean of logarithmic transformed C max of the sialic acid Reference Drug from about 0.80 to about 1.25.
  • the extended release pharmaceutical formulation may be formulated for parenteral administration (e.g., by injection, for example, bolus injection or continuous mfusion) and may be presented in unit dose form in ampoules, pre-filied syringes, small volume infusion containers or in multi-dose containers.
  • the extended release pharmaceutical formulation may be may form suspensions, solutions, or emulsions in oily or aqueous vehicles.
  • the one or more compounds in the sialic acid biosynthetic pathway or derivative thereof and other ingredients may be in powder form, obtained by aseptic isolation of sterile solid or by lyophilization from solution, for constitution with a suitable vehicle, e.g., sterile, pyrogen- free water, before use.
  • the extended release pharmaceutical formulation may be formulated as is known in the art for direct application to a target area.
  • Forms chiefly conditioned for topical application take the form, for example, of creams, milks, gels, dispersion or microemuisions, lotions thickened to a greater or lesser extent, impregnated pads, ointments or sticks, aerosol formulations ⁇ e.g., sprays or foams), soaps, detergents, lotions or cakes of soap.
  • Other conventional forms for this purpose include wound dressings, coated bandages or other polymer coverings, ointments, creams, lotions, pastes, jellies, sprays, and aerosols.
  • the extended release pharmaceutical formulation may be delivered via patches or bandages for dermal administration.
  • Ointments and creams may, for example, be formulated with an aqueous or oily base with the addition of suitable thickening and/or gelling agents.
  • Drops such as eye drops or nose drops, may be formulated with the one or more compounds in the sialic acid biosynthetic pathway or derivative thereof in an aqueous or non-aqueous base.
  • Liquid sprays are conveniently delivered from pressurized packs. Drops can be delivered via a simple eye dropper-capped bottle, or via a plastic bottle adapted to deliver liquid contents dropwise, via a specially shaped closure.
  • the extended release pharmaceutical formulation comprising one or more compounds in the sialic acid biosynthetic pathway or derivative thereof may also be used in combination with other therapeutic agents.
  • the formulation components (which may optionally be delumped and sieved to a desired range of particle size) are combined and mixed to provide a uniform formulation blend, which may further be used to prepare particular dosage forms, such as tablets or capsules, e.g., for oral administration.
  • Particular dosage forms, once prepared, may ⁇ be further modified to provide the final drug product, such as, e.g., by administering a coating to a tablet formed from an extended release formulation blend.
  • Preparation of the extended release formulations may be accomplished through known techniques, such as direct compression, dry granulation and wet granulation.
  • Direct compression may be accomplished by delumping the formulation components and sieving to a desired range of particle size, which may be the same or different size for individual formulation components.
  • the components are then blended, which may be accomplished by one or a series of blending steps until ail formulation components are blended.
  • the blended formulation may, if desired, be direct compressed to provide the desired product, which may be in the form of a dosage suitable for oral administration, such as a tablet.
  • the blended formulation may also be filled into capsules or other forms for solid-dosage administration, e.g., for oral administration.
  • Dry granulation may also be utilized to prepare the extended release formulations detailed herein, and may be used to improve the flow or other characteristic of a blend of formulation components to be formed into a final drag product.
  • dry granulation includes delumping and/or sieving the formulation components, blending the formulation components and feeding the blend through, e.g., a roller compactor that produces a ribbon of compressed product, then milling the resulting ribbon.
  • the milled product may then be compressed as detailed above or further blended with additional formulation components and compressed.
  • wet granulation may also be utilized to prepare the extended release formulations.
  • the formulation components may be delumped and sieved to the desired size, and blended.
  • the resulting blend may be added to an appropriate fluid bed processor equipped with a spray gun for fluidizmg the blended formulation components using standard practices.
  • the resulting granulation is dried (e.g., in the fluid bed) and milled to a desired range of particle sized and may be used for preparation of a final formulation.
  • Wet granulation may also utilize high shear wet granulation (blended components are mixed, and frequently chopped while the solvent, typically water or other aqueous-based solvent, is sprayed over the mass during granulation).
  • Extended release formulations that are in tablet form preferably are compressed to a sufficient hardness to prevent premature ingress of a medium (e.g., aqueous medium) and to prevent surface pitting and breakage during coating, when applicable.
  • a medium e.g., aqueous medium
  • extended release formulation blends are provided, such as a final formulation blend comprising a therapeutic agent and all formulation components in a final product (e.g., a blend comprising a therapeutic agent, a polymer, an excipient and a lubricant) as well as intermediate formulation blends that contain a portion of all formulation components in a final product (e.g., a blend comprising a therapeutic agent and a polymer but not an excipient or a lubricant, where the final product contains an excipient and a lubricant).
  • a final formulation blend comprising a therapeutic agent and all formulation components in a final product
  • intermediate formulation blends that contain a portion of all formulation components in a final product (e.g., a blend comprising a therapeutic agent and a polymer but not an excipient or a lubricant, where the final product contains an excipient and a lubricant).
  • the extended release formulation comprises sialic acid, or a pharmaceutically acceptable salt thereof, as the therapeutic agent.
  • the extended release formulation comprises Ma Ac, or a pharmaceutically acceptable salt thereof, as the therapeutic agent.
  • the extended release formulation comprises sialic acid, or a pharmaceutically acceptable salt thereof and MaNAc, or a pharmaceutically acceptable salt thereof, as the therapeutic agents.
  • the extended release formulation comprises a prodrug of one or more compounds in the sialic acid biosynthetic pathway such as a prodrug of sialic acid, or a pharmaceutically acceptable salt thereof, as the therapeutic agent.
  • the extended release formulation comprises sialic acid, or a pharmaceutically acceptable salt thereof, as the therapeutic agent and further comprises a hydrocolloid polymer, an anionic, pH-dependent gel forming co-polymer and a water swellable, pH independent polymer and optionally further comprises a lubricant and/or an excipient.
  • the extended release formulation comprises sialic acid, or a pharmaceutically acceptable salt thereof!, carrageenan, sodium alginate and either hypromeliose or polyethylene oxide.
  • the extended release formulation comprises sialic acid, or a pharmaceutically acceptable salt thereof, carrageenan, sodium alginate, either hypromeliose or polyethylene oxide, magnesium stearate and microcrystalline cellulose and colloidal silicon dioxide.
  • the extended release formulation is a formulation of Table E. in yet another aspect, the extended release formulation is a formulation of Table 8. In another aspect, the extended release formulation is a formulation of Example 6. In another aspect, the extended release formulation is a formulation of Example 7.
  • the one or more compounds in the sialic acid pathway or derivatives thereof include ManNAc or a derivative thereof and/or sialic acid or a derivative thereof.
  • the methods of treating and/or preventing sialic acid deficiencies in an individual in need thereof by administering an effective amount of ManNAc and sialic acid in any extended release formulation described herein.
  • the methods of treating and/or preventing sialic acid deficiencies increase sialic acid production.
  • the methods of treating and/or preventing sialic acid deficiencies increase sialylatioii of affected tissue.
  • the method of treating and/or preventing sialic acid deficiencies comprises administering an extended release formulation comprising a drug load of about 30-60% (e.g., sialic acid and/or ManNAc), about 20-30% w/w hypromellose (e.g.
  • hypromellose Type 2208 or Methocel 100M about 20-25%) w/w sodium alginate (e.g. Protanai), about 1-5% w/w lambda carrageenan (e.g. Viscarin GP-209), about 1-10% w/w of microcrystalline cellulose and colloidal silicon dioxide (e.g., Prosolv® SMCC HD90), about 0.1 - 1% w/w/ magnesium stearate (e.g. HyQual®), and about 1 - 5% of an enteric coating (e.g. Qpadry® II White).
  • Prosolv® SMCC HD90 microcrystalline cellulose and colloidal silicon dioxide
  • an enteric coating e.g. Qpadry® II White
  • the method of treating or preventing sialic acid deficiencies comprises administering an extended release formulation comprising a drug load of about 30-60% (e.g., sialic acid and/or ManNAc), about 20-30% w/w polyethylene oxide (e.g. Polyox WSii), about 20-25% w/w sodium alginate (e.g. Protanai), about 1-5% w/w lambda carrageenan (e.g. Viscarin GP-209), about 1-10% w/w of microcrystalline cellulose and colloidal silicon dioxide (e.g., Prosolv® SMCC HD90), about 0.1 - 1% w/w/ magnesium stearate (e.g. HyQual®), and about 1 -5% of an enteric coating (e.g. Opadry® I I White).
  • a drug load of about 30-60% (e.g., sialic acid and/or ManNAc), about 20-30% w/w polyethylene oxide (e.g. Polyox WS
  • sialic acid e.g., increasing production of sialic acid in muscle tissue
  • proximate substrate for glvcosylation, CMP-sialic acid in an individual in need thereof by administering an effective amount of one or more compounds in the sialic acid pathway or derivatives thereof in any extended release formulation described herein.
  • the one or more compounds in the sialic acid pathway or derivatives thereof include ManNAc or a derivative thereof and/or sialic acid or a derivative thereof.
  • methods of increasing production of sialic acid e.g., increasing production of sialic acid in muscle tissue
  • kits for increasing sialylation of muscle tissue in an individual in need thereof by administering an effective amount of one or more compounds in the sialic acid pathway or derivatives thereof in any extended release formulation described herein.
  • the one or more compounds in the sialic acid pathway or derivatives thereof include ManNAc or a derivative thereof and/or sialic acid or a derivative thereof.
  • methods of increasing sialylation of muscle tissue in an individual in need thereof by administering an efiective amount of ManNAc and sialic acid in any extended release formulation described herein.
  • kits for improving muscle function in an individual in need thereof by administering an effective amount of one or more compounds in the sialic acid pathway or derivatives thereof in any extended release formulation described herein.
  • the one or more compounds in the sialic acid pathway or derivatives thereof include ManNAc or a derivative thereof and/or sialic acid or a derivative thereof.
  • methods of improving muscle function in an individual in need thereof by administering an effective amount of ManNAc and sialic acid in any extended release formulation described herein,
  • conditions associated with one or more genetic defects in the sialic acid pathway can also be addressed by treatment with one or more compounds in the sialic acid biosynthetic pathway or derivative thereof in any extended release formulation described herein, whether presently known or to be discovered.
  • uridine diphospho-N-acetylglucosamine-2-epimerase (UDP-GlcNAc-2-epimerase) converts UDP-Glc Ac to N-acetylmannosamine (ManNAc), which is phosphorylated by ManNAc kinase in the presence of ATP to produce N-acerylmannosamme-6-phosphate (ManNAc-6-P).
  • ManN.Ac-6-P is converted to N-acetylneuraminic acid-9-phosphate (NeuAc-9-P) via Neu5 Ac-9-phosphate synthetase, followed by dephosphoiylation of NeuAc-9-P by Neu5Ac- 9-phosphate phosphatase to yield NeuSAc (sialic acid).
  • Sialic acid then enters the nucleus and is converted to cytidine monophosphate-sialic acid (CMP-sialic acid) via CMP-Neu5Ac synthetase.
  • any genetic deficiency regarding ManNAc kinase, Neu5Ac-9-phosphate synthetase, or Neu5Ac-9-phosphate phosphatase, or combination thereof, or condition related thereto can be treated with an effective amount of one or more compounds in the sialic acid biosynthetic pathway or a derivative thereof in any extended release formulation described herein.
  • administration of such a compound to block a particular enzymatic step in the pathway yields treatment of a condition associated with a defect regarding that particular enzyme.
  • a subject having a condition associated with a genetic defect regarding an enzyme in the sialic acid pathway such as ManNAc kinase, Neu5Ac-9- phosphate synthetase, or Neu5Ac-9-phosphate phosphatase or a combination thereof, comprising administering to the subject an effective amount of compound in the sialic acid biosynthetic pathway or a derivative thereof in any extended release formulation described herein.
  • an enzyme in the sialic acid pathway such as ManNAc kinase, Neu5Ac-9- phosphate synthetase, or Neu5Ac-9-phosphate phosphatase or a combination thereof
  • conditions associated with defects in the sialic acid biosynthetic pathway that may be treated with a compound in the sialic acid biosynthetic pathway or a derivative thereof in any extended release formulation described herein include, but are not limited to, sialuria, glomerular hyposiaiyiation, glomerular hematuria, proteinuria podocytopathy, renal disorders involving proteinuria and hematuria due to podocytopathy and/or segmental splitting of the glomerular basement membrane, minimal change nephrosis, focal and segmental glomerulosclerosis, membranous glomerulonephritis, idiopathic nephrotic syndrome, and giycosylation deficiencies (e.g., congenital disorders of giycosylation or muscular dystrophies).
  • a condition associated with a ManNac kinase defect is selected from sialuria, glomerular hyposiaiyiation, glomerular hematuria, proteinuria podocytopathy, renal disorders involving proteinuria and hematuria due to podocytopathy and/or segmental splitting of the glomerular basement membrane, minimal change nephrosis, focal and segmental glomerulosclerosis, membranous glomerulonephritis, and idiopathic nephrotic syndrome, in some embodiments, a condition associated with a Neu5Ac-9-phosphate phosphatase defect is a giycosylation deficiency (e.g., congenital disorders of giycosylation or muscular dystrophies).
  • a cause of sialic acid deficiency, reduced sialic acid production, or reduced sialylation is a genetic detect that affects regulation of the sialic acid pathway: that is, genetic defects that affect sialic acid productivity or sialylation need not be constrained to genetic defects of enzymes directly in the sialic acid pathway.
  • any underlying genetic defect involved in regulation of the sialic acid pathway that affects sialic acid production e.g., where the defect causes a decrease in sialic acid production or otherwise causes sialic acid deficiency
  • sialylation e.g., where the defect causes decreased sialylation
  • a genetic defect that reduces sialic acid productivity or reduces sialylation can be treated with a compound in the sialic acid biosynthetic pathway or a derivative thereof in any extended release formulation described herein.
  • methods of treating a subject having a condition associated with a genetic defect that reduces sialic acid productivity or reduces sialylation, such as wherein the defect affects regulation of GNE/MNK or another aspect of the sialic acid pathway comprising administering to the subject an effective amount of a compound in the sialic acid hiosynthetic pathway or a derivative thereof in any extended release formulation described herein.
  • sialic acids are important for proper development and functioning of many organs and tissues, and a deficiency of sialic acid can give rise to many different types of diseases and conditions. Other types of muscle diseases have also shown that glycosylation is important for muscle function. Nishino and Ozawa, Curr. Opin. Neurol 15:539-544 (2002).
  • the sialic acid deficiency is a myopathy, muscular atrophy and/or muscular dystrophy.
  • Myopathies that can be treated with the present compositions and methods also include distal myopathy with rimmed vacuoles (Nonaka myopathy) and the muscular dystrophy hereditary inclusion body myopathy (HIBM).
  • the methods of treating and/or preventing increase sialylatkm of muscle tissue. In some embodiments, the methods of treating and/or preventing improve muscle function and reduce muscle injur ⁇ ' from physical activity, as measures by creatine kinase plasma levels after exercise. In some embodiments, the methods of treating or preventing muscle dysfunction will improve independent ambulation, stair climbing, foot drop, getting up from a chair and walking, hand grip and manipulation and pulmonary function. In some embodiments, the method further comprises identifying an individual in need thereof by determining genotype or expression levels of the gene GNE.
  • the sialic acid deficiency is a kidney condition and diseases (e.g. , those involving proteinuria and hematuria).
  • Proteinuria involves leakage of protein from the blood into the urine. If the amount of protein in the urine is very high, this condition is often called nephrotic syndrome.
  • Several types of diseases exhibit the symptoms of proteinuria, including high blood pressure, infections, reflux nephropathy, diabetes, and various types of glomerulonephritis, including minimal change nephrosis.
  • Hematuria simply means blood in the urine (e.g., gross hematuria or microscopic hematuria).
  • the methods of treating and/or preventing increase sialylation of kidney tissue.
  • a therapeutically effective amount of one or more compounds in the sialic acid pathway or derivatives thereof is provided over a period of greater than about any of 8, 9, 10, 1 1, 12, 13, 14, 15, 16, 17, 18, 19, 20 hours. In some embodiments, a therapeutically effective amount of one or more compounds in the sialic acid pathway or derivatives thereof is provided over a period of greater than about 12 hours or greater than about 24 hours. In embodiments of any of the methods, a therapeutically effective amount of one or more compounds in the sialic acid pathway or derivatives thereof is provided over a period of between about any of 6-10 hours, 8-12 hours, 10-16, or 12-20 hours.
  • a therapeutically effective amount of one or more compounds in the sialic acid pathway or derivatives thereof is provided over a period of about any of 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 hours.
  • a therapeutical [y effective amount of one or more compounds in the sialic acid pathway or derivatives thereof is provided over a period of about 12 hours or about 24 hours.
  • the therapeutically effective amount is provided to the bloodstream of the individual.
  • the therapeutically effective amount is provided to muscle tissue of the individual.
  • the one or more compounds in the sialic acid pathway or derivatives thereof include ManNAc or a derivative thereof and/or sialic acid or a derivative thereof.
  • a therapeutically effective amount of ManNAc and/or sialic acid is provided to muscle tissue of the individual over a period of between about any of 6-10 hours, 8-12 hours, 10-16, or 12-20 hours.
  • the individual in need thereof is provided a substantially constant (i.e., without large burst of drug availability and deficiencies in drug availability to the blood and/or tissues of interest (e.g., muscle tissue)) therapeutically effective amount of one or more compounds in the sialic acid pathway or derivatives thereof over a period of greater than about any of 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 hours.
  • the individual in need thereof is provided a substantially constant therapeutically effective amount of one or more compounds in the sialic acid pathway or derivatives thereof over a period of between about any of 1 -24 hours, 4-24 hours, 6-24 hours, 8-24 hours, or 12-24 hours.
  • the individual in need thereof is provided a substantially constant therapeutically effective amount of one or more compounds in the sialic acid pathway or derivatives thereof over a period of about any of 8, 9, 10, 1 1 , 12, 13, 14, 15, 16, 17, 18, 19, or 20 hours.
  • the one or more compounds in the sialic acid pathway or derivatives thereof include ManNAc or a derivative thereof and/or sialic acid or a derivative thereof.
  • the individual in need thereof is provided a substantially constant therapeutically effective amount of ManNAc and/or sialic acid to muscle tissue of the individual over a period of between about any of 6-10 hours, 8-12 hours, 10-16, or 12-20 hours.
  • any of the methods less than about any of 10%, 20%, 30%, 40%, 50%, 60%, or 70% of one or more compounds in the sialic acid pathway or derivatives thereof is excreted from the individual after one hour, in embodiments of any of the methods, less than about any of 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90% of one or more compounds in the sialic acid pathway or derivatives thereof is excreted from the individual after four hours.
  • the one or more compounds in the sialic acid pathway or derivatives thereof include Man Ac or a derivative thereof and/or sialic acid or a derivative thereof.
  • the one or more compounds in the sialic acid pathway or derivatives thereof include ManNAc and/or sialic acid.
  • the one or more compounds in the sialic acid pathway or derivatives thereof are administered to an individual in need thereof between about any of 0.1-50 g/day, 0.5-25 g day, 1-15 g/day, 1-10 g/day, 2-5 g/day, 0.2-25 g/ ' day, 0.3- 12 g/day, 0.4-10 g/day, 0.5-8 g/day, and 0.7-6 g/day.
  • the one or more compounds in the sialic acid pathway or derivatives thereof are administered between about 2 g/day and 5 g/day.
  • the one or more compounds in the sialic acid pathway or derivatives thereof are administered to an individual in need thereof between about any of 0.01-750 mg/kg, 0.5-500 mg/kg, 1-250 mg/kg, 2.5-100 mg kg, or 5-50 mg/kg. In some embodiments, the one or more compounds in the sialic acid pathway or derivatives thereof are administered to an individual in need thereof between about 5 mg kg and 50 mg kg. In some embodiments, the one or more compounds in the sialic acid pathway or derivatives thereof include ManNAc or a derivative thereof and/or sialic acid or a derivative thereof. For example, in some embodiments, ManNAc and/or sialic acid are administered to an individual in need thereof between about 5 mg/kg and 50 mg/kg.
  • the one or more compounds in the sialic acid pathway or derivatives thereof are administered to an individual in need thereof between about any of 0.01-750 mg/kg/day, 0.5-500 mg/kg/day, 1-250 mg/kg/day, 2.5-100 mg/kg/day, or 5-50 mg/kg/day. In some embodiments, the one or more compounds in the sialic acid pathway or derivatives thereof are administered to an individual in need thereof between about 5 mg/kg/day and 50 mg/kg/day. In some embodiments, the one or more compounds in the sialic acid pathway or derivatives thereof include ManNAc or a derivative thereof and/or sialic acid or a derivative thereof.
  • ManNAc and/or sialic acid are administered to an individual in need thereof between about 5 mg/kg/day and 50 mg/kg/day.
  • the effective amount of one or more compounds in the sialic acid pathway or derivatives thereof in any extended release formulation is administered once a day, twice a day, three times a day, or four times a day.
  • the amount of the extended release formulation according to an embodiment of the invention to be administered to a human body may be appropriately selected in accordance with the absorption rate in the body, rate of inactivation, rate of excretion, the age, gender and condition of the patient, severity of the disease, or the like. Such factors can be readily determined by the clinician employing animal models or other test systems that are available in the art.
  • Administration of the therapeutic agents in accordance with the present invention may be in a single dose, in multiple doses, in a continuous or intermittent manner, depending, for example, upon the recipient's physiological condition, whether the purpose of the administration is therapeutic or prophylactic, and other factors known to skilled practitioners.
  • the administration of one or more compounds in the sialic acid pathway or derivatives thereof may be essentially continuous over a pre-selected period of time or may be in a series of spaced doses. Both local and systemic administration is contemplated.
  • the present invention provides a method for treating a sialic acid deficiency in an individual in need thereof comprising administering to a patient under fed conditions the present extended release formulation, wherein the extended release formulation provides an improved absorption profile when administered under fed conditions than being administered under fasting conditions.
  • the absorption profile is described by the area under the plasma concentration-time curve (AUC) over a 8, 12, or 24 hours period of time (correlating to the amount of drug absorbed or bioavailability ), Cmax (maximum concentration of the drug in the blood), and T max (time to reach C ma x).
  • the improved absorption profile denotes a less sharp and more flat shape of the concentration-time curve.
  • the improved absorption profile can denote an AUC with somewhat lower, somewhat higher, or substantially the same value but a lower C max and higher T max .
  • the mean AUC determined at a fed state is substantially similar to or higher than the mean AUC determined at a fasted state
  • the mean Cm a determined at a fed state is lower than the mean AUC determined at a fasted state.
  • the mean C max determined at a fed state is lower than the mean AUC determined at a fasted state.
  • the mean T max determined at a fed state is higher than the mean AUC determined at a fasted state.
  • articles of manufacture and unit dosages which include the extended release formulations comprising one or more compounds in the sialic acid pathway or derivatives thereof described herein.
  • articles of manufacture or kits comprising: (a) a container comprising the extended release pharmaceutical formulation comprising one or more compounds in the sialic acid biosyiithetic pathway or derivative thereof described herein; and (b) a package insert with instructions for treating and/or preventing a sialic acid deficiency in a patient.
  • the one or more compounds in the sialic acid pathway or derivatives thereof include ManNAc or a derivative thereof and/or sialic acid or a derivative thereof.
  • the article of manufacture comprises a container and a label or package insert on or associated with the container.
  • Suitable containers include, for example, bottles, vials, syringes, etc.
  • the containers may be formed from a variety of materials such as glass or plastic.
  • the container holds or contains a formulation and may have a sterile access port (for example the container may be an intravenous solution bag or a vial having a stopper pierceable by a hypodermic injection needle).
  • At least one active agent in the composition is the polypeptide.
  • the label or package insert indicates that the composition's use in a subject with specific guidance regarding dosing amounts and intervals of polypeptide and any other drug being provided.
  • the article of manufacture may further include other materials desirable from a commercial and user standpoint, including other buffers, diluents, filters, needles, and syringes.
  • the container is a syringe.
  • the syringe is further contained within an injection device.
  • the injection device is an autoinjector.
  • a "package insert” is used to refer to instructions customarily included in commercial packages of therapeutic products, that contain information about the indications, usage, dosage, administration, contraindications, other therapeutic products to be combined with the packaged product, and/or warnings concerning the use of such therapeutic products.
  • unit dosages which include the extended release formulations comprising one or more compounds in the sialic acid pathway or derivatives thereof.
  • the one or more compounds in the sialic acid pathway or derivatives thereof include ManNAc or a derivative thereof and/or sialic acid or a derivative thereof,
  • Unit dosage forms comprising any of the extended release formulations described herein, including but not limited to those formulations detailed under the heading "Extended Release Formulations,” such as any of the formulations of Tables A-E, Example 6, or Example 7, are described. These unit dosage forms can be stored in a suitable packaging in single or multiple unit dosages and may also be further sterilized and sealed. For convenience and ease of patient compliance, the extended release formulations may be delivered in the form of unit dosage forms, which may be administered to an individual. In one variation, the extended release formulation is a solid substance and unit dosage forms thereof may be prepared in the form of tablets, capsules, sachets and chewable tablets or tablets not intended to be chewed.
  • the dosage form is in the form of a capsule or tablet, preferably in the form of a tablet.
  • the dosage form is in the form of a tablet not intended to be chewed, in some embodiments, the dosage form is in the form of a tablet not intended to be crushed. In some embodiments, the dosage form is in the form of a tablet not intended to be chewed or crashed,
  • the preparation of the unit forms generally involves a step of preparing a blend filling, either by volume or weight.
  • a blend filling for example, in production of tablets and capsules, the extended release formulation blend is volume filled into a die or capsule, respectively.
  • a batch of unit dosage forms has the same potency (amount of drug per unit dosage form) within an allowable margin, which in one variation is a relative standard deviation (RSD) of less than 6% and in another variation is less than 8.0 or 7,8%.
  • RSD relative standard deviation
  • Sialic Acid 250 mg Strength Tablets Using Dry Blend Method of Manufacture Experimental/Materials
  • Sialic Acid Food & Bio Research center, Inc. Kyoto japan
  • Sialic Acid Food & Bio Research center, Inc. Kyoto japan
  • In-process materials and bulk tablets were stored in double polyethylene bags with desiccant.
  • the sialic acid was evaluated for physical properties consisting of morphology, particle size by sieve analysis, bulk and tap density.
  • Sialic Acid, hyprom.ell.ose Type 2208, sodium alginate, carrageen an and microcrystalline cellulose with colloidal silicon dioxide were delumped using a #20 USA standard sieve and weighed per the quantitative formula.
  • the ingredients were combined in a smal l ziplock bag and blended for 15 mmutes.
  • Magnesium stearate was delumped using a # 40 USA standard screen, weighed per quantitative formula, and added to the blended ingredients in the bag. The ingredients were blended for an additional three minutes.
  • the final blends, as well as the n-sieved sialic acid were characterized using bulk density, tap density, particle size sieve analysis, Carr's Compressibility Index, and minimum critical orifice.
  • the final blend of each prototype was compressed on the Korsch PHI 00 tablet press. The resulting tablets were submitted to the analytical lab for dissolution testing.
  • Sialic Acid was visually characterized as a white fluffy powdery substance. Its bulk density was Q.293g mL, and its tap density was 0.419 g/ml. The Carr's Compressibility Index was 30 %, and the minimum critical orifice diameter was .18 mm.
  • the particle size sieve analysis of Sialic Acid (Table 3) revealed a distribution of coarse and midsize particles as shown in Figure 2. The sialic acid was sized prior to blending to faci litate blend homogeneity.
  • the granulation was transferred into the MP-1 fluid bed and dried with an inlet temperature of 75°C until the loss on drying (LQD) was ⁇ 3%; equal to or slightly lower than the baseline moisture of the un-granulated formulations.
  • the dried granulation was passed through a #4 mesh hand screen. The large granules retained on the #4 mesh were segregated and discarded. The remaining granules were sized through the FitzMill at low speed, knives forward.
  • the blend was then lubricated with the magnesium stearate for 3 minutes.
  • the final blend was compressed into tablets using a Korsch rotary press. After dissolution results were obtained, the core tablets were coated with a non-functional, Gpadry K, white to a weight gain of approximately 4.5%w/w.
  • the Poly Ethylene Oxide (Polyox) based formulation did not granulate as easily.
  • the Polyox formulation was over-granulated.
  • the over-granulation can be alleviated in the future by spraying less granulation water at a slower rate.
  • An appreciable amount of the granulation was lost when the partially dried granulation was screened through a 4 mesh sieved to remove large over-granulated agglomerates that resisted drying in the fluid bed.
  • the batch yield was poor at 83%.
  • the portion of the batch that was retained produced an excellent final blend, however. It flowed and compressed well on the tablet process and produced good quality tablets.
  • Polyox is known for being difficult to granulate so this is not entirely unexpected. However, with the proper granulation parameters an excellent granulation can be attained.
  • Airflow approximately 200 cfm
  • ManNAc 325 mg Development Prototypes The ManNAc title formulation was prepared according to the method detailed above for Sialic Acid. The dissolution profile of ManNAc 325 mg Tablets is shown in Figure 7.
  • the first day of dosing was designated as Day 1 .
  • the subsequent dos ling days were Days 6, 9 and 13.
  • test articles 1 through 6 are specified in Table 16.
  • Formulation IV (polyethylene oxide) per tablet animal
  • Blood samples were collected into serum separate tubes from all animals on Days 1, 6, 9, 13 for processing to serum at the following time points: predose, 2 minutes (i.v. only), 5 minutes (i.v. only), 10 minutes (i.v. only), 15 minutes, 30 minutes, 1, 2, 4, 6, 8 and 24 hours postdose.
  • Urine samples were collected into jars on wet ice or ice packs from all animals on Days 1, 6, 9, 13 at the followmg time intervals: predose (overnight for approximate 15 hours), 0 to 4, 4 to 8, 8 to 12 hours postdose. Samples were collected according to Table 17 and Table 18:
  • Drug concentrations in serum and urine were determined by LC MS/MS using a validated analytical procedure (Validation of a Method for the Determination of Free Soluble Sialic Acid in Dog Serum and Urine by Liquid Chromatography-Tandem Mass Spectrometry (LC-MS/MS) - PN 102653; Long-term Matrix Stability Assessment of Free Soluble Sialic Acid in Dog Serum and Urine by Liquid Chromatography-Tandem Mass Spectrometry (LC- MS/MS) - PN 102654.
  • the method had a linear range from 10 -1000 g/mL and the lower limit of quantitation was 10 lig/ L.
  • Pharmacokinetic parameters were estimated using WinNonlin® pharmacokinetic software (Version 5.2.1 , Pharsight Corp., Mountain View, California, USA). A non-compartmental approach consistent with the intravenous or oral route of administration was used for parameter estimation. All parameters were generated from individual sialic acid concentrations in serum. Parameters were estimated using nominal sampling times relative to the start of each dose administration. Mean concentrations were derived from 3 animals /group/time point for intravenous dosing occasion only. The actual timepoints were within the range of protocol specified. Serum concentration values obtained at the predose time point were used as the concentration at time zero for oral doses. The actual dose levels of test articles 1 through 5 were calculated using the total amount of SA given to each animal based on their most practical body weight.
  • the area under the sialic acid individual serum concentration versus time curve was calculated using the linear trapezoidal method with linear interpolation.
  • the terminal elimination phase of each individual concentration versus time curve was identified using at least the final three observed concentration values.
  • the slope of the terminal elimination phase was determined using log linear regression on the unweighted concentration data.
  • the terminal elimination phase related parameters were not reported if the coefficient of determination was less than 0.800, or the extrapolation of the AUC to infinity represented more than 20% of the total area, or the terminal elimination phase could not be identified.
  • the parameters described in Table 19 were observed or calculated.
  • Tmax The time after dosing when the maximum observed arithmetic individual concentration of sialic acid was observed.
  • AUC(O-t) The area under the sialic acid arithmetic individual concentration versus time curve from time zero to the time after dosing when the last quantifiable concentration of the drug was observed.
  • MRT(O-t) The mean residence time of sialic acid estimated from time zero to the time after dosing at which the last quantifiable concentration of the drug was observed estimated or imputed by the linear or linear/log trapezoidal method.
  • AUC(O-inf) The area under the arithmetic individual concentration versus time curve from time zero to infinity.
  • MRT(O-mi) The mean residence time estimated from time zero to infinity.
  • CL(1V only) Clearance the apparent volume of serum cleared of sialic acid per unit time following intravenous dosing. Clearance was calculated for intravenous dose only.
  • Vd (IV only) The apparent volume of distribution of sialic acid, determined from the terminal elimination phase following intravenous dosing. Volume of distribution was calculated for intravenous dose only.
  • the bioavailability of TA-1 was estimated to be ranging from 2.73% to 6.76%, based on the individual AUC(O-t) value following IV and oral administration,
  • TA-1 The bioavailability of TA-1 was estimated to be ranging from 1.29% to 39.1 % based on the individual urinary percent excretion value following IV and oral administration.
  • TA-2 The bioavailability of TA-1 was estimated to be ranging from 1.29% to 39.1 % based on the individual urinary percent excretion value following IV and oral administration.
  • Tmax was observed from 2.00 to 4.00 hours postdose with the peak concentrations ranging from 7.98 to 13.7 g/mL.
  • concentrations of sialic acid generally decreased after T max to levels below zero at 24 hours postdose, for ail dosed animals.
  • the elimination half life of sialic acid was estimated to be 1.28 hour in Animal No. 103. For Animal Nos. 101 and 102, the half-life could not be estimated as the measurable data were not enough to identify the termination elimination phase.
  • the oral bioavailability of TA-2 was estimated to be ranging from 1.64% to 3,25%, based on the individual AUC(O-t) value following IV and oral administration.
  • All the predose urine samples had a measureable concentration of sialic acid ranging from 13.5 to 34.8 ,ug/mL.
  • the maximum excretion of sialic acid was observed for samples collected 4-8 hours postdose for all animals.
  • the total increase of sialic acid excreted in the urine postdose was equivalent to 1.08-3.20% of the doses of SA contained in TA-2.
  • the bioavailability of TA-2 was estimated to be 2.53%) and 3.73% for Animal Nos. 102 and 103, respectively, based on the individual urinary percent excretion value following IV and oral administration.
  • the bioavailability is 97.4%) for Animal No. 101, which was markedly higher than the other two animals due to its low percent excretion value of IV doses.
  • Tmax was observed from 2.00 to 4.00 hours postdose with the peak concentrations ranging from 6.52 to 17.0 g/ ' mL.
  • concentrations of sialic acid generally decreased after Tmax to levels below zero at 24 hours postdose for all three animals.
  • the half-life could not be estimated for the three animals as the measurable data were not enough to identify the termination elimination phase or the extrapolation of the AUC to infinity represented more than 20% of the total area.
  • the oral bioavailability of TA-3 was estimated to be ranging from 1.46% to 4,14%, based on the individual AUC(O-t) value following IV and oral administration.
  • the bioavailability of TA-3 was estimated to be 3.49% and 1.51% for Animal Nos. 102 and 103, respectively, based on the individual urinary percent excretion value following IV and oral administration.
  • the bioavailability is 85.0% for Animal No. 101, which was markedly higher than the other two animals due to its low percent excretion value of IV doses.
  • All the predose urine samples had a rneasureable concentration of sialic acid ranging from 6.4 to 42.6 ⁇ ig/mL.
  • the maximum excretion of sialic acid was observed for samples collected 8-12 hours postdose for Animal Nos. 201 and 203, and 0-4 hours for Animal No. 202, respectively.
  • the total increase of sialic acid excreted in the urine postdose was equivalent to 0.54-1 .93% of the doses of SA contained in TA-4.
  • the bioavailability of TA-4 was estimated to be 1.42% and 2.55% for Animal Nos. 202 and 203 based on the individual urinary percent excretion value following IV and oral administration.
  • the bioavailability of Animal No. 101 could not be estimated as the mass excreted of sialic acid postdose was set to be zero when corrected by predose data.
  • the oral bioavailability of TA-5 was estimated to be 0.52 % and 2.24%, for Animal Nos. 202 and 203, respectively, based on individual urinary percent excretion value following IV and oral administration.
  • the bioavailability of Animal No. 101 could not be estimated as the mass excreted of sialic acid postdose was set to be zero when corrected by predose data.
  • the serum levels of sialic acid were below zero for predose samples of most animals except for one dog, Animal No. 102, of which was slightly above zero but below 20% of the LLOQ.
  • SA-ER Sialic Acid Extended-Release
  • PK canine pharmacokinetics
  • Serum levels showed a dose-dependent difference though not proportional to the dose level
  • API gavage was better absorbed with a higher C max than SA-ER possibly due to early stomach based absorption
  • Goal was for broad, flat absorption curve, without a peak
  • SA-ER Tablets in Patients with Hereditary inclusion Body Myopathy
  • SA-ER Sialic Acid E tended-Release
  • each potential subject Before undergoing any study-related screening procedures, each potential subject, provided informed consent. Informed consent was documented by means of a written, signed, and dated informed consent, form. The investigator determined the potential subject's suitability for the study by interviewing the potential subject and by performing per-protocol screening assessments. A sufficient number of potential subjects were screened to enroll approximately 24 study subjects at approximately two (2) study sites. Patients who withdraw or were removed from the study after receiving test drug were replaced on a case-by-case basis.
  • each patient who qualified for the study was sequentially assigned a unique patient number. This patient number identified the patient's case report form (CRF) data throughout the study.
  • CRF case report form
  • Each patient could participate in the study for approximately 4-8 weeks, including a 14-day treatment phase requiring 7 overnight stays in the hospital unit or Phase 1 unit.
  • HIBM hereditary inclusion body myopathy
  • DMRV rimmed vacuoles
  • Nonaka myopathy due to demonstrated mutations in gene encoding the GNE/MNK enzyme.
  • Females of childbearing potential must have a negative pregnancy test at screening and be willing to have additional pregnancy tests during the study.
  • Females considered not of childbearing potential include those who have been in menopause at least 2 years, or had bilateral tubal ligation at least I year prior to screening, or who have had total hysterectomy.
  • ManNAc ManNAc, sialic acid, or related metabolites or sialic acid donors that provide this substrate in either chemical or nutritional supplement form during the 30 days prior to screening. If ManNAc or other substrate was used more than 30 days prior to screening, the time period of use, the compound used, and the dose and dose regimen should be recorded in the patient's history. If a patient has been on substrate replacement therapy in the past, the investigator must consider the potential confounding effects of this therapy before enrolling the patient.
  • patients could receive concomitant medications as required. If a patient took any medication other than SA-ER, the patient recorded the date and time the medication was taken, the name of the medication, and the reason the medication was taken in the drug administration diary.
  • Sialic acid extended-release tablets used in this study were white, oval, film-coated tablets containing 325 rng of sialic acid active ingredient and weighed approximately 780 rng (43% active) as exemplified in the Examples described above.
  • the tablets were for oral dosing and were developed to have sustained release of the active ingredient, SA, for up to 24 hours. All the excipients (inactive) contained in the tablet formulation met USP or USP NF compendia specifications and were generally regarded as safe (GRAS). No animal-derived products were used in the manufacture of the tablets.
  • the drug product (the tablet form) was manufactured, packaged, and labeled according to Good Manufacturing Practice (GMP) regulations.
  • GMP Good Manufacturing Practice
  • SA-ER 325 rng tablets were bottled and labeled. Each bottle was marked with a label that displayed the protocol number, the name and city, state, and zip code of the sponsor, the identity and strength of the contents ("Sialic Acid Extended Release Tablets, 325 mg"), the number of tablets in the bottle, the lot number, the storage conditions, and the statement, "Caution: New Drug - Limited by Federal (US) Law to Investigational Use.”
  • Each of the 24 enrolled patients was sequentially assigned to a specific dose level and received two single-dose exposures at that same dose level (fasted and fed). The low-dose cohorts were filled before assigning higher-dose cohorts. The patient was then assigned to receive one repeat-dose regimen. The lower-dose repeat-dose cohorts were filled before proceeding to higher repeat-dose levels. Dose levels were as follows.
  • the maximum daily dose of SA-ER in this study was 4,875 mg, administered as 1,625 mg TID.
  • the maximum duration of administration of study drug was a single dose followed by a 2-day washout period and then a second single dose (without subsequent, washout, if applicable) followed by a 7-day TID dosing period.
  • Study days may or may not have been consecutive depending on enrollment and dose level staging.
  • Screening procedures included obtaining a medical history, performing a physical and neurological examinatio , obtaining samples for clinical laboratory tests (blood chemistry, hematology, urinalysis, tests for communicable viral diseases [hepatitis A, B, and C and human immunodeficiency virus], and urine pregnancy test [women only]), and recording vital signs (after 5 minutes sitting, including heart rate, blood pressure, respiratory rate, and temperature), height and weight, and prior medications.
  • Study days were or were not consecutive depending on enrollment and dose level staging. Therefore, most subjects were discharged from the hospital or Phase 1 unit on Study Day 8 without receiving study medication for the 7 day repeat dosing. For these patients an additional study visit as required solely for the purposes of dispensing study medication for the 7 days of TID dosing. This visit was scheduled prior to discharge from the hospital or Phase 1 unit. This visit occurred 1 week up to 4 weeks following discharge from the hospital or Phase 1 unit on Study Day 8. For the purpose of the study this visit was considered resumption of Study Day 8 for these subjects.
  • the total volume of blood collected for all scheduled study assessments was approximately 219 niL.
  • the sample size of 6 per group for the single-dose phase and 8 per group for the repeat- dosing phase was expected to provide sufficient information to meet the objectives of the study.
  • the sample size was estimated by evaluating the number of patients required to assess PK parameters. Based on prior historical PK studies in rare diseases, 6 to 8 patients per dose group was determined to be sufficient for PK determinations, particularly with the slow extended- release profile expected. A sample size of 6 to 8 patients per dose group and the total of 24 patients was also believed to be an indication of dose-drug level relationship adequate for planning dose levels for future studies,
  • Free sialic acid and its metabolites were quantified using a specific liquid cbromatograpby-tandem mass spectroscopy (LC-MS/MS) analytical method. Serum concentrations of free sialic acid were measured, and the resulting data was listed and tabulated.
  • LC-MS/MS liquid cbromatograpby-tandem mass spectroscopy
  • Clinical trial supplies were stored in a secure location at controlled room temperature, shielded from bright light, and kept off " the floor.
  • Figures 14-17 show PK data obtamed for single dose fasted administration for doses of 650 mg (Figure 13), 1,950 mg (Figure 14), 2,925 mg (Figure 15), and 4,825 mg (Figure 16) for human patients.
  • Figure 17 shows PK data obtained for repeated dose administration (650 mg x 3; 1 ,950 mg) for human patients.
  • Figure 18 show's PK data obtained for different repeated dose administration (975 x 3; 2,925 mg). The levels observed exceed normal patient levels and were close to levels observed in childhood before H1BM disease onset occurs. This suggests that the levels are clinically relevant.
  • the data of Figures 18 and 19 demonstrate achievement of excellent steady state control levels without substantial peaks or troughs at which the high enough doses are twice that of normal continuously all day and all night.
  • SA-ER Sialic Acid-Extended Release
  • HIBM Hereditary Inclusion Body Myopathy
  • the original protocol included doses up to 4875 mg/ ' day utilizing a 325 mg tablet size (see Table 8, with Hypromellose), and was subsequently amended to include an additional cohort at 6000 mg day utilizing a 500 mg tablet size.
  • the 500 mg tablet is the same formulation as the 325 mg tablet and was developed for the convenience of patient administered higher doses of SA-ER.
  • Enrollment status and assignment to treatment groups of subjects are shown in Table 28 and Table 29 below. A total of 37 patients were screened, and 27 were enrolled. Twenty-six (26) individual subjects completed dosing, one subject terminated early (prior to dosing), and eight (8) subjects withdrew consent before being dosed. All subjects dosed with at, least one dose, completed all dosing.
  • GI disorders The most common adverse event was GI disorders. Six total GI events were reported by 3 patients, and 4 of the 6 events were from a single patient (subject 101 -003) at the 1950 mg dose. Three of those four events in subject 101 -003 were deemed possibly related and they occurred at the same time before and at the beginning of the 7 day treatment period. However, the timing did not appear to reflect a treatment emergent event and there were no GI events in the highest 6000 mg dose group. There was no pattern to the gastrointestinal disorders that suggested a treatment or dose related effect.
  • the amount of sialic acid being ingested is well below the amount needed to generate osmotic diarrhea, i.e., loosening of stools was observed in the canine chronic toxicology study at the very highest 2,000 mg/kg dose level, but this effect is not relevant to the clinical study based on these results.
  • a comprehensive medical history was obtained at screening. This history was reviewed in the course of determining each potential subject's eligibility for enrollment.
  • SGOT serum glutamic-oxaloaceiic transaminase
  • SGPT serum glutamic- pyruvic transaminase
  • [00366] A number of mild clinical lab abnormalities were observed most often in screening, but there were no abnormalities that were distinctly treatment emergent. The following common abnormalities were observed: [00367] In general, an elevation in creatine kinase was observed which is a known finding in HIBM patients and is expected. These abnormal levels ranged from mildly above the normal range to about 2-3 x the normal range and were present at baseline. There was no pattern of change with treatment.
  • Creatinine was usually about 1 ⁇ 2 the normal level at, baseline and did not change with treatment. This finding is mostly likely due to the low muscle mass in HIBM patients which results in a decrease in the total amount of creatinine.
  • Low urinary uric acid levels were observed in these subjects at, screening, and this did not change with treatment.
  • the low urinary uric acid levels may be related to low muscle mass (like creatinine) and a low amount of adenosine-5'-triphosphate (ATP) turnover and purine degradation.
  • ATP adenosine-5'-triphosphate
  • the no change with treatment suggests that SA-ER is not inducing an adverse secondary nucleotide metabolic turnover. That is, sialic acid requires addition of cytidine triphosphate (CTP) to become the CMP-sialic acid carrier. If CTP was being excessively consumed, this would lead to the need for increased ATP degradation to balance nucleotide concentrations, and would generate increased uric acid from purine degradation. This degradation pathwa is not occurring based on these results.
  • CTP cytidine triphosphate
  • Alkaline phosphatase was low in many subjects at baseline and this did not change with treatment. This result may reflect a lack of physical activity and less bone turnover in HIB patients.
  • Lipase and LDH were marginally elevated in some subjects at baseline. Also noted were marginal low hemoglobins and/or hematocrits, variations in white cell counts, modest or borderline transaminase levels. There was no relationship to treatment observed.
  • SA free serum sialic acid
  • Day 1 24-hour monitoring of SA levels as a baseline to establish the diurnal cycle of free serum sialic acid levels.
  • Day 14 24-hour monitoring of SA levels during the 7th day of administration of SA-ER in three times per day divided dosing. During the 7th day, SA-ER was administered during monitoring of the subjects to help establish steady state SA levels on chronic administration.
  • SA Free serum sialic acid
  • LC/MS/MS liquid chromatography tandem mass spectrometry
  • LLOQ Lower Limit of Quantitation
  • the mean baseline level of SA was 0.143 (SD 0.0094) meg/ml for all enrolled HIBM- affected subjects, which is significantly lower than the mean SA of 0.203 (SD 0.047) mcg/ml for normal individuals (samples obtained outside this protocol; n :::: 47, age range 1 8-78 years, and tested using the same validated assay).
  • Baseline SA levels do not reveal any significant diurnal variation in SA levels for any of the subjects individually (not shown) nor as a group with fairly tight standard deviations for the flat baseline curves ( Figure 21 ).
  • the PK plots in Figure 21 show that the drug is being absorbed in a generally dose dependent fashion, with increasing doses leading to an increase in the size and shape of the curve, except for the 6000 rng dose (with 500 mg tablet) for which the curve had a lower peak level than the 4875 mg dose level (with 325 mg tablet).
  • the PK curves show increased SA levels for 8-12 hours for most dose levels, with the 6000 mg dose achieving increased levels for 12-16 hours. In general, the onset of absorption was earlier for the fasted treatment relative to fed, and the fed curves extended out longer than the more rapidly declining fasted treatment, curves.
  • the fasted curve hit a higher C max , but for the 1950 mg and the 6000 mg dose, the apparent C max for fed and fasted is similar.
  • the shift in time and the broadening of the exposure curve is particularly notable for the 6000 mg dose with the 500 mg tablet, which shows a significant increase in blood levels for 16-20 hours.
  • Each subject was administered one of four repeat dose levels divided into three times per day dosing over a period of 7 days.
  • the PK curves over the 24-hour monitoring period are shown in Figure 24.
  • Individual repeat dose group PK curves are shown ( Figures 24A-24D), and then all curves are graphed on one panel for comparison ( Figure 24E).
  • the last panel at the bottom right shows a comparison of mean SA levels over a 24-hour cycle for each dose group.
  • the two lower repeat dose groups When compared with untreated HIBM patient baselines, the two lower repeat dose groups have free SA levels about 2x baseline and the two highest dose levels are about 3x the baseline SA level. All doses resulted in free SA levels well above the normal free SA serum levels of 0.203 (SD 0.047) nicg/ml.
  • PK analyses were performed using WiiiNonLin, version 5.3 (PharSight Inc. Mountain View CA, USA) to assess the standard PK parameters for the single dose data. Given that there is an endogenous level of SA, the proper calculation of PK parameters required the subtraction of the baseline SA levels in order to assess the changing levels for the administered and absorbed SA. Although there was no significant, diurnal effect, the baseline SA levels for each subject were subtracted from, the corresponding PK level for that time point to create an "adjusted" data point. Therefore, whenever the term "adjusted” is used, it means that the PK parameter was calculated after subtraction of the baseline SA levels.
  • the C max data shows that in general, fasted data. (Day 2) showed the highest C,nax , for a l dose levels except for the 1950 mg dose level.
  • the C miSK achieved at, the 6000 mg dose level (n 6), using the 500 mg tablet, was lower at 0.520 mcg/ml but with a much tighter standard deviation and range of values from 0.335 to 0.71 1 mcg/ml.
  • the AUCo-24 bo m s data (Table 35) shows adjusted values for day 2, 7 and 14, The baseline P values (Day 1 ) are not adjusted and are not relevant given that no drug was given. All curves showed a slower onset of absorption and longer exposure curves with food. Unlike the impact 011 Cj propel ax , the impact of food on AUG is complex with some dose levels showing higher AUG with fasted conditions (650 nig and 4,875 mg dose), similar AUG under both fasted and fed conditions (2925 mg dose) and higher AUC with food ( 1950 and 6000 mg dose).
  • the extension of the curves appear to compensate for the effect of a lower C ma x peak for some dose levels by a wider cun'e in the 8-16 hour period leading to greater potential overlap between doses.
  • the AUG is significantly greater ( ⁇ +46%) when administered in the fed state at 4.165 mcg-hr/ml compared with 2.856 fasted.
  • the 6000 mg dose was administered using the 500 mg tablet, the differences observed may be due to a subtle effect of the larger tablet size on the absorption curve, even though in vitro dissolution data is comparable for the 325 mg and 500 mg tablets.
  • the larger tablet may have a longer time of release in vivo.
  • AUCo-24 hours during Day 14 shows that overall higher AUC levels can be achieved at steady state when dosing is divided three times per day, which suggests that there is some saturation effect on absorption.
  • the adjusted repeat dose AUCo-24 hours was 6.740 mcg*hr/ml, as compared with the AUC levels of 2,856 mcg*hr/ml (Fasted state) and 4. 165 mcg*hr/ml (Fed state) at single doses of 6000 mg.
  • the 6000 mg dose group's AUC is ⁇ 235% and -1 60% higher when the dose was given as a divided repeat dose rather than as one single dose.
  • the AUCo-24 hours for the 4875 mg repeat dose group was 7.442 mcg*hr/ml (Std dev 2,702), which is comparable to that for 6000 mg repeat dose group at 6.740 mcg*hr/ml (Std, dev 3.487).
  • the difference in PK for the 4875 mg and 6000 mg following single dose administration appears large, the data look similar following administration of divided doses three times a day, which is more relevant to the clinical setting.
  • the T max during repeat dosing shows a peak in the evening/nighttime (i.e., when the evening dose and the bedtime dose overlap). This timing is positive in terms of assuring an adequate level of sialic acid at, night, during peak protein synthesis.

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US9241896B2 (en) 2008-12-19 2016-01-26 Ultragenyx Pharmaceutical Inc. Methods and formulations for treating sialic acid deficiencies
US9511015B2 (en) 2010-07-13 2016-12-06 Ultragenyx Pharmaceutical Inc. Methods and formulations for treating sialic acid deficiencies
WO2019101489A1 (en) 2017-11-21 2019-05-31 Jennewein Biotechnologie Gmbh Process for the purification of a sialic acid from a fermentation broth
US10385085B2 (en) 2015-09-14 2019-08-20 Ultragenyx Pharmaceutical Inc. Crystal forms of sialic acid or salt or solvate thereof

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AU2013209610A1 (en) 2014-07-10
EP2804600A2 (en) 2014-11-26
EP2804600A4 (en) 2015-09-02
KR20150000872A (ko) 2015-01-05
JP2017186381A (ja) 2017-10-12
BR112014017587A8 (pt) 2017-07-04
BR112014017587A2 (pt) 2017-06-13
CN104271125A (zh) 2015-01-07

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