US20140056973A1 - Oral Dosage Forms Having a High Loading of a Methyl Hydrogen Fumarate Prodrug - Google Patents

Oral Dosage Forms Having a High Loading of a Methyl Hydrogen Fumarate Prodrug Download PDF

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US20140056973A1
US20140056973A1 US13/973,542 US201313973542A US2014056973A1 US 20140056973 A1 US20140056973 A1 US 20140056973A1 US 201313973542 A US201313973542 A US 201313973542A US 2014056973 A1 US2014056973 A1 US 2014056973A1
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dosage form
methyl
disease
ene
dioate
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Sarina Grace Harris Ma
Laura Elizabeth Bauer
Sami karaborni
David J. Wustrow
Peter A. Virsik
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XenoPort Inc
Arbor Pharmaceuticals LLC
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XenoPort Inc
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Priority to US13/973,542 priority Critical patent/US20140056973A1/en
Assigned to XENOPORT, INC. reassignment XENOPORT, INC. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: BAUER, Laura Elizabeth, KARABORNI, SAMI, MA, SARINA GRACE HARRIS, VIRSIK, PETER A., WUSTROW, DAVID J.
Priority to US14/072,138 priority patent/US20150157590A9/en
Publication of US20140056973A1 publication Critical patent/US20140056973A1/en
Assigned to DEUTSCHE BANK AG NEW YORK BRANCH reassignment DEUTSCHE BANK AG NEW YORK BRANCH SECURITY INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: ARBOR PHARMACEUTICALS, LLC, XENOPORT, INC.
Assigned to XENOPORT, INC. reassignment XENOPORT, INC. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: ARBOR PHARMACEUTICALS, LLC
Assigned to ARBOR PHARMACEUTICALS, LLC reassignment ARBOR PHARMACEUTICALS, LLC ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: XENOPORT, INC.
Assigned to JPMORGAN CHASE BANK, N.A., AS ADMINISTRATIVE AGENT reassignment JPMORGAN CHASE BANK, N.A., AS ADMINISTRATIVE AGENT SECURITY INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: ARBOR PHARMACEUTICALS, LLC
Assigned to XENOPORT, INC., ARBOR PHARMACEUTICALS, LLC, WILSHIRE PHARMACEUTICALS, INC. reassignment XENOPORT, INC. RELEASE BY SECURED PARTY (SEE DOCUMENT FOR DETAILS). Assignors: DEUTSCHE BANK AG NEW YORK BRANCH
Priority to US18/333,804 priority patent/US20240024249A1/en
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Definitions

  • the present disclosure relates to oral dosage forms with a high loading of a methyl hydrogen fumarate prodrug.
  • MHF methyl hydrogen fumarate
  • MMF monomethyl fumarate
  • Fumaric acid esters i.e., dimethylfumarate (DMF) in combination with salts of ethylhydrogenfumarate, have been used in the treatment of psoriasis for many years.
  • the combination product marketed under the tradename Fumaderm®, is in the form of oral tablets and is available in two different dosage strengths (Fumaderm® initial and Fumaderm®):
  • Fumaderm ® Fumaderm ® Fumarate Compound Initial (mg) (mg) Dimethylfumarate 30 120 Ethyl hydrogen fumarate, calcium salt 67 87 Ethyl hydrogen fumarate, magnesium 5 5 salt Ethyl hydrogen fumarate, zinc salt 3 3
  • the two strengths are intended to be applied in an individually based dosing regimen starting with Fumaderm® initial in an escalating dose, and then after, e.g., three weeks of treatment, switching to Fumaderm®.
  • Both Fumaderm® initial and Fumaderm® are enteric coated tablets.
  • Fumaraat 120® Another marketed composition is Fumaraat 120® containing 120 mg of DMF and 95 mg of calcium monoethyl fumarate (TioFarma, Oud-Beijerland, Netherlands).
  • the pharmacokinetic profile of Fumaraat 120® in healthy subjects is described in Litjens et al., Br. J. Clin. Pharmacol., 2004, vol. 58:4, pp. 429-432.
  • the results show that a single oral dose of Fumaraat 120® is followed by a rise in serum MHF concentration and only negligible concentrations of DMF and fumaric acid is observed.
  • DMF is thought to be a precursor or prodrug of MHF.
  • U.S. Pat. Nos. 6,277,882 and 6,355,676 disclose respectively the use of alkyl hydrogen fumarates and the use of certain fumaric acid monoalkyl ester salts for preparing microtablets for treating psoriasis, psoriatic arthritis, neurodermatitis and enteritis regionalis Crohn.
  • U.S. Pat. No. 6,509,376 discloses the use of certain dialkyl fumarates for the preparation of pharmaceutical preparations for use in transplantation medicine or the therapy of autoimmune diseases in the form of microtablets or micropellets.
  • 4,959,389 discloses compositions containing different salts of fumaric acid monoalkyl esters alone or in combination with a dialkyl fumarate.
  • GB 1,153,927 relates to medical compositions comprising dimethyl maleic anhydride, dimethyl maleate and/or DMF.
  • Biogen Idec's BG12 an oral dosage form of DMF that is an enteric coated capsule containing DMF in micropellet form, has been in human clinical testing for the treatment of MS and has shown promising results in reducing MS relapses and MS disability progression, at daily doses of 480 mg DMF, which translates to 435 mg of MHF assuming complete conversion of DMF to MHF in vivo.
  • DMF is highly irritating to the skin and mucosal membranes with the result that oral administration of DMF tends to cause serious digestive tract irritation with attendant nausea, vomiting, abdominal pain and diarrhea. This irritation problem is particularly problematic with the mucosal tissue lining the stomach. For this reason, products such as Fumaderm® and BG12 are made with enteric coatings that prevent the DMF from being released from the dosage form until after the dosage form passes out of the stomach and into the small intestine.
  • the weight of the active metabolite portion of the prodrug molecule comprises only a portion of the total weight of the prodrug.
  • the promoiety portion comprises about 47 wt % of the total weight of the prodrug while the MHF portion comprises about 53 wt % of the total weight of the prodrug. This means that almost one-half of the prodrug loading in a dosage form is taken up by the non-pharmacologically active promoiety.
  • prodrugs such as (N,N-Diethylcarbamoyl)methylmethyl (2E)but-2-ene-1,4-dioate
  • the use of such conventional tablet formulations would result in either very large tablet or capsule sizes, or the need for a patient to take multiple tablets or capsules for each dosing of prodrug, neither of which is desirable.
  • oral dosage forms comprising a high loading of (N,N-Diethylcarbamoyl)methylmethyl (2E)but-2-ene-1,4-dioate and that are amenable to high throughput commercial tableting manufacture are disclosed.
  • Oral dosage forms prepared from granulations having a high loading of (N,N-Diethylcarbamoyl)methylmethyl (2E)but-2-ene-1,4-dioate are disclosed.
  • oral tablet dosage forms comprising about 70 wt % to about 98 wt % (N,N-Diethylcarbamoyl)methylmethyl (2E)but-2-ene-1,4-dioate.
  • the oral tablet dosage forms comprise about 80 wt % to about 97 wt % (N,N-Diethylcarbamoyl)methylmethyl (2E)but-2-ene-1,4-dioate.
  • solid granulations comprising greater than about 95 wt % (N,N-Diethylcarbamoyl)methylmethyl (2E)but-2-ene-1,4-dioate are disclosed. In certain embodiments, the solid granulations comprise greater than about 97 wt % (N,N-Diethylcarbamoyl)methylmethyl (2E)but-2-ene-1,4-dioate.
  • mixtures comprising the above-described solid granulations and one or more pharmaceutically acceptable excipients are disclosed.
  • mixtures comprising a small amount of glidant markedly improve the flowability of the mixture including high loading granules.
  • the mixtures may contain up to 3 wt % of a glidant, e.g., silicon dioxide as a flow aid. In other embodiments, the mixtures contain up to 1 wt %, e.g., silicon dioxide.
  • methods of treating a disease in a subject comprising orally administering to a subject in need of such treatment at least one oral dosage form provided by the present disclosure.
  • the dosage forms can be used to treat multiple sclerosis and/or psoriasis.
  • FIG. 1 is a graph showing the particle size distribution of blends and granulations made in Example 3;
  • FIG. 2 is a graph showing the particle size distribution of blends and granulations made in Example 4.
  • FIG. 3 is a graph showing the particle size distribution of blends and granulations made in Example 5;
  • FIG. 4 is a graph showing the in vitro MHF prodrug release profile (percent MHF prodrug released over time) for the tablets of Example 7;
  • FIG. 5 is a plot illustrating flow characterization of dry powder blends and granulations of Example 9;
  • FIG. 6 is a graph showing the in vitro MHF prodrug release profile (percent MHF prodrug released over time) for the tablets of Example 10, tested in accordance with Example 13;
  • FIG. 7 is a graph showing the in vitro MHF prodrug release profile (percent MHF prodrug released over time) for the tablets of Example 11, tested in accordance with Example 13;
  • FIG. 8 is a graph showing the in vitro MHF prodrug release profile (percent MHF prodrug released over time) for the tablets of Example 12, tested in accordance with Example 13;
  • FIG. 9 is a graph showing the concentration of MHF in the blood of fasted monkeys following administration of the tablets of Examples 10 and 11;
  • FIG. 10 is a graph showing the concentration of MHF in the blood of fed monkeys following administration of the tablets of Examples 10 and 11;
  • FIG. 11 is a graph showing the in vitro MHF prodrug release profile (percent MHF prodrug released over time) for the dosage forms of Example 15, tested in accordance with Example 17;
  • FIG. 12 is a graph showing the in vitro MHF prodrug release profile (percent MHF prodrug released over time) for the dosage forms of Example 16, tested in accordance with Example 17.
  • Compound (1) means the MHF prodrug (1), (N,N-Diethylcarbamoyl)methylmethyl (2E)but-2-ene-1,4-dioate, alternatively named 1-[2-(diethylamino)-2-oxoethyl]4-methyl (2E)but-2-ene-1,4-dioate, pharmaceutically acceptable solvates thereof, and crystalline forms of any of the foregoing.
  • Compounds may be identified either by their chemical structure and/or chemical name. Compounds are named using Chemistry 4-D Draw Pro, version 7.01c (Chem Innovation Software, Inc., San Diego, Calif.). When the chemical structure and chemical name conflict, the chemical structure is determinative of the identity of the compound.
  • the compounds described herein may comprise one or more chiral centers and/or double bonds and therefore may exist as stereoisomers such as double bond isomers (i.e., geometric isomers), enantiomers, or diastereomers.
  • any chemical structures within the scope of the specification depicted, in whole or in part, with a relative configuration are deemed to encompass all possible enantiomers and stereoisomers of the illustrated compounds including the stereoisomerically pure form (e.g., geometrically pure, enantiomerically pure, or diastereomerically pure) and enantiomeric and stereoisomeric mixtures.
  • Enantiomeric and stereoisomeric mixtures may be resolved into their component enantiomers or stereoisomers using separation techniques or chiral synthesis techniques well-known to those skilled in the art.
  • Compounds include, for example, optical isomers, racemates thereof, and other mixtures thereof.
  • a single enantiomer or diastereomer i.e., optically active form
  • Resolution of the racemates may be accomplished, for example, by methods such as crystallization in the presence of a resolving agent, or chromatography using, for example, chiral stationary phases.
  • the configuration of the illustrated double bond is only in the E configuration (i.e., trans configuration).
  • Compound (1) also includes isotopically labeled compounds where one or more atoms have an atomic mass different from the atomic mass conventionally found in nature.
  • isotopes that may be incorporated into the compounds disclosed herein include, but are not limited to, 2 H, 3 H, 11 C, 13 C, 14 C, 15 N, 18 O, 17 O, etc.
  • Compound (1) may exist in unsolvated forms as well as solvated forms, including hydrated forms and as N-oxides. In general, compound (1) may be the free acid, hydrated, solvated, N-oxides, or combinations of any of the foregoing.
  • Compound (1) may exist in multiple crystalline, co-crystalline, or amorphous forms.
  • Compound (1) includes pharmaceutically acceptable solvates thereof, as well as crystalline forms of any of the foregoing.
  • Compound (1) also includes solvates.
  • a solvate refers to a molecular complex of a compound with one or more solvent molecules in a stoichiometric or non-stoichiometric amount.
  • solvent molecules are those commonly used in the pharmaceutical art, which are known to be innocuous to a subject, e.g., water, ethanol, and the like.
  • a molecular complex of a compound or moiety of a compound and a solvent can be stabilized by non-covalent intra-molecular forces such as, for example, electrostatic forces, van der Waals forces, or hydrogen bonds.
  • the term “hydrate” refers to a solvate in which the one or more solvent molecules is water.
  • Controlled-release refers to release of a drug from a dosage form in which the drug release is controlled or modified over a period of time. Controlled can mean, for example, sustained, delayed, or pulsed-release at a particular time. Controlled can also mean that release of the drug from the dosage form is extended for longer than it would be in an immediate-release dosage form, i.e., at least over several hours.
  • in vivo release of the compound occurs over a period of at least 2 hours, in some embodiments, over a period of at least about 4 hours, in some embodiments, over a period of at least about 8 hours, in some embodiments over a period of at least about 12 hours, in some embodiments, over a period of at least about 16 hours, in some embodiments, over a period of at least about 20 hours, and in some embodiments, over a period of at least about 24 hours.
  • a composition or material that is “substantially free of carboxylic acid moieties” is a composition or material that has less than 2% w/w of carboxylic acid moieties. In some embodiments, a composition or material that is “substantially free of carboxylic acid moieties” is a composition or material that has less than 1% w/w of carboxylic acid moieties. In other embodiments, a composition or material that is “substantially free of carboxylic acid moieties” is a composition or material that has less than 0.01% w/w of carboxylic acid moieties.
  • Dosage form refers to a form of a formulation that contains an amount of active agent or prodrug of an active agent, i.e., MHF prodrug compound (1), which can be administered to a subject to achieve a therapeutic effect.
  • An oral dosage form is intended to be administered to a subject via the mouth and swallowed.
  • a dose of a drug may include one or more dosage forms administered simultaneously or over a period of time.
  • Immediate release refers to formulations or dosage forms that rapidly dissolve in vitro and in vivo and are intended to be completely dissolved and absorbed in the stomach or upper gastrointestinal tract. Immediate release formulations can release at least 90% of the active ingredient or precursor thereof within about 15 minutes, within about 30 minutes, within about one hour, or within about two hours of administering an immediate release dosage form.
  • Subject includes mammals, such as for example, humans.
  • “Pharmaceutically acceptable” refers to approved or approvable by a regulatory agency of a federal or a state government, listed in a U.S. Pharmacopeia, or listed in other generally recognized pharmacopeia for use in mammals, including humans.
  • “Pharmaceutically acceptable salt” refers to a salt that is pharmaceutically acceptable and that possesses the desired pharmacological activity of the parent compound.
  • Such salts include: (1) acid addition salts, formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or formed with organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethane-disulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid,
  • “Pharmaceutically acceptable vehicle” or “pharmaceutically acceptable excipient” refers to a pharmaceutically acceptable diluent, a pharmaceutically acceptable adjuvant, a pharmaceutically acceptable excipient, a pharmaceutically acceptable carrier, or a combination of any of the foregoing with which a compound such as the MHF prodrug, (N,N-Diethylcarbamoyl)methylmethyl (2E)but-2-ene-1,4-dioate, compound (1), may be administered to a subject, which does not substantially compromise the pharmacological activity thereof, and which is nontoxic when administered in doses sufficient to provide a therapeutically effective amount of the MHF prodrug or MHF metabolite.
  • Prodrug refers to a derivative of an active compound (drug) that undergoes a transformation under the conditions of use, such as within the body, to release an active drug. Prodrugs are frequently, but not necessarily, pharmacologically inactive until converted into the active drug. Prodrugs may be obtained by bonding a promoiety (defined herein), typically via a functional group, to a drug. For example, MHF prodrug compound (1) is metabolized within a subject's body to form the parent drug MHF.
  • “Promoiety” refers to a group bonded to a drug, typically to a functional group of the drug, via a bond(s) that is cleavable under specified conditions of use.
  • the bond(s) between the drug and promoiety may be cleaved by enzymatic or non-enzymatic means. Under the conditions of use, for example following administration to a subject, the bond(s) between the drug and promoiety may be cleaved to release the parent drug.
  • the cleavage of the promoiety may proceed spontaneously, such as via a hydrolysis reaction, or it may be catalyzed or induced by another agent, such as by an enzyme, by light, by acid, or by a change of or exposure to a physical or environmental parameter, such as a change of temperature, pH, etc.
  • the agent may be endogenous to the conditions of use, such as an enzyme present in the systemic circulation of a subject to which the prodrug is administered or the pH conditions of the gastrointestinal tract or the agent may be supplied exogenously.
  • the drug is MHF and the promoiety has the structure:
  • dissolution profiles may be considered similar based on a difference factor (f 1 ) and a similarity factor (f 2 ).
  • f 1 values should be close to 0, and f 2 values should be close to 100.
  • f 1 values up to 15 (0-15) and f 2 values greater than 50 (50-100) ensure sameness or equivalence of two dissolution profiles.
  • sustained release refers to release of a compound from a dosage form at a rate effective to achieve a therapeutic amount of a compound, e.g., MHF in the systemic blood circulation over a prolonged period of time relative to that achieved by oral administration of an immediate release formulation, e.g., of MHF.
  • a compound e.g., MHF
  • an immediate release formulation e.g., of MHF
  • in vivo release of MHF, from a high prodrug load tablet disclosed herein occurs over a period of at least about 4 hours, in some embodiments, over a period of at least about 8 hours, in some embodiments over a period of at least about 12 hours, in some embodiments, over a period of at least about 16 hours, in some embodiments, over a period of at least about 20 hours, and in some embodiments, over a period of at least about 24 hours.
  • “Therapeutically effective amount” refers to the amount of (N,N-Diethylcarbamoyl)methylmethyl (2E)but-2-ene-1,4-dioate that, when administered to a subject for treating a disease, is sufficient to reduce the severity of, eliminate, or prevent the disease, or a symptom of the disease, in the subject.
  • the therapeutically effective amount may vary depending, for example, on the form of the compound (1), the cause of disease, the severity of the disease, the age, weight, and/or health of the subject to be treated, and the judgment of the prescribing physician.
  • a therapeutically effective amount may be ascertained by those skilled in the art and/or capable of determination by routine experimentation.
  • Treating” or “treatment” of any disease refers to reversing, alleviating, arresting, or ameliorating a disease or at least one of the clinical symptoms of a disease, reducing the risk of acquiring at least one of the clinical symptoms of a disease, inhibiting the progress of a disease or at least one of the clinical symptoms of the disease or reducing the risk of developing at least one of the clinical symptoms of a disease. “Treating” or “treatment” also refers to inhibiting the disease, either physically, (e.g., stabilization of a discernible symptom), physiologically, (e.g., stabilization of a physical parameter), or both, and to inhibiting at least one physical parameter that may or may not be discernible to the patient. In certain embodiments, “treating” or “treatment” refers to protecting against or delaying the onset of at least one or more symptoms of a disease in a patient.
  • Compound (1) may be prepared using the methods described in Gangakhedkar et al. U.S. Pat. No. 8,148,414, which is herein incorporated by reference.
  • Oral dosage forms disclosed herein comprise a tablet or capsule containing (N,N-Diethylcarbamoyl)methylmethyl (2E)but-2-ene-1,4-dioate and one or more pharmaceutically acceptable excipients.
  • the oral dosage forms comprise granules having a high loading of (N,N-Diethylcarbamoyl)methylmethyl (2E)but-2-ene-1,4-dioate.
  • high drug loading solid granulations comprise at least about 95 wt % compound (1), and in certain embodiments, at least about 97% compound (1).
  • the high drug loading granulations may also comprise one or more pharmaceutically acceptable excipients.
  • the pharmaceutically acceptable excipient may comprise a pharmaceutically acceptable binder.
  • granulations, or granules as used interchangeably herein may comprise from about 0.5 wt % to about 5.0 wt %, and in certain embodiments about 1 wt % to about 3.0 wt % of a pharmaceutically acceptable binding agent. Binding agents may be included in granules to facilitate adhesion of the constituents.
  • binding agents useful in tablet dosage forms include polyvinyl acetate phthalate, molasses, starch, methylcellulose, hydroxypropyl cellulose (HPC), hydroxypropyl methyl cellulose (HPMC), sodium carboxymethyl cellulose, microcrystalline cellulose, polyvinyl pyrrolidone, and other polymers including vinyl pyrrolidone as a sub-unit, and combinations thereof.
  • a binder may be a polymer selected from hydroxypropyl cellulose, hydroxypropylmethyl cellulose, polyvinyl pyrrolidone and combinations thereof.
  • the binder may be hydroxypropyl cellulse (Klucel EXF, Ashland).
  • Granules having a high loading of compound (1) may be prepared using high shear wet granulation. At least in part, the amount of binder and other pharmaceutically acceptable excipients are chosen to provide a wide processing window for the amount of water used during granulation. For manufacturing, it is generally desirable to be able to vary process parameters without significantly negatively impacting the properties of the granules and to produce granules having optimal physical and mechanical properties to facilitate subsequent processes for manufacture of oral dosage forms.
  • a mixture comprising the high drug load granules of compound (1) may be formed.
  • the mixture may comprise a blend of one or more pharmaceutically acceptable excipients and high drug load granules. If desired, the mixture may be used in preparation of oral dosage forms, as described herein. In certain embodiments it was unexpectedly found that the additional of a small amount of glidant markedly improved the flowability of the mixture including high loading granules, as described in further detail herein. Glidants may be included in blends provided by the present disclosure to reduce sticking effects during processing, film formation, and/or drying.
  • glidants examples include talc, magnesium stearate, glycerol monostearate, colloidal silicon dioxide, precipitated silicon dioxide, fumed silicon dioxide, and combinations of any of the foregoing.
  • the blends may contain up to 3 wt % of a glidant as a flow aid. In other embodiments, the mixtures may contain up to 1 wt % glidant as a flow aid. In other embodiments, the mixtures may contain 0.1 to about 0.5 wt % glidant as a flow aid. In certain embodiments, a glidant is colloidal silicon dioxide.
  • the high drug loading granulations and mixtures of the disclosure may be used to prepare any suitable pharmaceutical formulations, including oral dosage forms.
  • the oral dosage forms may provide immediate release, sustained release, delayed release or any combination thereof.
  • an oral dosage form comprising a high drug load granulation may be compressed into a tablet dosage form.
  • a mixture comprising a high drug load granulation may be inserted into and contained in a capsule dosage form.
  • an oral dosage form comprising a high drug load granulation may be a liquid oral dosage from such as an emulsion or suspension.
  • the amount of compound (1) in a dosage form provided by the present disclosure is from about 50 mg to about 2,000 mg, in certain embodiments, from about 100 mg to about 1,200 mg, and in certain embodiments is about 200 mg to about 800 mg.
  • the amount of compound (1) in a dosage form refers to the mass equivalent weight of compound (1) comprising the solvate.
  • one (1) mg compound (1) corresponds to 0.53 mg-equivalents of MHF.
  • dosage forms may be in the form of tablets comprising compound (1).
  • Tablet dosage forms may be of any shape suitable for oral administration of a drug such as spheroidal, cube-shaped, oval, or ellipsoidal.
  • tablet dosage forms e.g., an oral dosage form in the form of a tablet, provided by the present disclosure are matrix systems in which the compound (1) is dispersed in a matrix comprising at least one release-rate modifying compound. Matrix systems are well-known in the art as described, for example, in “Handbook of Pharmaceutical Controlled Release Technology,” ed. Wise, Marcel Dekker, Inc. (2000) and “Treatise on Controlled Drug Delivery, Fundamentals, Optimization, and Applications,” ed. Kydonieus, Marcel Dekker, Inc. (1992).
  • Oral dosage forms may comprise a tablet core with greater than about 70 wt % compound (1), greater than about 80 wt % compound (1), greater than about 85 wt % compound (1), greater than about 90 wt % compound (1), greater than about 95 wt % compound (1), greater than about 97 wt % compound (1), where wt % is based on the weight of an uncoated tablet core of a dosage form.
  • the oral dosage form may comprise at least one additional pharmaceutically acceptable excipient where the pharmaceutical excipient is selected from fillers, diluents, binders, lubricants, disintegrants, glidants, sustained release agents, surfactants, plasticizers, anti-adherents, buffers, dyes, wetting agents, emulsifying agents, pH buffering agents, thickening agents, coloring agents, enteric agents, and combinations thereof.
  • the pharmaceutical excipient is selected from fillers, diluents, binders, lubricants, disintegrants, glidants, sustained release agents, surfactants, plasticizers, anti-adherents, buffers, dyes, wetting agents, emulsifying agents, pH buffering agents, thickening agents, coloring agents, enteric agents, and combinations thereof.
  • Diluents, or fillers may be added to increase the bulk to make dosage forms a practical size for compression.
  • Fillers may be added to increase the bulk to make dosage forms.
  • Examples of fillers useful in the present disclosure include dibasic calcium phosphate, dibasic calcium phosphate dihydrate, calcium sulfate, dicalcium phosphate, tricalcium phosphate, lactose, cellulose including microcrystalline cellulose, mannitol, sodium chloride, dry starch, pregelatinized starch, compressible sugar, mannitol, and combinations of any of the foregoing.
  • a filler is lactose monohydrate. Fillers may be water insoluble, water soluble, or combinations thereof.
  • water insoluble fillers examples include starch, dibasic calcium phosphate dihydrate, calcium sulfate, dicalcium phosphate, tricalcium phosphate, powdered cellulose, microcrystalline cellulose, and combinations of any of the foregoing.
  • water-soluble fillers include water soluble sugars and sugar alcohols, such as lactose, glucose, fructose, sucrose, mannose, dextrose, galactose, the corresponding sugar alcohols and other sugar alcohols, such as mannitol, sorbitol, xylitol, and combinations of any of the foregoing.
  • Lubricants and anti-static agents may be included in a pharmaceutically acceptable coating to aid in processing.
  • lubricants useful in coatings provided by the present disclosure include calcium stearate, glycerol behenate, glyceryl monostearate, magnesium stearate, mineral oil, polyethylene glycol, sodium stearyl fumarate, sodium lauryl sulfate, stearic acid, talc, vegetable oil, zinc stearate, and combinations of any of the foregoing.
  • the lubricant is magnesium stearate.
  • coatings may comprise an amount of lubricant ranging from about 0.5 wt % to about 3 wt %, from about 1 wt % to about 3 wt %, and in certain embodiments is about 1 to about 2 wt %, based on the total solids weight of the coating.
  • Disintegrants may be included in the tablet core to cause a tablet core to break apart, for example, by expansion of a disintegrants when exposed to water.
  • useful disintegrants include water swellable substances such as croscarmellose sodium, sodium starch glycolate, cross-linked polyvinyl pyrrolidone, and combinations of any of the foregoing.
  • the disintegrants can be selected to be substantially free of carboxylic acid moieties.
  • surfactants useful in tablet dosage forms provided by the present disclosure include pharmaceutically acceptable anionic surfactants, cationic surfactants, zwitterionic, amphoteric (amphiphatic/amphiphilic) surfactants, non-ionic surfactants, polyethyleneglycol esters or ethers, and combinations of any of the foregoing.
  • useful pharmaceutically acceptable anionic surfactants include monovalent alkyl carboxylates, acyl lactylates, alkyl ether carboxylates, N-acyl sarcosinates, polyvalent alkyl carbonates, N-acyl glutamates, fatty acid-polypeptide condensates, sulfuric acid esters, alkyl sulfates such as sodium lauryl sulfate and sodium dodecyl sulfate, ethoxylated alkyl sulfates, ester linked sulfonates such as docusate sodium and dioctyl sodium succinate, alpha olefin sulfonates, or phosphated ethoxylated alcohols.
  • useful pharmaceutically acceptable cationic surfactants include monoalkyl quaternary ammonium salts, dialkyl quaternary ammonium compounds, amidoamines, and aminimides.
  • useful pharmaceutically acceptable amphoteric surfactants include N-substituted alkyl amides, N-alkyl betaines, sulfobetaines, and N-alkyl-6-aminopropionates.
  • nonioinic surfactants examples include diblock and triblock copolymers of polyethylene oxide, polypropylene oxide, polyoxyethylene (20) sorbitan monooleate, and polyethyleneglycol esters or ethers such as polyethoxylated castor oil, polyethoxylated hydrogenated castor oil, and hydrogenated castor oil.
  • a surfactant is chosen from sodium lauryl sulfate and sodium dodecyl sulfate.
  • Tablet dosage forms provided by the present disclosure may further comprise one or more coatings, which may partially or fully cover the tablets. While certain coatings may be applied to modify or affect the release of compound (1) from a tablet dosage form in the gastrointestinal tract, others may have no such effect. For example, one or more additional coatings may be for physical protection, chemical protection, aesthetics, ease in swallowing, identification, and/or to facilitate further processing of the tablets. Coatings may be impermeable to moisture or may be moisture permeable. Moisture impermeable exterior tablet coatings may be useful for maintaining low moisture content in a dosage form that is packaged in the presence of a desiccant and may thereby enhance, for example, the storage stability of a tablet dosage form.
  • Examples of materials useful in coatings for physical protection include permeable or soluble materials such as hydroxypropyl methylcellulose, hydroxypropyl cellulose, lactose, hydroxypropyl ethylcellulose, hydroxyethyl cellulose, and xanthan gum.
  • Examples of materials useful in external tablet coatings to facilitate further processing include talc, colloidal silica, polyvinyl alcohol, titanium dioxide, micronized silica, fumed silica, glycerol monostearate, magnesium trisilicate, and magnesium stearate.
  • An external tablet coating may further include one or more vehicles such as plasticizers, binders, fillers, lubricants, compression aides, and combinations of any of the foregoing.
  • the one or more additional coatings may comprise a single material or a combination of more than one material including any of those disclosed herein. These additional coatings may be applied to tablet dosage forms by methods known to those skilled in the art.
  • Plasticizers may also be included in tablet dosage forms, e.g., in coatings, provided by the present disclosure.
  • plasticizers useful in tablet dosage forms provided by the present disclosure include alkyl citrates such as triethyl citrate, acetyl triethyl citrate, tributyl citrate, acetyl triethyl citrate, and acetyl tributyl citrate; alkyl acetates such as triethyl acetate, acetyl triethyl acetate, tributyl acetate, acetyl triethyl acetate, and acetyl tributyl acetate; sucrose fatty acid esters; glycerin mono-, di- and tri-fatty acid esters such as triacetin, glycerin mono-fatty acid esters, glycerin monostearate and acetylated monoglyceride; polyglycerin fatty acid esters
  • the tablet core may be coated with a compression coating to provide, e.g., a desired release profile.
  • the compression coating layers typically release no more than 20% of compound (1) over a period of 2 hours after the oral dosage form is placed in an aqueous solution free of compound (1).
  • the compression coating may comprise a the compression coating layer comprises (i) a non-ionizable polymer that is (a) a proton-donating acidic material having a pKa of greater than 8 or (b) a proton-accepting basic material having a pKa of less than 2, (ii) a natural gum or polysaccharide, (iii) a neutral polymer salt, (iv) a sugar, or (v) a lipid.
  • a non-ionizable polymer that is (a) a proton-donating acidic material having a pKa of greater than 8 or (b) a proton-accepting basic material having a pKa of less than 2, (ii) a natural gum or polysaccharide, (iii) a neutral polymer salt, (iv) a sugar, or (v) a lipid.
  • the tablet core may be coated with a barrier layer to provide, e.g., physical or chemical protection.
  • the barrier layer may comprise a (i) non-ionizable polymer material that is (a) a weakly acidic (proton-donating) material having a pKa of greater than 8 or (b) a weakly basic (proton-accepting) material having a pKa of less than 2, (ii) a natural gum or polysaccharide, (iii) a neutral polymer salt, (iv) a sugar, or (v) a lipid.
  • non-ionizable polymers examples include non-ionizable cellulosic polymers, non-ionizable vinyl and polyvinyl alcohol polymers, and/or non-ionizable polymers that are not cellulose or vinyl-based. In various embodiments, non-ionizable polymers are substantially free of carboxylic acid moieties.
  • non-ionizable cellulosic polymers include methylcellulose, ethylcellulose, propylcellulose, butylcellulose, cellulose acetate, cellulose propionate, cellulose butyrate, cellulose acetate butyrate, cellulose acetate propionate, methyl cellulose, methyl cellulose acetate, methyl cellulose propionate, methyl cellulose butyrate, ethyl cellulose acetate, ethyl cellulose propionate, ethyl cellulose butyrate, hydroxymethyl cellulose, hydroxyethyl cellulose, hydroxyethyl methyl cellulose, hydroxypropyl cellulose, hydroxybutyl cellulose, hydroxyethyl cellulose acetate, hydroxyethyl ethyl cellulose, low-substituted hydroxypropyl cellulose, hydroxypropyl methylcellulose, hydroxypropyl methylcellulose acetate, hydroxypropyl methylcellulose propionate, hydroxypropyl
  • Exemplary vinyl-based polymers include polyvinyl alcohol, polyvinvyl acetate, polyvinylpyrrolidone, and crospovidone (polymers of N-vinyl-2-pyrrolidone).
  • Exemplary vinyl-containing polymers further include vinyl polymers and copolymers having hydroxyl-containing repeat units, alkylacyloxy-containing repeat units, or cyclicamido-containing repeat units.
  • vinyl-containing polymers also include polyvinyl alcohols that have at least a portion of their repeat units in the unhydrolyzed (vinyl acetate) form, polyvinylhydroxyethyl ether, polyvinyl alcohol polyvinyl acetate copolymers, polyvinyl pyrrolidone, polyvinylpyrrolidone-polyvinvylacetate copolymers, polyethylene polyvinyl alcohol copolymers, and polyoxyethylene-polyoxypropylene copolymers.
  • vinyl copolymers can include a second polymer can having (1) substantially carboxy-free hydroxyl-containing repeat units and (2) hydrophobic repeat units.
  • the non-ionizable polyvinyl materials show no degradation as an excipient.
  • Non-limiting examples of such materials include polyvinylpyrrolidone and crospovidone.
  • non-cellulosic non-vinyl-based non-ionizable polymers include poly(lactide) poly(glycolide), poly( ⁇ -caprolactone), poly(lactide-co-glycolide), poly(lactide-co- ⁇ -caprolactone), poly(ethylene oxide-co- ⁇ -caprolactone), poly(ethylene oxide-co-lactide), poly(ethylene oxide-co-lactide-co-glycolide), poly(isobutyl)cyanoacrylate, and poly(hexyl)cyanoacrylate, polyethylene glycol, polyethylene glycol, polypropylene glycol copolymers, polyoxyethylene-polyoxypropylene block copolymers, polyethylene glycol, poly(ethyl acrylate-co-methyl methacrylate) 2:1 (Eudragit NE), polyethylene glycol, polyethylene glycol polypropylene glycol copolymers, and polyoxyethylene-polyoxypropylene block copolymers (i.e.
  • non-ionizable polymers such as polyoxyethylene-polyoxypropylene block copolymers show no degradation as an excipient.
  • the non-cellulosic non-vinyl based non-ionizable polymers do not contain carboxylic acid moieties, or are substantially free of carboxylic acid moieties.
  • Suitable examples of such natural gums and polysaccharides include starch, chitin, guar gum, tara gum, locust bean gum, carrageenan, gellan gum, alginate, and xanthan gum.
  • the natural gums and polysaccharides contain carboxylic acid moieties, including salts thereof.
  • carboxylic acid moieties including salts thereof.
  • Non-limiting examples of such materials include gellan gum, Alginate, and xanthan gum.
  • natural gums or polysaccharides are substantially free of carboxylic acid moieties.
  • Non-limiting examples of such materials include starch, chitin, guar gum, tara gum, locust bean gum, carrageenan.
  • Non-limiting examples of such neutral polymer salts include poly(ethyl acrylate-co-methyl methacrylate-co-trimethylammonioethyl methacrylate chloride) 1:2:0.1, Poly(ethyl acrylate-co-methyl methacrylate-co-trimethylammonioethyl methacrylate chloride) 1:2:0.2, crosslinked sodium carboxymethyl cellulose (croscarmellose sodium), crosslinked sodium carboxymethyl cellulose (sodium starch glycolate), salts of carboxymethyl cellulose, salts of carboxyethyl cellulose, salts of carboxypropyl cellulose, salts of carboxybutyl cellulose, salts of carboxymethyl starch, and salts of carboxyethyl starch.
  • the neutral polymer salts do not include a carboxylate group.
  • the neutral polymer salts do not degrade as excipients.
  • Non-limiting examples of such materials include poly(ethyl acrylate-co-methyl methacrylate-co-trimethylammonioethyl methacrylate chloride) 1:2:0.1, poly(ethyl acrylate-co-methyl methacrylate-co-trimethylammonioethyl methacrylate chloride) 1:2:0.2, and croscarmellose sodium.
  • certain neutral polymer salts do not include carboxyl groups. These materials include poly(ethyl acrylate-co-methyl methacrylate-co-trimethylammonioethyl methacrylate chloride) 1:2:0.1 and poly(ethyl acrylate-co-methyl methacrylate-co-trimethylammonioethyl methacrylate chloride) 1:2:0.2
  • certain neutral polymer salts include a carboxyl group that is neutralized with a counterion.
  • Such compounds include crosslinked croscarmellose, crosslinked sodium carboxymethyl cellulose (sodium starch glycolate), salts of carboxymethyl cellulose, salts of carboxyethyl cellulose, salts of carboxypropyl cellulose, salts of carboxybutyl cellulose, salts of carboxymethyl starch, and salts of carboxyethyl starch.
  • the ionizable polymers do not contain carboxylic acid groups.
  • Such materials include poly(butyl methacylate-co-(2-dimethylaminoethyl)methacrylate-co-methyl methacrylate) 1:2:1 (Eudragit E), chitosan, and methyl methacrylate diethylaminoethyl methacrylate copolymer.
  • Eudragit E has polymer free amino groups, and is neutral at pH>5 and prontonated at pH ⁇ 5.
  • Suitable sugars include lactose, mannitol, sorbitol, sucrose, and trehalose.
  • lipids examples include glyceryl behenate, castor oil, hydrogenated vegetable oil, hydrogenated carnauba wax, and microcrystalline wax. In certain variations, the lipids are substantially free of carboxylic acid moieties.
  • the barrier layer may disposed between the tablet core and an enteric coating layer.
  • the barrier layer is sufficiently thick and sufficiently continuous to prevent direct contact between the enteric coating and the core. Typically this can be accomplished by coating the cores to a target weight percent range.
  • the barrier layer can comprise at least 5 wt % of the coated core.
  • the barrier layer comprises at least 0.5 wt % of the coated core.
  • the barrier layer can be applied to a specified average thickness.
  • the barrier layer can have an average thickness of at least 5 ⁇ m. In other embodiments, the barrier layer has an average thickness of at least 15 ⁇ m.
  • the enteric coating comprises an enteric polymer that is substantially insoluble in aqueous solutions having a pH level below 4.5 but which starts to become soluble at a pH between 4.5 and 7.5 and is soluble in aqueous solutions having a pH above 7.5.
  • the enteric coating remains intact while the oral dosage form is in the low pH environs of the stomach, which means that the fumarate compound remains in the core while the dosage form is in the stomach.
  • Suitable enteric polymers include methacrylic acid polymers, cellulose acetate phthalate polymers, hydroxypropylmethyl cellulose acetate succinate polymers, hydroxypropylmethyl cellulose phthalate polymers and polyvinyl acetate phthalate polymers.
  • Other examples of pH-sensitive polymers that can be used in the enteric coating include methyl acrylate-methacrylic acid copolymers, cellulose acetate succinate, hydroxy propyl methyl cellulose phthalate, hydroxy propyl methyl cellulose acetate succinate (hypromellose acetate succinate), polyvinyl acetate phthalate (PVAP), methyl methacrylate-methacrylic acid copolymers and shellac.
  • enteric polymers include hydroxypropyl methyl cellulose acetate succinate, hydroxypropyl methyl cellulose succinate, hydroxypropyl cellulose acetate succinate, hydroxyethyl methyl cellulose succinate, hydroxyethyl cellulose acetate succinate, hydroxypropyl methyl cellulose phthalate, hydroxyethyl methyl cellulose acetate succinate, hydroxyethyl methyl cellulose acetate succinate, hydroxyethyl methyl cellulose acetate phthalate, carboxyethyl cellulose, carboxymethyl cellulose, cellulose acetate phthalate, methyl cellulose acetate phthalate, ethyl cellulose acetate phthalate, hydroxypropyl cellulose acetate phthalate, hydroxypropyl methyl cellulose acetate phthalate, hydroxypropyl cellulose acetate succinate, hydroxypropyl methyl cellulose succinate phthalate, hydroxypropyl methyl cellulose succinate phthal
  • the oral dosage forms can be either immediate release, sustained release, delayed release or combinations thereof.
  • the dosage form in order to minimize contact between the compound (1) and the tissues lining the stomach and to prevent exposure of the compound (1) to the low pH environs of the stomach, the dosage form may be a delayed release dosage form, and following the delay in prodrug release, thereafter provide either immediate release of the compound (1) or sustained release of the compound (1).
  • the oral dosage forms may be formulated to include compression coating layers to provide, e.g., delayed release, and the tablet cores may be prepared as immediate release formulations or sustained release formulations, depending on the desired release profile.
  • the oral dosage forms may be formulated to include a sustained release tablet core, an enteric coating, and a protective barrier layer intermediate the tablet core and the enteric coating.
  • Exemplary oral dosage forms are disclosed in co-owned applications, filed concurrently herein, entitled “ORAL DOSAGE FORMS OF METHYL HYDROGEN FUMARATE AND PRODRUGS THEREOF”, under Attorney Docket Number P234942.US.01 (X-0184 P1), and “ORAL DOSAGE FORMS OF METHYL HYDROGEN FUMARATE AND PRODRUGS THEREOF” under Attorney Docket Number P234941.US.01 (X-0183 P1), the contents of which are both herein incorporated by reference.
  • tablet dosage forms comprise less than a therapeutically effective amount of compound (1)
  • multiple tablet dosage forms may be administered to a subject simultaneously or over a period of time to provide a therapeutically effective dose of compound (1).
  • the oral dosage form may be formulated to comprise an amount of compound (1) suitable for twice a day administration (BID), three times a day administration (TID), etc.
  • the release characteristics of dosage forms provided by the present disclosure comprising compound (1) may be characterized, in part, by the in vitro dissolution profile.
  • Methods for determining dissolution profiles of dosage forms are well known to those skilled in the pharmaceutical arts. Standard methodologies set forth in the U.S. Pharmacopeia may be used.
  • a dissolution profile may be determined using either a U.S. Pharmacopeia Type I Apparatus (baskets) or a U.S. Pharmacopeia Type II Apparatus (paddles).
  • dissolution, or release, profiles of dosage forms provided by the present disclosure may be determined by immersing the dosage forms into a dissolution vessel (USP, Type I, basket) containing 750 mL of 0.1 N hydrochloric acid (pH 1.2). After 2 hours, 250 mL of 200 mM tribasic sodium phosphate was added to the vessel resulting in a pH adjustment from 1.2 to 6.8. The dissolution medium was kept at 37° C. and was agitated at 100 rpm.
  • Samples are withdrawn from the dissolution medium at intervals and the content of compound (1) in the dissolution medium determined using reverse phase high pressure liquid chromatography (HPLC).
  • HPLC reverse phase high pressure liquid chromatography
  • release of compound (1) from tablet dosage forms provided by the present disclosure exhibits an in vitro dissolution profile in wherein about 20% to about 45% of the (N,N-Diethylcarbamoyl)methylmethyl (2E)but-2-ene-1,4-dioate in the dosage form is released within about 4 hours; about 40% to about 70% of the (N,N-Diethylcarbamoyl)methylmethyl (2E)but-2-ene-1,4-dioate is released within about 8 hours; about 60% to about 85% of the (N,N-Diethylcarbamoyl)methylmethyl (2E)but-2-ene-1,4-dioate is released within about 12 hours; and about 80% to about 100% of the (N,N-Diethylcarbamoyl)methylmethyl (2E)but-2-ene-1,4-dioate is released within about 20 hours.
  • a tablet exhibits a dissolution profile that is similar to the foregoing profile as determined using the f1 difference factor and the f2 similarity factor according to FDA guidelines.
  • a tablet dosage form exhibiting the foregoing release profiles comprises about 700 mg to about 1,000 mg compound (1).
  • tablets have a friability of less than about 1 wt % determined according to USP Test No. 1216.
  • tablets provided by the present disclosure have a friability of less than about 1 wt %, in certain embodiments, less than about 0.5 wt %, in certain embodiments, less than about 0.3 wt %, and in certain embodiments, less than about 0.1 wt %.
  • the dosage forms disclosed herein may be administered to a patient suffering from any disease including a disorder, condition, or symptom for which MHF is known or hereafter discovered to be therapeutically effective.
  • Indications for which MHF has been prescribed, and hence for which a dosage form disclosed herein is also expected to be effective, include psoriasis.
  • Other indications for which the disclosed dosage forms may be therapeutically effective include multiple sclerosis, an inflammatory bowel disease, asthma, chronic obstructive pulmonary disease, and arthritis.
  • Methods of treating a disease in a patient comprise administering to a patient in need of such treatment a dosage form disclosed herein.
  • the dosage forms disclosed herein may provide therapeutic or prophylactic plasma and/or blood concentrations of MHF following administration to a patient.
  • the dosage forms disclosed herein may be administered in an amount and using a dosing schedule as appropriate for treatment of a particular disease.
  • daily doses of compound (1) may range from about 0.01 mg/kg to about 50 mg/kg, from about 0.1 mg/kg to about 50 mg/kg, from about 1 mg/kg to about 50 mg/kg, and in certain embodiments, from about 5 mg/kg to about 25 mg/kg.
  • the compound (1) may be administered at a dose over time from about 1 mg to about 5 g per day, from about 10 mg to about 4 g per day, and in certain embodiments from about 20 mg to about 2 g per day.
  • An appropriate dose of compound (1) may be determined based on several factors, including, for example, the body weight and/or condition of the patient being treated, the severity of the disease being treated, the incidence and/or severity of side effects, the manner of administration, and the judgment of the prescribing physician. Appropriate dose ranges may be determined by methods known to those skilled in the art.
  • MHF may be assayed in vitro and in vivo for the desired therapeutic or prophylactic activity prior to use in humans.
  • In vivo assays for example using appropriate animal models, may also be used to determine whether administration of compound (1) is therapeutically effective.
  • a therapeutically effective dose of compound (1) may provide therapeutic benefit without causing substantial toxicity including adverse side effects.
  • Toxicity of compound (1) and/or metabolites thereof may be determined using standard pharmaceutical procedures and may be ascertained by those skilled in the art.
  • the dose ratio between toxic and therapeutic effect is the therapeutic index.
  • a dose of compound (1) may be within a range capable of establishing and maintaining a therapeutically effective circulating plasma and/or blood concentration of MHF that exhibits little or no toxicity.
  • the dosage forms disclosed herein may be used to treat diseases, disorders, conditions, and symptoms of any of the foregoing for which MHF is known to provide or is later found to provide therapeutic benefit.
  • MHF is known to be effective in treating psoriasis, multiple sclerosis, an inflammatory bowel disease, asthma, chronic obstructive pulmonary disease, and arthritis.
  • the dosage forms disclosed herein may be used to treat any of the foregoing diseases and disorders.
  • the underlying etiology of any of the foregoing diseases being treated may have a multiplicity of origins.
  • a therapeutically effective amount of compound (1) may be administered to a patient, such as a human, as a preventative measure against various diseases or disorders.
  • a therapeutically effective amount of compound (1) may be administered as a preventative measure to a patient having a predisposition for and/or history of immunological, autoimmune, and/or inflammatory diseases including psoriasis, asthma and chronic obstructive pulmonary diseases, cardiac insufficiency including left ventricular insufficiency, myocardial infarction and angina pectoris, mitochondrial and neurodegenerative diseases such as Parkinson's disease, Alzheimer's disease, Huntington's disease, retinopathia pigmentosa and mitochondrial encephalomyopathy, transplantation rejection, autoimmune diseases including multiple sclerosis, ischemia and reperfusion injury, AGE-induced genome damage, inflammatory bowel diseases such as Crohn's disease and ulcerative colitis; and NF- ⁇ B mediated diseases.
  • immunological, autoimmune, and/or inflammatory diseases including psoriasis, asthma and chronic obstructive pulmonary diseases, cardiac insufficiency including left ventricular insufficiency, myo
  • Psoriasis is characterized by hyperkeratosis and thickening of the epidermis as well as by increased vascularity and infiltration of inflammatory cells in the dermis.
  • Psoriasis vulgaris manifests as silvery, scaly, erythematous plaques on typically the scalp, elbows, knees, and buttocks.
  • Guttate psoriasis occurs as tear-drop size lesions.
  • Fumaric acid esters are recognized for the treatment of psoriasis and dimethyl fumarate is approved for the systemic treatment of psoriasis in Germany (Mrowietz and Asadullah, Trends Mol Med 2005, 11(1), 43-48; and Mrowietz et al., Br J Dermatology 1999, 141, 424-429).
  • Efficacy of compound (1) for treating psoriasis can be determined using animal models and in clinical trials.
  • Inflammatory arthritis includes diseases such as rheumatoid arthritis, juvenile rheumatoid arthritis (juvenile idiopathic arthritis), psoriatic arthritis, and ankylosing spondylitis, each of which produces joint inflammation.
  • the pathogenesis of immune-mediated inflammatory diseases including inflammatory arthritis is believed to involve TNF and NK- ⁇ B signaling pathways (Tracey et al., Pharmacology & Therapeutics 2008, 117, 244-279).
  • Dimethyl fumarate has been shown to inhibit TNF and inflammatory diseases including inflammatory arthritis, which are believed to involve TNF and NK- ⁇ B signaling and therefore may be useful in treating inflammatory arthritis (Lowewe et al., J Immunology 2002, 168, 4781-4787).
  • the efficacy of compound (1) for treating inflammatory arthritis can be determined using animal models and in clinical trials.
  • MS Multiple sclerosis
  • MS is typified pathologically by multiple inflammatory foci, plaques of demyelination, gliosis, and axonal pathology within the brain and spinal cord, all of which contribute to the clinical manifestations of neurological disability (see e.g., Wingerchuk, Lab Invest 2001, 81, 263-281; and Virley, NeuroRx 2005, 2(4), 638-649).
  • axonal pathology within the brain and spinal cord
  • evidence implicates an autoimmune etiology together with environmental factors, as well as specific genetic predispositions.
  • Functional impairment, disability, and handicap are expressed as paralysis, sensory and octintive disturbances spasticity, tremor, a lack of coordination, and visual impairment, which impact on the quality of life of the individual.
  • the clinical course of MS can vary from individual to individual, but invariably the disease can be categorized in three forms: relapsing-remitting, secondary progressive, and primary progressive.
  • MS treatment efficacy in clinical trials can be accomplished using tools such as the Expanded Disability Status Scale and the MS Functional as well as magnetic resonance imaging lesion load, biomarkers, and self-reported quality of life.
  • Animal models of MS shown to be useful to identify and validate potential therapeutics include experimental autoimmune/allergic encephalomyelitis (EAE) rodent models that simulate the clinical and pathological manifestations of MS and nonhuman primate EAE models.
  • EAE experimental autoimmune/allergic encephalomyelitis
  • IBD Inflammatory bowel disease
  • Crohn's disease which is characterized by areas of inflammation with areas of normal lining in between, can affect any part of the gastrointestinal tract from the mouth to the anus.
  • the main gastrointestinal symptoms are abdominal pain, diarrhea, constipation, vomiting, weight loss, and/or weight gain.
  • Crohn's disease can also cause skin rashes, arthritis, and inflammation of the eye.
  • Ulcerative colitis is characterized by ulcers or open sores in the large intestine or colon.
  • the main symptom of ulcerative colitis is typically constant diarrhea with mixed blood of gradual onset.
  • Other types of intestinal bowel disease include collagenous colitis, lymphocytic colitis, ischaemic colitis, diversion colitis, Behcet's colitis, and indeterminate colitis.
  • FAEs are inhibitors of NF- ⁇ B activation and therefore may be useful in treating inflammatory diseases such as Crohn's disease and ulcerative colitis (Atreya et al., J Intern Med 2008, 263(6), 59106).
  • the efficacy of compound (1) for treating inflammatory bowel disease can be evaluated using animal models and in clinical trials.
  • Useful animal models of inflammatory bowel disease are known.
  • Asthma is reversible airway obstruction in which the airway occasionally constricts, becomes inflamed, and is lined with an excessive amount of mucus. Symptoms of asthma include dyspnea, wheezing, chest tightness, and cough. Asthma episodes may be induced by airborne allergens, food allergies, medications, inhaled irritants, physical exercise, respiratory infection, psychological stress, hormonal changes, cold weather, or other factors.
  • FAEs may be useful in treating pulmonary diseases such as asthma and chronic obstructive pulmonary disorder.
  • the efficacy of compound (1) for treating asthma can be assessed using animal models and in clinical trials.
  • COPD chronic obstructive pulmonary disease
  • COPD chronic obstructive airway disease
  • emphysema a group of diseases characterized by the pathological limitation of airflow in the airway that is not fully reversible, and includes conditions such as chronic bronchitis, emphysema, as well as other lung disorders such as asbestosis, pneumoconiosis, and pulmonary neoplasms (see, e.g., Barnes, Pharmacological Reviews 2004, 56(4), 515-548).
  • the airflow limitation is usually progressive and associated with an abnormal inflammatory response of the lungs to noxious particles and gases.
  • COPD is characterized by a shortness of breath that can last for months or years, possibly accompanied by wheezing, and a persistent cough with sputum production. COPD is most often caused by tobacco smoking, although it can also be caused by other airborne irritants such as coal dust, asbestos, urban pollution, or solvents. COPD encompasses chronic obstructive bronchiolitis with fibrosis and obstruction of small airways, and emphysema with enlargement of airspaces and destruction of lung parenchyma, loss of lung elasticity, and closure of small airways.
  • the efficacy of administering compound (1) for treating chronic obstructive pulmonary disease may be assessed using animal models of chronic obstructive pulmonary disease and in clinical studies.
  • murine models of chronic obstructive pulmonary disease are known.
  • Neurodegenerative diseases such as Parkinson's disease, Alzheimer's disease, Huntington's disease and amyoptrophic lateral sclerosis are characterized by progressive dysfunction and neuronal death.
  • NF- ⁇ B inhibition has been proposed as a therapeutic target for neurodegenerative diseases (Camandola and Mattson, Expert Opin Ther Targets 2007, 11(2), 123-32).
  • Parkinson's disease is a slowly progressive degenerative disorder of the nervous system characterized by tremor when muscles are at rest (resting tremor), slowness of voluntary movements, and increased muscle tone (rigidity).
  • nerve cells in the basal ganglia e.g., substantia nigra, degenerate, and thereby reduce the production of dopamine and the number of connections between nerve cells in the basal ganglia.
  • the basal ganglia are unable to properly control smooth muscle movements and coordinate changes in posture as normal, leading to tremor, incoordination, and slowed, reduced movement (bradykinesia) (Blandini, et al., Mol. Neurobiol. 1996, 12, 73-94).
  • the efficacy of compound (1) for treating Parkinson's disease may be assessed using animal and human models of Parkinson's disease and in clinical studies.
  • Alzheimer's disease is a progressive loss of mental function characterized by degeneration of brain tissue, including loss of nerve cells and the development of senile plaques and neurofibrillary tangles.
  • parts of the brain degenerate, destroying nerve cells and reducing the responsiveness of the maintaining neurons to neurotransmitters.
  • Abnormalities in brain tissue consist of senile or neuritic plaques, e.g., clumps of dead nerve cells containing an abnormal, insoluble protein called amyloid, and neurofibrillary tangles, twisted strands of insoluble proteins in the nerve cell.
  • the efficacy of compound (1) for treating Alzheimer's disease may be assessed using animal and human models of Alzheimer's disease and in clinical studies.
  • Huntington's disease is an autosomal dominant neurodegenerative disorder in which specific cell death occurs in the neostriatum and cortex (Martin, N Engl J Med 1999, 340, 1970-80). Onset usually occurs during the fourth or fifth decade of life, with a mean survival at age of onset of 14 to 20 years. Huntington's disease is universally fatal, and there is no effective treatment. Symptoms include a characteristic movement disorder (Huntington's chorea), cognitive dysfunction, and psychiatric symptoms. The disease is caused by a mutation encoding an abnormal expansion of CAG-encoded polyglutamine repeats in the protein, huntingtin.
  • the efficacy of compound (1) for treating Huntington's disease may be assessed using animal and human models of Huntington's disease and in clinical studies.
  • ALS Amyotrophic lateral sclerosis
  • ALS is a progressive neurodegenerative disorder characterized by the progressive and specific loss of motor neurons in the brain, brain stem, and spinal cord (Rowland and Schneider, N Engl J Med 2001, 344, 1688-1700).
  • ALS begins with weakness, often in the hands and less frequently in the feet that generally progresses up an arm or leg. Over time, weakness increases and spasticity develops characterized by muscle twitching and tightening, followed by muscle spasms and possibly tremors.
  • the average age of onset is 55 years, and the average life expectancy after the clinical onset is 4 years.
  • the only recognized treatment for ALS is riluzole, which can extend survival by only about three months.
  • the efficacy compound (1) for treating ALS may be assessed using animal and human models of ALS and in clinical studies.
  • rheumatica granuloma annulare, lupus, autoimmune carditis, eczema, sarcoidosis, and autoimmune diseases including acute disseminated encephalomyelitis, Addison's disease, alopecia greata, ankylosing spondylitis, antiphospholipid antibody syndrome, autoimmune hemolytic anemia, autoimmune hepatitis, autoimmune inner ear disease, bullous pemphigoid, Behcet's disease, celiac disease, Chagas diseas, chronic obstructive pulmonary disease, Crhon's disease, dermatomyositis, diabetes mellitus type I, endometriosis, Goodpasture's syndrome, Graves' disease, Guillain-Barre syndrome, Hashimoto's disease, hidradenitis suppurativea, Kawasaki disease, IgA neuropathy, idiopathic rhinitis, rheumatica, gran
  • Compound (1) may be administered at dosage levels of about 0.001 mg/kg to about 50 mg/kg, from about 0.01 mg/kg to about 25 mg/kg, or from about 0.1 mg/kg to about 10 mg/kg of subject body weight per day, one, two, three, four or more times a day, to obtain the desired concentrations and AUC for MHF in the blood plasma.
  • the amount of MHF or a MHF prodrug that will be effective in the treatment of a disease in a patient will depend, in part, on the nature of the condition and can be determined by standard clinical techniques known in the art. In addition, in vitro or in vivo assays may be employed to help identify optimal dosage ranges.
  • a therapeutically effective amount of compound (1) to be administered may also depend on, among other factors, the subject being treated, the weight of the subject, the severity of the disease, the manner of administration, and the judgment of the prescribing physician.
  • a therapeutically effective dose may be estimated initially from in vitro assays.
  • a dose may be formulated in animal models to achieve a beneficial circulating composition concentration range.
  • Initial doses may also be estimated from in vivo data, e.g., animal models, using techniques that are known in the art. Such information may be used to more accurately determine useful doses in humans.
  • One having ordinary skill in the art may optimize administration to humans based on animal data.
  • a dose may be administered in a single dosage form or in multiple dosage forms. When multiple dosage forms are used the amount of compound (1) contained within each dosage form may be the same or different. The amount of compound (1) contained in a dose may depend on whether the disease in a patient is effectively treated by acute, chronic, or a combination of acute and chronic administration.
  • an administered dose is less than a toxic dose.
  • Toxicity of the compositions described herein may be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., by determining the LD50 (the dose lethal to 50% of the population) or the LD100 (the dose lethal to 100% of the population). The dose ratio between toxic and therapeutic effect is the therapeutic index.
  • compound (1) may exhibit a high therapeutic index. The data obtained from these cell culture assays and animal studies may be used in formulating a dosage range that is not toxic for use in humans.
  • a dose of compound (1) provided by the present disclosure may be within a range of circulating concentrations in for example the blood, plasma, or central nervous system, that include the effective dose and that exhibits little or no toxicity. A dose may vary within this range depending upon the dosage form employed. In certain embodiments, an escalating dose may be administered.
  • compound (1) is a prodrug of MHF
  • dosage forms containing compound (1) provide MHF to a subject.
  • the promoiety of compound (1) may be cleaved either chemically and/or enzymatically.
  • One or more enzymes present in the stomach, intestinal lumen, intestinal tissue, blood, liver, brain or any other suitable tissue of a mammal can enzymatically cleave the promoiety of compound (1). If the promoiety is cleaved after absorption by the gastrointestinal tract, compound (1) can be absorbed into the systemic circulation from the large intestine. In certain embodiments, the promoiety is cleaved after absorption by the gastrointestinal tract.
  • the promoiety is cleaved in the gastrointestinal tract and MHF is absorbed into the systemic circulation form the large intestine.
  • compound (1) is absorbed into the systemic circulation from the gastrointestinal tract, and the promoiety is cleaved in the systemic circulation, after absorption of compound (1) from the gastrointestinal tract.
  • dosage forms comprising compound (1) may be administered concurrently with the administration of another therapeutic agent, which may be part of the same dosage form as, or in a different dosage form than that comprising compound (1).
  • Compound (1) may be administered prior or subsequent to administration of another therapeutic agent.
  • the combination therapy may comprise alternating between administering compound (1) and a composition comprising another therapeutic agent, e.g., to minimize adverse drug effects associated with a particular drug.
  • the other therapeutic agent may advantageously be administered at a dose that falls below the threshold at which the adverse drug reaction is elicited.
  • a dosage form comprising compound (1) may be administered in conjunction with an agent known or believed to be effective in treating multiple sclerosis, including Gilenya (fingolimod), Avonex (interferon ⁇ 1a), Rebif (interferon- ⁇ 1a), Betaseron/Extavia (interferon ⁇ 1b), Copaxone (Copolymer1), Tysabri (natralizumab), Aubagio (teriflunomide), dimethyl fumarate, laquinimod, modafinil, azathioprine, mycophenolate mofetil, mitoxantrone, corticosteroids such as predisolone, methylprednisolone; glatiramer, glatiramer acetate; monoclonal antibodies that bind to the very late antigen-4 (VLA-4) integrin such as natalizumab; immunomodulatory agents such as FTY 720 sphin
  • a dosage form comprising compound (1) may be administered in conjunction with an agent known or believed to be effective in treating psoriasis, including steroids such as flurandrenolide, fluocinonide, alclometasone, amcinonide, desonide, halcinonide, triamcinolone, clobetasol, clocortolone, mometasone, desoximetasone, and halobetasol; anti-rheumatics such as Enbrel (etanercept), Remicade (infliximab), and Humira (adalimumab); immunosuppressive agents such as cyclosporine, alefacept, and efalizumab; psoralens such as methoxsalen; and other such as calcipotriene, methotrexate, hydrocortisone/pramoxine, Soriata
  • steroids such as flurandrenolide, fluocinonide, alclometa
  • (2E)-3-(Methoxycarbonyl)prop-2-enoic acid (methyl hydrogen fumarate, MHF), (2E)-3-(tert-butoxycarbonyl)prop-2-enoic acid (tert-butyl hydrogen fumarate), or fumaric acid (FA) (1.0 equivalents) is dissolved in 5-10 mL/3.0 mmol of an inert solvent such as N-methylpyrrolidone (NMP), N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMA, DMAc), acetonitrile (MeCN), dimethylsulfoxide (DMSO), tetrahydrofuran (THF), toluene, or mixtures thereof.
  • NMP N-methylpyrrolidone
  • DMF N,N-dimethylformamide
  • DMA, DMAc N,N-dimethylacetamide
  • MeCN dimethylsulfoxide
  • THF tetrahydrofuran
  • 0.8 to 1.2 equivalents of an appropriate inorganic base such as cesium hydrogen carbonate (CsHCO 3 ), cesium carbonate (Cs 2 CO 3 ), or potassium carbonate (K 2 CO 3 ) is added.
  • 0.8 b is 1.2 equivalents of a silver salt such silver(I) oxide (Ag 2 O) or silver(I) carbonate (Ag 2 CO 3 ); an organic secondary or tertiary base such as dicyclohexylamine (DCHA), triethylamine (TEA), diisopropylethylamine (DIEA), tetrabutylammonium hydroxide (TBAOH), amidine; or a guanidine-based base such as 1,5-diazabicyclo[4.3.0]non-5-ene (DBN), 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), or 1,1,3,3-tetramethylguanidine (TMG), can be employed.
  • the corresponding alkali, silver, di-, tri- and tetraalkylammonium, amidine, or guanide salt of monoalkyl fumarate can also be preformed.
  • the solution is stirred for 10-60 min at room temperature followed by addition of 0.8-1.2 equivalents of an appropriately functionalized 1-haloacetamide, 1-halo acetic acid derivative, acyloxyalkyl halide, or alky- or aryloxycarbonyloxyalkyl halide.
  • the reaction mixture is stirred overnight at a temperature between 40 to 100° C.
  • insolubles can optionally be filtered off and the reaction mixture diluted with one molar (1.0 M) hydrochloric acid (HCl) and an appropriate organic solvent such as methyl tert-butyl ether (MTBE), diethyl ether (Et 2 O), ethylacetate (EtOAc), or mixtures thereof.
  • MTBE methyl tert-butyl ether
  • Et 2 O diethyl ether
  • EtOAc ethylacetate
  • the aqueous phase is extracted several times with the same solvent.
  • the combined organic extracts are washed with water, brine, and dried over anhydrous magnesium sulfate (MgSO 4 ).
  • MgSO 4 anhydrous magnesium sulfate
  • the organic solvents are removed under reduced pressure using a rotary evaporator.
  • the crude reaction products are further purified by well known purification techniques such as silica gel flash column chromatography (i.e., Biotage), mass-guided reversed
  • methyl hydrogen fumarate (MHF, 9 kg) and toluene (48.3 kg) were added to a 100 L glass-lined stainless steel conical reactor.
  • the reactor was agitated at 125 rpm and charged with N,N-diethylchloroacetamide (10.4 kg).
  • the reaction mixture was heated to 52° C. and diisopropylethylamine (9.8 kg) was added over 31 minutes, with a final internal temperature of 57° C.
  • the reaction was then heated to 85-90° C. for 4 hours.
  • the reaction was then cooled to 50-55° C., a sample was removed for in process analysis and then further cooled to 30° C. Water (13.5 kg) was added to the mixture and agitated for 30 minutes.
  • the reaction mixture was filtered through a pressure plate with a polypropylene cloth and a bed of diatomaceous earth (9.0 kg) into a 100 L glass lined reactor.
  • the filter bed was rinsed forward into the reactor with toluene (15.6 kg).
  • the layers were allowed to separate and the lower aqueous layer was removed into a USP water drum.
  • Water (6.8 kg) was charged to the reactor and agitated for 10 minutes. Agitation was stopped and the layers were allowed to separate for 30 minutes.
  • the lower aqueous layer was removed into a USP water drum.
  • Toluene (116.8 kg) was added to the upper organic phase, the resulting solution was then passed through a previously prepared plug of silica gel (23.4 kg).
  • the filtrate was collected through a 1 uM in-line filter into a 100 L glass-lined stainless steel reactor.
  • the silica gel plug was rinsed with toluene (116.8 kg) into a clean GMP drum.
  • Di(N,N-diethylcarbamoyl)methyl(2E)but-2-ene-1,4-dioate was taken on both the reactor contents and the drum.
  • the reaction solution from the drum and reactor was concentrated under reduced pressure to an approximate volume of 20 L, with an internal temperature of 51° C.
  • n-heptane (43.1 kg) which was cooled to 2° C.
  • the granules were prepared using a high shear wet granulation process.
  • the granulation batch size was 680 g.
  • Compound (1) was passed through the Quadro Comil U5 with an 813 micron screen at 2000 rpm. Hydroxypropyl cellulose was passed through a 600 micron mesh screen.
  • Compound (1) and hydroxypropyl cellulose were combined in a Diosna P1/6 equipped with a 4 L bowl and mixed for 2 minutes with the impeller speed of approximately 500 rpm ( ⁇ 5.8 m/s) and chopper set to 2000 rpm. After 2 minutes of dry mixing, the purified water (43.5 g) was added to the granulator using a peristaltic pump at a rate of approximately 20g/min.
  • the wet granules were screened through an 1180 micron mesh screen and dried on trays in an oven at 30° C. for 6 hours.
  • the dried granules were passed through a 0.050′′ (1270 microns) grater hole screen using a Quadro Comil U5.
  • FIG. 1 shows the particle size distribution both before ( ⁇ - ⁇ ) and after (o-o) granulation.
  • FIG. 1 clearly shows the increase in particle size due to the formation of granules.
  • the granules were prepared using a high shear wet granulation process. The granulation was performed in two batches of 494.88 g each.
  • Compound (1) was passed through a 1.0 mm mesh screen. Hydroxypropyl cellulose was passed through a 600 micron mesh screen.
  • Compound (1) and hydroxypropyl cellulose were combined in a 3 L bowl and mixed at 660 rpm (impeller) for 10 minutes using the Quintech granulator. The mixture was then transferred to a 2 L bowl and granulated with purified water (approximately 55 g) was added to the granulator using a peristaltic pump at a rate of approximately 5.5 g/min.
  • the wet granules were screened through a 2000 micron mesh screen and dried on trays in an oven at 30° C. for 4 hours and 20 minutes. The dried granules were passed through an 850 micron mesh screen.
  • the particle size distributions of the blend before granulation and the granules after granulation were determined using a Sympatec QicPic particle size analyzer with a lens capable of detecting particles from 5-1705 microns and a RODOS dry powder dispersion system at 1.0 bar of pressure.
  • FIG. 2 shows the particle size distribution both before ( ⁇ - ⁇ ) and after ( ⁇ - ⁇ ) granulation.
  • FIG. 2 clearly shows the increase in particle size due to the formation of granules.
  • the granules were prepared using a high shear wet granulation process.
  • the granulation batch size was 170.0 g.
  • Compound (1) was passed through the Quadro Comil U5 with an 813 micron screen at 2000 rpm. Hydroxypropyl cellulose was passed through a 500 micron mesh screen.
  • Compound (1) and hydroxypropyl cellulose were combined in a Diosna P1/6 equipped with a 1 L bowl and mixed for 2 minutes with the impeller speed of approximately 770 rpm ( ⁇ 6.0 m/s) and chopper set to 2000 rpm.
  • the purified water (17.2 g) was added to the granulator using a peristaltic pump at a rate of approximately 4.9 g/min.
  • the wet granules were screened through an 1180 micron mesh screen and dried on trays in an oven at 30° C. for 3 hours and 35 minutes. The dried granules were passed through a 600 micron mesh screen.
  • the particle size distributions of the blend before granulation and the granules after granulation were determined using a Sympatec QicPic particle size analyzer with a lens capable of detecting particles from 5-1705 microns and a RODOS dry powder dispersion system at 1.0 bar of pressure.
  • FIG. 3 shows the particle size distribution both before ( ⁇ - ⁇ ) and after ( ⁇ - ⁇ ) granulation.
  • FIG. 3 clearly shows the increase in particle size due to the formation of granules.
  • the dried granules (97% (N,N-Diethylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioate and 3% hydroxypropyl cellulose), hypromellose 2208 (100000 mPa ⁇ s viscosity), and the silicon dioxide were then passed through a 600 micron mesh screen, combined in a glass jar and blended on a Turbula mixer for 5 minutes (except for blend 6a which was not blended until addition of magnesium stearate). Magnesium stearate was passed through a 250 micron screen and added to the blend and blended for 1.5 minutes.
  • Tablets were compressed using a Carver Press with 1 ⁇ 4 inch (6.4 mm) round standard concave tooling at 0.4 metric ton (MT) force.
  • the tablets had a final hardness of approximately 7.4 to 8.4 kp (72 to 82 Newtons).
  • Example Component 6a 6b 6c 6d Compound (1) (wt %) 95.9 90.5 87.6 85.7 Hydroxypropyl Cellulose (wt %) 3.0 2.8 2.7 2.6 Hypromellose 2208 (100000 mPa ⁇ s) 0.0 5.0 8.0 10.0 (wt %) Silicon Dioxide (wt %) 0.1 0.2 0.2 0.2 Magnesium Stearate (wt %) 1.0 1.5 1.5 1.5 Total Tablet (wt %) 100.0 100.0 100.0 100.0 100.0 Tablet Weight (mg) 104.2 110.5 114.2 116.8 Total Blend Batch Size (g) 10.0 5.0 5.0 5.0 Tablet Hardness (kP) 7.4 7.6 8.4 8.3
  • a two-stage dissolution method was used to determine the in vitro dissolution profile of dosage forms prepared according to Example 6.
  • the two-stage dissolution test was used to better approximate the pH conditions experienced by a dosage form after swallowing by a patient, i.e., low pH of the stomach followed by near neutral pH of the intestines.
  • the dosage forms were first placed into a dissolution vessel (USP, Type I, basket) containing 750 mL of 0.1 N hydrochloric acid (pH 1.2). After 2 hours, 250 mL of 200 mM tribasic sodium phosphate was added to the vessel resulting in a pH adjustment from 1.2 to 6.8.
  • the dissolution medium was kept at 37° C. and was agitated at 100 rpm.
  • FIG. 4 shows that the rate at which (N,N-Diethylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioate is released from the tablets slows with increasing percentage of hydroxypropylmethyl cellulose (hypromellose 2208 (100000 mPa ⁇ s viscosity)) in the tablets.
  • Tablet 6a (0% HPMC K100M, ⁇ - ⁇ symbols in FIG. 4 ) is an immediate release tablet.
  • Tablets 6b 5% HPMC K100M, ⁇ - ⁇ symbols in FIG. 4
  • 6c 8% HPMC K100M, ⁇ - ⁇ symbols in FIG. 4
  • 6d (10% HPMC K100M, ⁇ - ⁇ symbols in FIG. 4 ) are sustained release tablets with the amount of released drug reaching 90% at approximately 5, 7, and 9 hours, respectively.
  • the flow of dry powders was characterized using a FLODEXTM Powder Flowability Index Test Instrument (Hanson Research Corporation, Chatsworth, Calif.).
  • the instrument was equipped with a cylindrical metal reservoir, which holds the test powder prior to flow testing.
  • the cylindrical reservoir has an inside diameter of 5.7 cm and a length of 7.4 mm.
  • the bottom end of the reservoir can be closed with removable metal discs.
  • Each disc has a round orifice centered in the disc. Orifice diameters range from 4 mm to 10 mm in 1 mm increments, and from 10 mm to 34 mm in 2 mm increments. Prior to flow testing, the orifice is blocked. Powder is then placed over the blocked orifice.
  • Powder that flows through small orifices is considered to have flow properties useful for tableting.
  • a Flodex measurement (Flodex) of less than about 24 mm is typically used for high-speed tableting operations at commercial scale.
  • a Flodex less than about 20 mm is useful for high-speed tableting operations.
  • a Flodex of 18 mm or less is considered especially useful for high speed tableting operations.
  • the Flodex is determined by first gently filling the reservoir with approximately 70 cc of test powder while the orifice at the bottom is blocked, while avoiding severe piling, and without vibrating or tapping the powder bed. Next, the orifice is unblocked. This can be accomplished by opening a shutter that is supplied with the instrument. Alternatively, if a shutter is not used, the powder-filled reservoir fitted with a disc can be set on a dry, flat surface to block the orifice. Then, slowly and evenly, the reservoir is lifted to allow the powders to flow. In either procedure, if the powder flows through the orifice, a clear channel is left within the powder bed.
  • an arch-shaped cavity within the powder bed is formed above the orifice and is referred to as an arch.
  • the flow test is conducted with various orifice sizes until the minimum orifice size for good flow is identified, which is referred to as the Flodex.
  • the Flodex is the minimum orifice diameter at which the powder flows through the orifice more times than it does not in at least three measurement trials.
  • Granulation blends of (N,N-Diethylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioate containing varying amounts of colloidal silicon dioxide were prepared in order to assess the impact of silicon dioxide on flow.
  • the granules of Example 5 containing no silicon dioxide (blend 9a) were used as a control.
  • Blend 9b through 9f (at 30 g scale), (N,N-Diethylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioate granules (from Example 3), hypromellose 2208, lactose, and the silicon dioxide were combined in a glass jar and blended on the Turbula mixer for 2 min, passed through a 600 micron mesh screen, and then blended for another 2 min.
  • Blend 9g was prepared at 1099.2 g scale.
  • the hypromellose 2208 (100000 mPa ⁇ s viscosity) and the silicon dioxide were combined, passed through a 600 micron mesh screen, and added to the dry (N,N-Diethylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioate granules in a 5 L cube blender and blended for 10 minutes.
  • Magnesium stearate was passed through a 600 micron screen and added to the blend before blending an additional 4 minutes.
  • Blend flow was assessed by the Flodex method described in Example 8.
  • the measured Flodex for each blend is listed in Table 6.
  • Blend 9a (the granules from Example 5) without any silicon dioxide had a Flodex value of 34 mm.
  • the Flodex improves to 24 mm when granules are blended with other excipients (i.e., lactose and hypromellose 2208 in Blend 9b); however, these Flodex values are considered to be high for high speed tableting operations.
  • the Flodex values for blends 9c through 9g show significantly improved Flowdex measurements corresponding to increased levels of colloidal silicon dioxide from 0.1 to 0.5 wt % (blends 9c through 9f are also shown in FIG. 5 ). This is especially important for high drug loading dosage forms that do not use filler excipients as in blend 9g.
  • the tablets were made according to the following steps.
  • the core tablets were prepared from the high drug load granules (97% N,N-Diethylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioate and 3% hydroxypropyl cellulose) described in Example 3.
  • the core blend batch size was 5 g.
  • the dried granules, hydroxypropylmethylcellulose (i.e., hypromellose 2208 having 100000 mPa ⁇ s viscosity), and the silicon dioxide were then passed through a 600 micron mesh screen, combined in a glass jar and blended on a Turbula mixer for 5 minutes.
  • Magnesium stearate was passed through a 250 micron screen and added to the blend before blending an additional 1.5 minutes.
  • Core tablets 114.2 mg total weight; 87.6% wt/wt N,N-Diethylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioate
  • the core tablets had a final hardness of approximately 7.6 kp ( ⁇ 74 Newtons).
  • the mantle blend was prepared using a direct compression process and a batch size of 10 g.
  • the hypromellose 2208 (100 MPa ⁇ s viscosity) and lactose hydrate were passed through a 600 micron mesh screen, combined in a glass jar and blended on a Turbula mixer for 5 minutes.
  • Magnesium stearate was passed through a 250 micron screen and added to the blend and blended an additional 1.5 minutes.
  • the mantle blend was then applied to the core tablets using the Carver Press with 3 ⁇ 8 inch (9.53 mm) round standard concave tooling.
  • Half the mantle blend (114.2 mg) was weighed out, added to the die, and tamped slightly to flatten.
  • the core tablet was placed into the die and pressed down gently into the mantle blend.
  • the second half of the mantle blend (114.2 mg) was then added on top of the core tablet and the mantle was compressed using 1.5 MT force.
  • the final compression coated tablets had a total weight of 342.6 mg with a (N,N-Diethylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioate loading of 100 mg (29.19%).
  • the tablets had a final hardness around 14.7 kp ( ⁇ 144 Newtons).
  • the tablets were made according to the following steps.
  • the core tablets were prepared from the high drug load granules (97% N,N-Diethylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioate and 3% hydroxypropyl cellulose) described in Example 3.
  • the core blend batch size was 5 g.
  • the dried granules and the silicon dioxide were then passed through a 600 micron mesh screen, combined in a glass jar and blended on a Turbula mixer for 5 minutes.
  • Magnesium stearate was passed through a 250 micron screen and added to the blend before blending an additional 1.5 minutes.
  • Core tablets (104.9 mg total weight; 95.3% N,N-Diethylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioate) were compressed using a Carver Press with 1 ⁇ 4 inch (6.35 mm) round standard concave tooling at 0.4 metric ton (MT) force.
  • the core tablets had a final hardness of approximately 6.1 kp ( ⁇ 60 Newtons).
  • the mantle blend was prepared using a direct compression process and a batch size of 100 g.
  • the hydroxypropylmethylcellulose (i.e., hypromellose 2208 having 100000 MPa ⁇ s viscosity) and lactose hydrate were passed through a 600 micron mesh screen, combined in a 1 quart (0.95 I) V-blender and blended for 10 minutes.
  • Magnesium stearate was passed through a 250 micron screen and added to the blend and blended an additional 4 minutes.
  • the mantle blend was then applied to the core tablets using the Carver Press with 3 ⁇ 8 inch (9.53 mm) round standard concave tooling.
  • Half the mantle blend (104.9 mg) was weighed out, added to the die, and tamped slightly to flatten.
  • the core tablet was placed into the die and pressed down gently into the mantle blend.
  • the second half of the mantle blend (104.9 mg) was then added on top of the core tablet and the mantle was compressed using 1.5 MT force.
  • the final compression coated tablets had a total weight of 314.7 mg with a (N,N-Diethylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioate loading of 100 mg (31.78%).
  • the tablets had a final hardness around 13.1 kp ( ⁇ 128 Newtons).
  • the tablets were made according to the following steps.
  • the core tablets were prepared from the high drug load granules (97% N,N-Diethylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioate and 3% hydroxypropyl cellulose) described in Example 4.
  • the core blend batch size was 1099.2 g.
  • the hydroxypropylmethylcellulose (i.e., Hypromellose 2208 having 100000 mPa ⁇ s viscosity) and the silicon dioxide were combined, passed through a 600 micron mesh screen, and added to the dry granules in a 5 L cube blender and blended for 10 minutes at 25 rpm.
  • Magnesium stearate was passed through a 600 micron screen and added to the blend before blending an additional 4 minutes at 25 rpm.
  • Core tablets (114.5 mg total weight; 87.3% wt/wt N,N-Diethylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioate) were compressed using a Manesty F3 tablet press with 6.0 mm round concave tooling.
  • the core tablets had a final mean hardness between 8.1 to 10.2 kp (79-100 Newtons).
  • the mantle blend was prepared using a direct compression process and a batch size of 5.0 kg.
  • the hypromellose 2208 (100 MPa ⁇ s viscosity) and lactose hydrate were combined and passed through a 600 micron mesh screen, placed in and blended on the Tumblemix 18 L Bin Blender for 8.5 minutes at 30 rpm.
  • Magnesium stearate was passed through a 600 micron screen and added to the blend and blended an additional 3.5 minutes.
  • the mantle blend was then applied to the core tablets using a Kikusui tablet press (Kikusui Seisakusho Ltd., Kyoto, Japan) specially designed for the manufacture of compression coated tablets. Compression was completed using 9.5 mm round concave tooling and approximately 1000 kp force.
  • the final compression coated tablets had a total weight of 362.4 mg with a (N,N-Diethylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioate loading of 100 mg (27.59%).
  • the compression coated tablets had a final mean hardness between 10.9 to 14.0 kp (107-137 Newtons).
  • a two-stage dissolution method was used to determine the in vitro dissolution profile of dosage forms prepared according to Examples 10, 11 and 12 in order to mimic the conditions of a dosage form as it transits the gastrointestinal tract.
  • the dosage forms were first placed into a dissolution medium having a pH of 1.2, to mimic the conditions of the stomach, and then placed into a dissolution medium of pH 6.8, to mimic the conditions of the intestines.
  • the dissolution vessel (USP, Type I, basket) initially contained 750 mL of 0.1 N hydrochloric acid (pH 1.2). After 2 hours of dissolution, 250 mL of 200 mM tribasic sodium phosphate was added to the vessel resulting in a pH adjustment from 1.2 to 6.8.
  • the dissolution medium was kept at 37° C. and was agitated at 100 rpm.
  • Example 10 dosage forms samples of the dissolution medium were withdrawn at 1 and 2 hours following the start of the low pH stage, and at 0.5, 2, 4, 7, 10 and 14 hours following the start of the neutral pH/buffered stage.
  • Example 11 dosage forms samples were withdrawn at 1 and 2 hours following the start of the low pH stage, and at 0.5, 2, 4, 7, 10, 16 and 22 hours following the start of the neutral pH/buffered stage.
  • Example 12 dosage forms samples were withdrawn at 1 and 2 hours following the start of the low pH stage, and at 0.5, 2, 4, 7, 10, 14 and 20 hours following the start of the neutral pH/buffered stage.
  • the amount of (N,N-Diethylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioate in the dissolution medium samples was determined by reverse phase HPLC using a C18 column and a 7 minute gradient method according to Table 10 where Mobile Phase A is water/0.1% H 3 PO 4 and Mobile Phase B is water/acetonitrile/H 3 PO 4 (10/90/0.1 by volume) with UV detection at 210 nm.
  • drug release is delayed for approximately 2 hours, and thereafter the drug is released gradually, reaching more than 90% released at 16 hours.
  • drug release is delayed for approximately 2 hours, followed by near zero order release, reaching more than 90% released at 24 hours.
  • drug release is delayed for approximately 2 hours, and thereafter the drug is released gradually, reaching more than 90% released at 16 hours.
  • the concentration ⁇ 1 SD of monomethyl fumarate (MMF) in the blood of Cynomologous monkeys following oral dosing of delayed release enteric coated tablets prepared according to Examples 10 and 11 is shown in FIGS. 9 and 10 .
  • the MMF concentrations following dosing with the Example 10 tablets are shown with ⁇ - ⁇ symbols and the MMF concentrations following dosing with the Example 11 tablets are shown with ⁇ - ⁇ symbols.
  • the data in FIG. 9 is from animals dosed in a fasted state and the data in FIG. 10 is from animals dosed in a fed state.
  • Tablets prepared according to Examples 10 and 11 were administered by oral dosing to groups of four adult male Cynomologous ( Macaca fascicularis ) monkeys (each monkey weighed about 4 to 5 kg). Each monkey was administered two tablets in either a fasted state or a fed state. All animals were fasted overnight before the study. For the fed leg, animals were administered blended food via oral gavage in the morning 30 minutes prior to administration of each test formulation. For the fasted leg, the animals remained fasted for 4 hours post-dosing.
  • Blood samples (1.0 mL) were obtained from all animals via the femoral vein at pre-dose and intervals over 24 hours after oral dosing. Blood was collected in pre-chilled K 2 EDTA, quenched with acetonitrile and stored at ⁇ 50° C. to ⁇ 90° C. until analyzed. There was a minimum 7 day wash out period between dosing sessions.
  • Standard Preparation One hundred ⁇ L of blood was added to 290 ⁇ L of acetonitrile in Eppendorf tubes. 10 ⁇ L of MMF standard solution (0.2, 0.5, 1, 2.5, 5, 10, 25, 50 and 100 ⁇ g/mL) was added to each tube to make up the final calibration standards (0.02, 0.05, 0.1, 0.25, 0.5, 1, 2.5, 5 and 10 ⁇ g/mL).
  • the concentration of MMF in monkey blood was determined using an API 4000 LC/MS/MS instrument equipped with Agilent Binary pump and autosampler.
  • the column was a Luna C8 (2) 4.6 ⁇ 150 mm, 5 ⁇ column operating at 2 to 8° C. temperature.
  • the mobile phases were (A) 0.1% formic acid in water, and (B) 0.1% formic acid in acetonitrile.
  • the gradient condition was: 2% B for 1 min, increasing to 95% B in 3.5 min and maintained for 2 min, then decreasing to 2% B in 5.6 min and maintained for 2.3 min. 30 ⁇ L of sample was injected into the column.
  • a Turbo-Ion Spray source was used, and was detected in negative ion mode for the MRM transition of 128.95/84.8. Peaks were integrated using Analyst 1.5 quantitation software.
  • Delayed release tablets containing compound (1) were made having the ingredients shown in Table 11:
  • the tablets were made according to the following steps.
  • the core tablets were prepared using a high drug load wet granulation process.
  • the granulation was performed in two batches at 463.9 g per batch.
  • Compound (1) and hydroxypropyl cellulose were first passed through a conical mill with a 610 micron round holed screen.
  • the granulation was then performed by combining 97% of compound (1) and 3% of hydroxypropyl cellulose in a Key KG-5 granulator bowl followed by mixing with water addition for approximately 9 minutes.
  • the wet granules were dried in a Glatt GPCG-1 fluid bed dryer at 40° C.
  • the two portions of dried granules were combined and blended with the silicon dioxide in an 8 quart (7.6 liter) V-blender for 5 minutes and then sized by passing through a conical mill with an approximately 1300 micron grater type screen.
  • the milled granules were blended with the croscarmellose sodium and lactose monohydrate for 10 minutes in an 8 quart (7.6 I) V-blender.
  • the magnesium stearate was passed through a 600 micron mesh screen and blended with the additional core materials in the V-blender for 5 minutes.
  • Core tablets (254.87 mg) were compressed using a GlobePharma Minipress II rotary tablet press with 11/32 inch (8.7 mm) round concave tooling.
  • the core tablets had a final mean hardness of approximately 15.5 kp.
  • An aqueous suspension was prepared by mixing with an impeller 68.85 g Opadry 03O19184 with 792.0 g of purified water. The water contained in the suspension is removed during the film coating process and therefore not included in the final formulation in Table 1.
  • the tablets were coated with the aqueous suspension in an O'Hara Technologies Labcoat M coater with a 12′′ (30.5 cm) diameter perforated pan until the desired weight gain of barrier coat was achieved. The coating process occurred at an inlet temperature of approximately 52° C. and an outlet temperature of 37° C. After coating, the tablets were dried for 2 hours at 40° C.
  • An aqueous suspension was prepared by mixing with an impeller 578.7 g methacrylic acid copolymer dispersion, 9.0 g triethyl citrate, 86.5 g PlasACRYLTM T20 with 325.8 g water.
  • the water contained in (i) the methacrylic acid copolymer dispersion and (ii) the PIasACRYLTM T20 is removed during the film coating process and therefore not included in the final formulation in Table 1.
  • the tablets were coated with the aqueous suspension in an O'Hara Technologies Labcoat M coater with a 12′′ (30.5 cm) diameter perforated pan until the desired weight gain of enteric film was achieved. The coating process occurred at an inlet temperature of approximately 40° C. and an outlet temperature of 30° C. After coating, the tablets were dried for 2 hours at 40° C.
  • Delayed sustained release tablets containing compound (1) were made having the ingredients shown in Table 12:
  • the tablets were made according to the following steps.
  • the core tablets were prepared using a high drug load wet granulation process.
  • the granulation was performed in two batches at 456 g per bath.
  • Compound (1) and hydroxypropyl cellulose were first passed through a conical mill with a 610 micron round holed screen.
  • the granulation was then performed by combining 97% of compound (1) and 3% of hydroxypropyl cellulose in a Key KG-5 granulator bowl followed by mixing with water addition for approximately 7 minutes.
  • the wet granules were dried in a Glatt GPCG-1 fluid bed dryer at 40° C.
  • the two portions of dried granules were sized by passing through a conical mill with an approximately 1300 micron grater type screen.
  • the milled granules were blended with the hypromellose 2208, silicon dioxide, and lactose monohydrate for 10 minutes in an 8 quart (7.6 I) V-blender. This blend was passed through an 850 micron mesh screen. The magnesium stearate was passed through a 600 micron mesh screen and blended with the additional core materials in the V-blender for 5 minutes. Core tablets (299.69 mg) were compressed using a GlobePharma Minipress II rotary tablet press with 8.6 mm round concave tooling. The core tablets had a final mean hardness of approximately 12 kp. An aqueous suspension was prepared by mixing with an impeller 63.8 g Opadry 03O19184 with 770.7 g of purified water.
  • the water contained in the suspension is removed during the film coating process and therefore not included in the final formulation in Table 2.
  • the tablets were coated with the aqueous suspension in an O'Hara Technologies Labcoat M coater with a 12′′ (30.5 cm) diameter perforated pan until the desired weight gain of barrier coat was achieved. The coating process occurred at an inlet temperature of approximately 52° C. and an outlet temperature of 36° C. After coating, the tablets were dried for 2 hours at 40° C.
  • An aqueous suspension was prepared by mixing with an impeller 405.1 g methacrylic acid copolymer dispersion, 6.3 g triethyl citrate, 60.6 g PIasACRYLTM T20 with 228.1 g water.
  • the water contained in the methacrylic acid copolymer dispersion and the PlasACRYLTM T20 is removed during the film coating process and therefore not included in the final formulation in Table 1.
  • the tablets were coated with the aqueous suspension in the O'Hara Technologies Labcoat M coater until the desired weight gain of enteric film was achieved. The coating process occurred at an inlet temperature of approximately 40° C. and an outlet temperature of 30° C. After coating, the tablets were dried for 2 hours at 40° C.
  • a two-stage dissolution method was used to determine the in vitro dissolution profile of dosage forms prepared according to Examples 15 and 16.
  • the 2-stage dissolution test was used to better approximate the pH conditions experienced by a dosage form after swallowing by a patient, i.e., low pH of the stomach followed by near neutral pH of the intestines.
  • the dosage forms were first placed into a dissolution vessel (USP, Type I, basket) containing 750 mL of 0.1 N hydrochloric acid (pH 1.2). After 2 hours, 250 mL of 200 mM tribasic sodium phosphate was added to the vessel resulting in a pH adjustment from 1.2 to 6.8.
  • the dissolution medium was kept at 37° C. and was agitated at 100 rpm.
  • Example 15 dosage forms samples of the dissolution medium were withdrawn after 1 and 2 hours in the low pH stage, and at 0.25, 0.5, 0.75, and 1 hours following buffer addition.
  • Example 16 dosage forms samples of the dissolution medium were withdrawn after 1 and 2 hours in the low pH stage, and at 0.5, 2, 4, 7, 10, and 14 hours following buffer addition.
  • the released amount of compound (1) in the samples was determined by reverse phase HPLC using a C18 column and a 7 minute gradient method according to Table 3 where Mobile Phase A is water/0.1% H 3 PO 4 and Mobile Phase B is water/acetonitrile/H 3 PO 4 (10/90/0.1 by volume) with UV detection at 210 nm.
  • drug release is delayed for approximately 2 hours, followed with near immediate release with >90% released between 2 and 3 hours.
  • drug release is delayed for approximately 2 hours, followed by sustained release reaching >90% at 12 hours.

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US9302977B2 (en) 2013-06-07 2016-04-05 Xenoport, Inc. Method of making monomethyl fumarate
US9326965B2 (en) 2014-02-28 2016-05-03 Banner Life Sciences Llc Controlled release fumarate esters
US9326947B1 (en) 2014-02-28 2016-05-03 Banner Life Sciences Llc Controlled release fumarate esters
US9416096B2 (en) 2013-09-06 2016-08-16 Xenoport, Inc. Crystalline forms of (N,N-Diethylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioate, methods of synthesis and use
US9421182B2 (en) 2013-06-21 2016-08-23 Xenoport, Inc. Cocrystals of dimethyl fumarate
US9452972B2 (en) 2008-08-19 2016-09-27 Xenoport, Inc. Methods of using prodrugs of methyl hydrogen fumarate and pharmaceutical compositions thereof
US9505776B2 (en) 2013-03-14 2016-11-29 Alkermes Pharma Ireland Limited Prodrugs of fumarates and their use in treating various diseases
US9566259B1 (en) 2015-08-31 2017-02-14 Banner Life Sciences Llc Fumarate ester dosage forms
US9597292B2 (en) 2012-08-22 2017-03-21 Xenoport, Inc. Oral dosage forms of methyl hydrogen fumarate and prodrugs thereof
US9604922B2 (en) 2014-02-24 2017-03-28 Alkermes Pharma Ireland Limited Sulfonamide and sulfinamide prodrugs of fumarates and their use in treating various diseases
US9999672B2 (en) 2014-03-24 2018-06-19 Xenoport, Inc. Pharmaceutical compositions of fumaric acid esters
US10098863B2 (en) 2014-02-28 2018-10-16 Banner Life Sciences Llc Fumarate esters
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CA2882727A1 (en) 2014-02-27
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US9597292B2 (en) 2017-03-21
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US20200246271A1 (en) 2020-08-06
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US20140056978A1 (en) 2014-02-27
US20210145755A1 (en) 2021-05-20

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