WO2017083348A1 - Formes pharmaceutiques orales à libération contrôlée de médicaments faiblement solubles et leurs utilisations - Google Patents

Formes pharmaceutiques orales à libération contrôlée de médicaments faiblement solubles et leurs utilisations Download PDF

Info

Publication number
WO2017083348A1
WO2017083348A1 PCT/US2016/061076 US2016061076W WO2017083348A1 WO 2017083348 A1 WO2017083348 A1 WO 2017083348A1 US 2016061076 W US2016061076 W US 2016061076W WO 2017083348 A1 WO2017083348 A1 WO 2017083348A1
Authority
WO
WIPO (PCT)
Prior art keywords
controlled release
compound
oral dosage
dosage form
release oral
Prior art date
Application number
PCT/US2016/061076
Other languages
English (en)
Inventor
Ming Chen
Ho-Wah Hui
Xiaole Shen
Original Assignee
Celgene Corporation
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from US14/938,714 external-priority patent/US9532977B2/en
Application filed by Celgene Corporation filed Critical Celgene Corporation
Priority to EP16798345.1A priority Critical patent/EP3373916A1/fr
Publication of WO2017083348A1 publication Critical patent/WO2017083348A1/fr

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A61K9/0065—Forms with gastric retention, e.g. floating on gastric juice, adhering to gastric mucosa, expanding to prevent passage through the pylorus
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/4035—Isoindoles, e.g. phthalimide
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/02—Inorganic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0002—Galenical forms characterised by the drug release technique; Application systems commanded by energy
    • A61K9/0007—Effervescent
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2009—Inorganic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/2027—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/2031—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyethylene oxide, poloxamers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
    • A61K9/2086—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
    • A61K9/2086—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat
    • A61K9/209—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat containing drug in at least two layers or in the core and in at least one outer layer

Definitions

  • One goal in developing a drug is to provide dosage forms which make it possible to maintain a certain amount or concentration of drug in a subject's body that will remain constant for several hours. Often this may not be achieved by traditional rapidly disintegrating tablets, as these tablets release the active ingredient contained therein all at once. For this reason, dosage forms have been developed which are capable of continuously releasing the drug contained therein in a controlled manner and over a prolonged period of time. Oral controlled drug delivery is typically by solid dosage forms including tablets, capsules, microspheres, granules and suspensions.
  • Gastroretentive systems drug delivery systems having a prolonged retention time in the stomach, represent a promising approach to controlled release oral delivery of drugs.
  • Many such systems have been developed.
  • U.S. Patent Nos. 6,635,280 and 6,723,340 describe compositions for gastric retentive tablets which, upon oral administration, swell to a size such that the tablet cannot move out of the stomach easily.
  • the drug is incorporated into a polymer matrix as the tablet swells and is released from the matrix into the gastric fluid by solution diffusion.
  • U.S. Patent No. 6,635,280 See U.S. Patent No. 6,635,280.
  • the tablet acts as a controlled released gastroretentive system.
  • Other similar gastroretentive systems are described in the art. See, e.g., European Patent No.
  • EP 941071 B l A variety of polymeric excipients designed to expand or swell in the stomach have been used for the preparation of gastroretentive systems. See e.g., U.S. Patent Nos. 6,210,710; 6,217,903; 5,945, 125; 5,451,409; 4,915,952; U.S. Patent Publication Nos. 2003/0104053; 2003/0104062; and 2010/0129445. Such systems have been employed for the controlled release of poorly soluble drugs in particular. See, e.g., U.S. Patent No. 6,635,280 and International Publication No. WO 97/22335. However, there exists a need for alternative controlled release dosage forms for drugs having poor aqueous solubility. Provided herein are controlled release dosage forms addressing this need. 3. SUMMARY OF THE INVENTION
  • the controlled release oral dosage forms provided herein comprise polymeric excipients which expand and/or become charged in the gastric fluid in acidic pH and control the release of the poorly soluble drug in the system.
  • the controlled release oral dosage forms provided herein are believed to enhance the bioavailability of a poorly soluble drug by increasing the time of release of the drug in the gastrointestinal tract.
  • the extended time of release of the poorly soluble drug occurs mainly in the stomach.
  • the controlled release oral dosage forms provided herein comprise positively charged polymers, negatively charged polymers and swelling excipients, which when combined with a poorly soluble drug in particular weight ratios of ingredients provide controlled release of the poorly soluble drug.
  • controlled release of the poorly soluble drug is achieved by action of the swelling excipients and the interaction of the polymers containing negative charges and positive charges in acidic pH of the stomach or upper gastrointestinal tract.
  • the controlled release oral dosage form comprises one or more of each of the following: (i) a poorly soluble drug; (ii) a swelling excipient; (iii) a cationic polymer in acidic pH; and (iv) an anionic polymer in acidic pH.
  • the controlled release oral dosage form further comprises a water absorbing agent.
  • the controlled release oral dosage form further comprises one or more additional pharmaceutically acceptable excipients.
  • the controlled release oral dosage form comprises one or more of each of the following: (i) a poorly soluble drug; (ii) a swelling excipient; (iii) a cationic polymer in acidic pH; (iv) an anionic polymer in acidic pH; and (v) a floating agent.
  • the controlled release oral dosage form further comprises a water absorbing agent.
  • the controlled release oral dosage form further comprises one or more additional pharmaceutically acceptable excipients.
  • the poorly soluble drug is (,S)-N- ⁇ 2-[l-(3-ethoxy-
  • the poorly soluble drug is cyclopropanecarboxylic acid ⁇ 2-[(7,S)-l-(3-ethoxy-4-methoxy-phenyl)-2-methanesulfonyl-ethyl]-3-oxo-2,3- dihydro-lH-isoindol-4-yl ⁇ -amide (Compound B).
  • kits for treating, preventing or managing disorders ameliorated by the reduction of levels of TNF-a in a patient which comprises administering to a patient in need of such treatment, prevention or management a therapeutically or prophylactically effective amount of a compound provided herein, or a pharmaceutically acceptable prodrug, metabolite, polymorph, solvate, hydrate, or clathrate thereof.
  • FIG. 1 shows the drug release profile of Compound A in Formulations 1 to 3 over 24 hours.
  • FIG. 2 shows the drug release profile of Compound A in Formulations 4 to 7 over 24 hours.
  • FIG. 3 shows the drug release profile of Compound A in Formulations 8 to 11 over 24 hours.
  • FIG. 4 shows the drug release profile of Compound A in Formulations 12 to 15 over 24 hours.
  • FIG. 5 shows the drug release profile of Compound A in Formulations 16 to 25 over 24 hours.
  • FIG. 6 shows the drug release profile of Compound A in Formulations 28 to 33 over 24 hours.
  • FIG. 7 shows the drug release profile of Compound A in Formulations 34 to 39 over 24 hours.
  • FIG. 8 shows the drug release profile of Compound A in Formulations 40 to 45 over 24 hours.
  • FIG. 9 shows the drug release profile of Compound A in Formulations 46 to 51 over 24 hours.
  • FIG. 10 shows the drug release profile of Compound A in Formulations 52 to 57 over 24 hours.
  • FIG. 11 shows the drug release profile of Compound A in Formulations
  • FIG. 12 shows the drug release profile of Compound A in Formulations
  • FIG. 13 shows the drug release profile of Compound A in Formulations
  • FIG. 14 shows the drug release profile of Compound A in Formulations
  • FIG. 15 shows the drug release profile of Compound A in Formulations
  • FIG. 16 shows the drug release profile of Compound A in Formulations
  • FIG. 17 shows the drug release profile of Compound A in Formulations
  • FIG. 18 shows the drug release profile of Compound A in bilayer tablets over 24 hours.
  • FIG. 19 shows the drug release profile of Compound A in Formulations 94 to 96 over 24 hours.
  • FIG. 20 A shows gastroretentive Formulation 98.
  • FIGS. 20B, C, and D show the floating, fast swelling, and bioadhesive properties of Formulation 98.
  • FIG. 21 shows the pharmacokinetic profile of Formulation 98 as compared to instant release (IR) formulation following a single oral dose under fasting and high fat meal conditions.
  • FIG. 22 shows the pharmacokinetic profile of Formulation 98 as compared to IR formulation following multiple oral doses under fasting and high fat meal conditions.
  • FIG. 23 shows the pharmacokinetic profile of Formulation 98 as compared to IR formulation following a single oral dose under fasting and standard meal conditions.
  • FIG. 24 shows the pharmacokinetic profile of Formulation 98 as compared to IR formulation following multiple oral doses under fasting and standard meal conditions.
  • FIG. 25 shows the drug release profile of Compound A in Formulation 98 over 24 hours.
  • FIG. 26 shows the observed pharmacokinetic profile of Formulations 98 and 101 following a single dose, and a modeled pharmacokinetic profile following multiple doses, both at standard meal conditions.
  • FIG. 27 shows the pharmacokinetic profile of Formulation 101 as compared to IR formulation following a single oral dose under fasting and standard meal conditions.
  • FIG. 28 shows the pharmacokinetic profile of Formulation 101 as compared to IR formulation following multiple oral doses under fasting and standard meal conditions.
  • FIG. 29 shows mean plasma Apremilast profiles for single dose of Formulation 98 and Formulation 101 under standard meal conditions.
  • FIG. 30 shows single dose cross over study data of Formulation 98 and
  • Formulation 101 under fed conditions to determine bioequivalence criteria.
  • the term "patient” refers to a mammal, particularly a human.
  • pharmaceutically acceptable salts refer to salts prepared from pharmaceutically acceptable non-toxic acids or bases including inorganic acids and bases and organic acids and bases.
  • prodrug means a derivative of a compound that can hydrolyze, oxidize, or otherwise react under biological conditions ⁇ in vitro or in vivo) to provide the compound.
  • prodrugs include, but are not limited to, derivatives and metabolites of a compound provided herein that include biohydrolyzable moieties such as biohydrolyzable amides, biohydrolyzable esters, biohydrolyzable carbamates, biohydrolyzable carbonates, biohydrolyzable ureides, and biohydrolyzable phosphate analogues.
  • Prodrugs can typically be prepared using well-known methods, such as those described by 1 Burger 's Medicinal Chemistry and Drug Discovery, 172-178, 949-982 (Manfred E. Wolff ed., 5th ed. 1995).
  • biohydrolyzable amide “biohydrolyzable ester,” “biohydrolyzable carbamate,”
  • biohydrolyzable carbonate means an amide, ester, carbamate, carbonate, ureide, or phosphate, respectively, of a compound that either: 1) does not interfere with the biological activity of the compound but can confer upon that compound advantageous properties in vivo, such as uptake, duration of action, or onset of action; or 2) is biologically inactive but is converted in vivo to the biologically active compound.
  • biohydrolyzable esters include, but are not limited to, lower alkyl esters, alkoxyacyloxy esters, alkyl acylamino alkyl esters, and choline esters.
  • biohydrolyzable amides include, but are not limited to, lower alkyl amides, a-amino acid amides, alkoxyacyl amides, and
  • alkylaminoalkylcarbonyl amides examples include, but are not limited to, lower alkylamines, substituted ethylenediamines, aminoacids, hydroxyalkylamines, heterocyclic and heteroaromatic amines, and polyether amines.
  • bioadhesive is a property of a substance (i.e. a tablet) to adhere to biological surfaces such as, but not limited to, tissue and mucous.
  • stereomerically pure means a composition that comprises one stereoisomer of a compound and is substantially free of other stereoisomers of that compound.
  • a stereoisomer of a compound for example
  • stereomerically pure composition of a compound having one chiral center will be substantially free of the opposite enantiomer of the compound.
  • a stereomerically pure composition of a compound having two chiral centers will be substantially free of other diastereomers of the compound.
  • a typical stereomerically pure compound comprises greater than about 80% by weight of one stereoisomer of the compound and less than about 20%) by weight of other stereoisomers of the compound, more preferably greater than about 90% by weight of one stereoisomer of the compound and less than about 10%> by weight of the other stereoisomers of the compound, even more preferably greater than about 95% by weight of one stereoisomer of the compound and less than about 5% by weight of the other stereoisomers of the compound, and most preferably greater than about 97%) by weight of one stereoisomer of the compound and less than about 3% by weight of the other stereoisomers of the compound.
  • enantiomerically pure means a stereomerically pure composition of a compound having one chiral center.
  • adverse effects includes, but is not limited to gastrointestinal, renal and hepatic toxicities, leukopenia, increases in bleeding times due to, e.g., thrombocytopenia, and prolongation of gestation, nausea, vomiting, somnolence, asthenia, dizziness, teratogenicity, extra-pyramidal symptoms, akathisia, cardiotoxicity including cardiovascular disturbances, inflammation, male sexual dysfunction, and elevated serum liver enzyme levels.
  • gastrointestinal toxicities includes but is not limited to gastric and intestinal ulcerations and erosions.
  • renal toxicities includes but is not limited to such conditions as papillary necrosis and chronic interstitial nephritis.
  • crystalline and related terms used herein, when used to describe a compound, substance, modification, material, component or product, unless otherwise specified, mean that the compound, substance, modification, material, component or product is substantially crystalline as determined by X-ray diffraction. See, e.g., Remington: The Science and Practice of Pharmacy, 21 st edition, Lippincott, Williams and Wilkins, Baltimore, MD (2005); The United States Pharmacopeia, 23 rd ed., 1843-1844 (1995).
  • Crystal forms and related terms herein refer to solid forms that are crystalline. Crystal forms include single-component crystal forms and multiple-component crystal forms, and include, but are not limited to, polymorphs, solvates, hydrates, and/or other molecular complexes. In certain embodiments, a crystal form of a substance may be substantially free of amorphous forms and/or other crystal forms. In certain
  • a crystal form of a substance may contain less than about 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45% or 50% of one or more amorphous forms and/or other crystal forms on a weight basis.
  • a crystal form of a substance may be physically and/or chemically pure.
  • a crystal form of a substance may be about 99%, 98%, 97%, 96%, 95%, 94%, 93%, 92%, 91% or 90% physically and/or chemically pure.
  • solvated refer to a crystal form of a substance which contains solvent.
  • hydrate and “hydrated” refer to a solvate wherein the solvent comprises water.
  • Polymorphs of solvates refers to the existence of more than one crystal form for a particular solvate composition.
  • polymorphs of hydrates refers to the existence of more than one crystal form for a particular hydrate composition.
  • desolvated solvate refers to a crystal form of a substance which may be prepared by removing the solvent from a solvate.
  • a numeric value or a range of values which is provided to characterize a particular solid form e.g., a specific temperature or temperature range, such as, e.g., that describing a DSC or TGA thermal event, including, e.g., melting, dehydration, desolvation or glass transition events; a mass change, such as, e.g., a mass change as a function of temperature or humidity; a solvent or water content, in terms of, e.g., mass or a percentage; or a peak position, such as, e.g., in analysis by IR or Raman spectroscopy or XRPD; indicate that the value or range of values may deviate to an extent deemed reasonable to one of ordinary skill in the art while still describing the particular solid form.
  • a sample comprising a particular crystal form or amorphous form that is "substantially pure,” e.g., substantially free of other solid forms and/or of other chemical compounds, contains, in particular embodiments, less than about 25%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.75%, 0.5%, 0.25% or 0.1% percent by weight of one or more other solid forms and/or of other chemical compounds.
  • a sample or composition that is "substantially free" of one or more other solid forms and/or other chemical compounds means that the composition contains, in particular embodiments, less than about 25%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.75%, 0.5%, 0.25% or 0.1% percent by weight of one or more other solid forms and/or other chemical compounds.
  • treating and “treatment” refer to the eradication or amelioration of a disease or disorder, or of one or more symptoms associated with the disease or disorder.
  • the terms refer to minimizing the spread or worsening of the disease or disorder resulting from the administration of one or more prophylactic or therapeutic agents to a patient with such a disease or disorder.
  • the terms refer to the administration of a compound provided herein, with or without other additional active agent, after the onset of symptoms of the particular disease.
  • the terms “prevent,” “preventing” and “prevention” refer to the prevention of the onset, recurrence or spread of a disease or disorder, or of one or more symptoms thereof.
  • the terms refer to the treatment with or administration of a compound provided herein, with or without other additional active compound, prior to the onset of symptoms, particularly to patients at risk of diseases or disorders provided herein.
  • the terms encompass the inhibition or reduction of a symptom of the particular disease.
  • Patients with familial history of a disease in particular are candidates for preventive regimens in certain embodiments.
  • patients who have a history of recurring symptoms are also potential candidates for the prevention.
  • the term “prevention” may be interchangeably used with the term “prophylactic treatment.”
  • “managing” and “management” refer to preventing or slowing the progression, spread or worsening of a disease or disorder, or of one or more symptoms thereof. Often, the beneficial effects that a patient derives from a prophylactic and/or therapeutic agent do not result in a cure of the disease or disorder. In this regard, the term “managing” encompasses treating a patient who had suffered from the particular disease in an attempt to prevent or minimize the recurrence of the disease.
  • a "therapeutically effective amount" of a compound is an amount sufficient to provide a therapeutic benefit in the treatment or management of a disease or disorder, or to delay or minimize one or more symptoms associated with the disease or disorder.
  • a therapeutically effective amount of a compound means an amount of therapeutic agent, alone or in combination with other therapies, which provides a therapeutic benefit in the treatment or
  • therapeutically effective amount can encompass an amount that improves overall therapy, reduces or avoids symptoms or causes of disease or disorder, or enhances the therapeutic efficacy of another therapeutic agent.
  • a prophylactically effective amount of a compound is an amount sufficient to prevent a disease or disorder, or prevent its recurrence.
  • a prophylactically effective amount of a compound means an amount of therapeutic agent, alone or in combination with other agents, which provides a prophylactic benefit in the prevention of the disease.
  • the term “prophylactically effective amount” can encompass an amount that improves overall prophylaxis or enhances the prophylactic efficacy of another prophylactic agent.
  • composition as used herein is intended to encompass a product comprising the specified ingredients (and in the specified amounts, if indicated), as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts.
  • pharmaceutically acceptable it is meant that the diluent, excipient or carrier must be compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
  • Compound A is achieved by a floating agent and a swelling agent that prolongs the residence time of Compound A in the upper GI tract.
  • Compound A is achieved by the tablet's bioadhesive properties, whereby the tablet adheres to the membrane of the gastrointestinal tract, increasing the transit time in the small intestine.
  • bioadhesive-based dosage forms can be found in Lee, J. Pharm. Sci. 2000, 89, 850.
  • controlled release oral dosage forms of poorly soluble drugs methods of making the solid forms, and methods of their use for the treatment of various diseases and/or disorders.
  • the controlled release oral dosage forms provided herein comprise polymeric excipients which expand and/or become charged in the gastric fluid in acidic pH and control the release of the poorly soluble drug in the system.
  • the controlled release oral dosage forms provided herein are believed to enhance the bioavailability of a poorly soluble drug by increasing the time of release of the drug in the gastrointestinal tract.
  • the extended time of release of the poorly soluble drug occurs mainly in the stomach.
  • the release profile of the dosage forms provided herein achieve controlled release over an 8 to 24 hour period. In some embodiments, controlled release is achieved over about an 8 hour period; a 10 hour period; a 12 hour period; a 14 hour period; a 16 hour period; an 18 hour period; a 20 hour period; a 22 hour period; or a 24 hour period.
  • the controlled release oral dosage forms provided herein comprise positively charged polymers, negatively charged polymers and swelling excipients, which when combined with a poorly soluble drug in particular weight ratios of ingredients provide controlled release of the poorly soluble drug.
  • controlled release of the poorly soluble drug is achieved by action of the swelling excipients and the interaction of the polymers containing negative charges and positive charges in acidic pH of the stomach or upper gastrointestinal tract.
  • the controlled release oral dosage form comprises one or more of each of the following: (i) a poorly soluble drug; (ii) a swelling excipient; (iii) a cationic polymer in acidic pH; and (iv) an anionic polymer in acidic pH.
  • the controlled release oral dosage form further comprises a water absorbing agent.
  • the controlled release oral dosage form further comprises one or more additional pharmaceutically acceptable excipients.
  • a controlled release oral dosage form comprising: (i) Compound A, or a pharmaceutically acceptable polymorph, solvate, or hydrate thereof; (ii) a swelling excipient; (iii) a cationic polymer in acidic pH; (iv) an anionic polymer in acidic pH; and (v) a floating agent.
  • the floating agent is sodium bicarbonate.
  • the controlled release oral dosage form further comprises a water absorbing agent.
  • the controlled release oral dosage form further comprises one or more additional
  • a controlled release oral dosage form comprises:
  • a swelling excipient in an amount from about 32.8% to about 50% by weight;
  • a cationic polymer in acidic pH;
  • Compound A is present in an amount of about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, or about 90% by weight.
  • Compound A is present in an amount of about
  • the swelling excipient is selected from the group consisting of polyethylene oxide, sodium carboxymethyl cellulose, hydroxypropyl cellulose, hydroxylpropyl methyl cellulose (HPMC), methyl celluloses, croscarmellose sodium, sodium starch glycolate, PolyplasdoneXL and Kollidon XL.
  • the swelling excipient is sodium carboxymethyl cellulose.
  • the swelling excipient is present in an amount of about 32.5%) to about 37% by weight.
  • the swelling excipient is present in an amount of about 34.5 percent.
  • the cationic polymer in acidic pH is selected from the group consisting of chitosan, methacrylic acid—methyl methacrylate copolymer (in an about 1 : 1 ratio), methacrylic acid— methyl methacrylate copolymer (in an about 1 :2 ratio), poly(butyl methacylate-co-2-dimethylaminoethyl methacrylate-co-methyl methacrylate) (in about an 1 :2: 1 ratio), and crosslinked acrylic acid copolymers.
  • the cationic polymer in acidic pH is poly(butyl methacylate-co-2-dimethylaminoethyl methacrylate-co-methyl methacrylate) (in about an 1 :2: 1 ratio).
  • the cationic polymer in acidic pH is present in an amount of about 5% to about 7% by weight.
  • the cationic polymer in acidic pH is present in an amount of about 5 percent.
  • the anionic polymer in acidic pH is selected from the group consisting of sodium alginate, sodium carboxymethyl cellulose (CMC), chondroitin sulfate, carrageenan, glycosaminoglycans, mucopolysaccharides, pectin, gelatin and hyalouronic acid.
  • CMC carboxymethyl cellulose
  • chondroitin sulfate chondroitin sulfate
  • carrageenan glycosaminoglycans
  • mucopolysaccharides pectin, gelatin and hyalouronic acid.
  • the anionic polymer in acidic pH is a sodium alginate.
  • the anionic polymer in acidic pH is present in an amount of about 19% by weight.
  • the sodium bicarbonate is in an amount of about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, or about 50% by weight.
  • the sodium bicarbonate is in an amount of about 5% by weight.
  • the controlled release oral dosage form further comprises a pH modifier.
  • the pH modifier is citric acid.
  • the pH modifier is present in an amount of about
  • the cationic polymer in acidic pH is present in an amount of about 8 percent.
  • the controlled release oral dosage form further comprises a disintegrant.
  • the disintegrant is selected from the group consisting of lactose, microcrystalline cellulose, sodium starch glycolate, agar-agar, alginic acid, calcium carbonate, microcrystalline cellulose, croscarmellose sodium, crospovidone, polacrilin potassium, sodium starch glycolate, potato or tapioca starch, pre-gelatinized starch and mixtures thereof.
  • the disintegrant is croscarmellose sodium.
  • the disintegrant is present in an amount of about 5% by weight.
  • the controlled release oral dosage form further comprises a lubricant.
  • the lubricant is selected from the group consisting of a syloid silica gel, a coagulated aerosol of synthetic silica, a pyrogenic silicon dioxide, magnesium stearate, and mixtures thereof.
  • the lubricant is magnesium stearate.
  • the lubricant is present in an amount of about 5% by weight.
  • the above-mentioned controlled release oral dosage form further comprises additional excipients, e.g., filler such as mannitol, and glydant such as colloidal silicon dioxide.
  • additional excipients e.g., filler such as mannitol, and glydant such as colloidal silicon dioxide.
  • about 92% to about 98%% of the Compound A is released after 24 hours, when dissolved in 2% Tween 80 in 50 mM sodium acetate buffer pH 4.5. In a specific embodiment, about 95% of the Compound A is released after 24 hours, when dissolved in 2% Tween 80 in 50 mM sodium acetate buffer pH 4.5.
  • the percentage of Compound A released is about 5% after 1 hour, about 14% after 2 hours, about 36% after 4 hours, about 58 after 6 hours, about 75%) after 8 hours, about 88%> after 12 hours, and about 91% after 16 hours.
  • a controlled release oral dosage form In a specific embodiment, a controlled release oral dosage form
  • the above controlled release oral dosage form further comprises (vi) citric acid in an amount of about 8% by weight; (vii) croscarmellose sodium in an amount of about 5% by weight; and (viii) magnesium stearate in an amount of about 1.5% by weight.
  • a "cationic polymer in acidic pH” or “positively charged polymer” refers to a polymer which is positively charged in acidic pH.
  • “Acidic pH” refers to a pH ⁇ 7. In some embodiments "acid pH” refers to a pH between 0 and 7; 0 and 5; 1 and 5; 0 and 4; 1 and 4; 0 and 3; or 1 and 3.
  • Nonlimiting examples of cationic polymer in acidic pH include chitosan (e.g., Chitopharm® S and Chitoclear® 2832, 3504, 3548 and 3568), methacrylic acid - methyl methacrylate copolymer (1 : 1)
  • an "anionic polymer in acidic pH” or “negatively charged polymer” refers to a polymer which is negatively charged in acidic pH.
  • Nonlimiting examples of negatively charged polymers include sodium alginate (e.g., Protanal® LF 120M, Protanal® LF 200M, Protanal® LF 200D), sodium carboxymethyl cellulose (CMC), chondroitin sulfate, carrageenan (e.g., Gelcarin® 209, Gelcarin® 379), glycosaminoglycans, mucopolysaccharides, pectin, gelatin and hyalouronic acid.
  • a "swelling excipient” refers to an excipient which swells or grows in size when in contact with a liquid, e.g., an aqueous solution.
  • Nonlimiting examples of swelling excipients include polymers, fibers and disintegrants, such as hydroxyethylcellulose (HEC, e.g., Natrosol® G, Natrosol® L), polyethylene oxide (e.g., Polyox® N10, Polyox® N12K, Polyox® N80, Polyox® N-205G, Polyox® N-1105 and Polyox® N750), sodium carboxymethyl cellulose (CMC, e.g., CMC 7L2P and CMC 7LF), hydroxypropyl cellulose, hydroxylpropyl methyl cellulose (HPMC), methyl celluloses, sodium crosscarmellose (Ac-Di-Sol®), sodium starch glycolate (Primojel®), Polyplasdone XL® and Kollidon® XL.
  • HEC hydroxyethylcellulose
  • HPMC hydroxypropylcellulose
  • HPMC sodium crosscarmellose
  • a floating agent refers to an excipient which facilitates the formulation's ability to float as a result of gas formation.
  • a floating agent may alternatively be referred to as a “foaming agent” or an “effervescent agent.”
  • Nonlimiting examples of floating agents include sodium bicarbonate, sodium carbonate, potassium bicarbonate, potassium carbonate, calcium bicarbonate, and calcium carbonate.
  • Nonlimiting examples of water absorbing agent include humectants such as sorbitol, xylitol, maltitol, polymeric polyols, calcium chloride, sodium chloride, carrageenan (Gelcarin®), polyacrylic acid and hydrogel.
  • humectants such as sorbitol, xylitol, maltitol, polymeric polyols, calcium chloride, sodium chloride, carrageenan (Gelcarin®), polyacrylic acid and hydrogel.
  • Fillers and processing aids may be used in the controlled release dosage forms provided herein.
  • fillers include, but are not limited to,
  • microcrystalline cellulose e.g., MCC, Avicel PH102
  • lactose dicalcium phosphate
  • pregelatinized starch pregelatinized starch and the mixture thereof.
  • Surfactants may be used in the controlled release dosage forms provided herein.
  • surfactants include, but are not limited to, sodium laural sulfate (SLS) and ethylene oxide - propylene oxide block copolymers (e.g., Pluronic® F108).
  • poorly soluble drug refers to a drug which has limited solubility in aqueous media. Poorly soluble drugs are not readily absorbed through the gastrointestinal tract upon oral administration.
  • Examples of poorly soluble drugs provided herein include (S)-N- ⁇ 2-[l -(3- ethoxy-4-methoxy-phenyl)-2-methanesulfonylethyl]-l,3-dioxo-2,3-dihydro-lH-isoindol- 4-yl ⁇ acetamide (Compound A) and cyclopropanecarboxylic acid ⁇ 2-[(7,S)-l-(3-ethoxy-4- methoxy-phenyl)-2-methanesulfonyl-ethyl]-3-oxo-2,3-dihydro-17J-isoindol-4-yl ⁇ -amide (Compound B).
  • Compound B is 6.9 ⁇ g/mL and 2.0 ⁇ g/mL, respectively.
  • Daily doses of Compound A ranging from 10 mg to 100 mg per day have been administered to approximately 1000 subject in clinical studies to date.
  • dose 10 mg/kg PO the pharmacokinetic parameters of Compound A in monkeys indicated that the t 1/2 is about 2 hours. Therefore a controlled release dosage is clearly needed for Compound A.
  • the poorly soluble drug provided herein is Compound
  • Compound A is crystalline.
  • Compound A is crystalline Form B.
  • Compound A is amorphous.
  • the controlled release oral dosage form comprises a poorly soluble drug, chitosan, an alginate, a swelling excipient, and optionally one or more additional excipients.
  • the swelling polymer is Natrosol. In one embodiment, the swelling polymer is Polyox.
  • the chitosan has an average molecular weight of 10,000 to 5,000,000 Da. In another embodiment, the chitosan has an average molecular weight of 10,000 to 2,000,000 Da. In some embodiments, the chitosan has a degree of deacylation of at least 70%. In other embodiments, the chitosan has a degree of deacylation of at least 90%. In one embodiment, the particle size of the chitosan is such that it passes through 20 mesh screen.
  • the alginate is a salt of aginic acid. In one embodiment, the alginate is sodium alginate.
  • the controlled release oral dosage form comprises a poorly soluble drug, chitosan, a salt of carboxymethyl cellulose, a swelling excipient, and optionally one or more additional excipients.
  • the swelling excipient is a polyethylene oxide or hydroxyethyl cellulose.
  • the controlled release oral dosage form further comprises a disintegrant.
  • the distintegrant is lactose.
  • the distintegrant is microcrystalline cellulose (MCC).
  • the distintegrant is sodium crosscarmellose.
  • the distintegrant is Primojel®.
  • kits for treating, preventing or managing disorders ameliorated by the reduction of levels of TNF-a in a patient which comprises administering to a patient in need of such treatment, prevention or management a therapeutically or prophylactically effective amount of a compound provided herein, or a pharmaceutically acceptable prodrug, metabolite, polymorph, solvate, hydrate, or clathrate thereof.
  • diseases or disorders ameliorated by the inhibition of TNF-a production in mammals include, but are not limited to: HIV;
  • hepatitis adult respiratory distress syndrome; bone resorption diseases; chronic obstructive pulmonary diseases; chronic pulmonary inflammatory diseases; asthma; dermatitis; cystic fibrosis; septic shock; sepsis; endotoxic shock; hemodynamic shock; sepsis syndrome; post ischemic reperfusion injury; meningitis; psoriasis; psoriatic arthritis; ankylosing spondylitis; Behcet's Disease; fibrotic disease; cachexia; graft rejection; auto immune disease; rheumatoid spondylitis; arthritic conditions, such as psoriatic arthritis, rheumatoid arthritis and osteoarthritis; osteoporosis; Crohn's disease; ulcerative colitis; inflammatory bowel disease; multiple sclerosis; systemic lupus erythematosus; cutaneous lupus erythematosus; pulmonary sarcoidosis; erythema nodosum le
  • Such disorders further include, but are not limited to, cancers, including, but not limited to cancer of the head, thyroid, neck, eye, skin, mouth, throat, esophagus, chest, bone, blood, bone marrow, lung, colon, sigmoid, rectum, stomach, prostate, breast, ovaries, kidney, liver, pancreas, brain, intestine, heart, adrenal, subcutaneous tissue, lymph nodes, heart, and combinations thereof.
  • cancers including, but not limited to cancer of the head, thyroid, neck, eye, skin, mouth, throat, esophagus, chest, bone, blood, bone marrow, lung, colon, sigmoid, rectum, stomach, prostate, breast, ovaries, kidney, liver, pancreas, brain, intestine, heart, adrenal, subcutaneous tissue, lymph nodes, heart, and combinations thereof.
  • Specific cancers that can be treated by this method are multiple myeloma, malignant melanoma, malignant glioma, leukemia and solid
  • cancer including but not limited to, solid tumor, blood-borne tumor, leukemias, and in particular, multiple myeloma in a patient which comprises
  • a method of inhibiting PDE4 which comprises contacting PDE4 in a cell (e.g. a mammalian cell) with an effective amount of a compound provided herein, or a pharmaceutically acceptable prodrug, metabolite, polymorph, solvate, hydrate, or clathrate thereof (wherein particular embodiments encompass solid forms comprising Compound A as described herein).
  • a cell e.g. a mammalian cell
  • a pharmaceutically acceptable prodrug, metabolite, polymorph, solvate, hydrate, or clathrate thereof wherein particular embodiments encompass solid forms comprising Compound A as described herein.
  • kits for treating or preventing diseases or disorders ameliorated by the inhibition of PDE4 in a patient which comprises administering to a patient in need of such treatment or prevention a therapeutically or prophylactically effective amount of a compound provided herein, or a pharmaceutically acceptable prodrug, metabolite, polymorph, solvate, hydrate, or clathrate thereof.
  • Disorders ameliorated by the inhibition of PDE4 include, but are not limited to, asthma, inflammation (e.g., inflammation due to reperfusion), chronic or acute obstructive pulmonary diseases, chronic or acute pulmonary inflammatory diseases, cutaneous lupus erythematosis, inflammatory bowel disease, Crohn' s Disease, Behcet' s Disease, or colitis.
  • controlling cAMP levels includes preventing or reducing the rate of the breakdown of Adenosine 3 ',5 '-cyclic monophosphate (cAMP) in a cell or increasing the amount of Adenosine 3 ',5 '-cyclic monophosphate present in a cell, preferably a mammalian cell, more preferably a human cell.
  • the rate of cAMP breakdown is reduced by about 10, 25, 50, 100, 200, or 500 percent as compared to the rate in comparable cells which have not been contacted with a compound of the invention.
  • provided herein are methods of treating or preventing depression, asthma, inflammation, contact dermatitis, atopic dermatitis, psoriasis, psoriatic arthritis, rheumatoid arthritis, osteoarthritis, cutaneous lupus erythematosis, ankylosing spondylitis, inflammatory skin disease, inflammation due to reperfusion, chronic or acute obstructive pulmonary diseases, chronic or pulmonary inflammatory diseases, autoimmune diseases, inflammatory bowel disease, Crohn's Disease, Behcet's Disease or colitis in a patient which comprises administering to a patient in need of such treatment or prevention a therapeutically or prophylactically effective amount of a compound provided herein, or a pharmaceutically acceptable prodrug, metabolite, polymorph, solvate, hydrate, or clathrate thereof; in particular wherein the patient is a mammal.
  • MDS myelodysplastic syndrome
  • administering to a patient in need of such treatment or prevention a therapeutically or prophylactically effective amount of a compound provided herein, or a pharmaceutically acceptable solvate, hydrate, clathrate, or prodrug thereof.
  • MDS refers to a diverse group of hematopoietic stem cell disorders. MDS is characterized by a cellular marrow with impaired morphology and maturation (dysmyelopoiesis), peripheral blood cytopenias, and a variable risk of progression to acute leukemia, resulting from ineffective blood cell production. See The Merck Manual 953 (17th ed. 1999) and List et al, 1990, J. Clin. Oncol. 8: 1424.
  • myeloproliferative disease which comprises administering to a patient in need of such treatment or prevention a therapeutically or prophylactically effective amount of a compound provided herein, or a pharmaceutically acceptable solvate, hydrate, clathrate, or prodrug thereof.
  • Myeloproliferative disease refers to a group of disorders characterized by clonal abnormalities of the hematopoietic stem cell. See e.g., Current Medical Diagnosis & Treatment, pp. 499 (37th ed., Tierney et al, ed., Appleton & Lange, 1998).
  • the administration is before, during or after surgery or physical therapy directed at reducing or avoiding a symptom of complex regional pain syndrome in the patient.
  • additional therapeutic agents include, but are not limited to, anti-cancer drugs, antiinflammatories, antihistamines and decongestants.
  • the controlled release dosage forms provided herein comprise positively charged polymers, negatively charged polymers and swelling excipients, which when combined with a poorly soluble drug in particular weight ratios of ingredients provide controlled release of the poorly soluble drug.
  • controlled release of the poorly soluble drug is achieved by action of the swelling excipients and the interaction of the polymers containing negative charges and positive charges in acidic pH of the stomach or upper gastrointestinal tract.
  • the release profile of the dosage forms provided herein achieves controlled release over an 8 to 24 hour period.
  • the controlled release dosage forms provided herein use opposite charged polymeric excipients to form an inter-penetrating network in situ when the compositions contact water, gradually forming a gel system in the outer shell of the dosage form ⁇ e.g., tablet).
  • a water absorbing agent enhances the rate of water penetration to boost the swelling of the inter-penetrating system in a short time.
  • specific excipients which contribute to the swelling result in a synergistic swelling ratio with the charged inter-penetrating network system.
  • Controlled release oral dosage forms comprise one or more of each of the following: (i) a poorly soluble drug; (ii) a swelling excipient; (iii) a cationic polymer in acidic pH; and (iv) an anionic polymer in acidic pH.
  • the controlled release oral dosage form further comprises a water absorbing agent.
  • the controlled release oral dosage form further comprises one or more additional pharmaceutically acceptable excipients.
  • Chitosans are exemplary positively charged polymers that may be used in the oral dosage forms provided herein. Chitosans have been described in the literature as pharmaceutical ingredients for controlled release systems. See e.g., Eur J Pharm Sci., 2003, 19(5):345-53. However, the use of chitosans is limited to controlled release systems for drug delivery in the colon, not the gastroretentive system. The gastric retention time described in these systems is too short; drugs pass the absorption window in stomach before being released.
  • the molecular weight, particle size, and degree of deacetylation of chitosans are factors which may affect release rates and lengthen the widow of absorption of a drug.
  • the degree of deacetylation of chitosans used in the formulations herein is greater than 90%.
  • chitosan was prepared by dissolving the granules in acid solution first, followed by drying to lumps and homogenized. As provided herein, chitosan granules are used directly without re-processing.
  • the controlled release dosage forms provided herein are developed such that the amount of the total excipients required for swelling and retaining in the stomach over time is determined such that the system delivers the drug in a controlled release manner.
  • Certain combinations of positively charged polymer (e.g., chitosan), negatively charged polymer (e.g. sodium alginate) and swelling ingredients (e.g., Ac-Di-Sol® or Natrosol®) are proved to be a synergistic controlled release system.
  • Such compositions result in extended controlled release profiles by USP I in vitro dissolution method using Distek dissolution apparatus. See Examples 4-6.
  • compositions and dosage forms provided herein typically also comprise one or more pharmaceutically acceptable excipient, diluent or carrier.
  • a pharmaceutical composition provided herein comprises one or more solid forms a compound provided herein and at least one additional therapeutic agent.
  • additional therapeutic agents include, but are not limited to: anti-cancer drugs and anti-inflammation therapies including, but not limited to, those provided herein.
  • oral dosage forms include, but are not limited to: tablets; caplets; capsules, such as soft elastic gelatin capsules; cachets; troches; lozenges;
  • dispersions e.g., inhalers
  • gels liquid dosage forms suitable for oral administration to a patient, including suspensions (e.g., aqueous or non-aqueous liquid suspensions, oil-in-water emulsions, or a water-in-oil liquid emulsions), solutions, and elixirs.
  • suspensions e.g., aqueous or non-aqueous liquid suspensions, oil-in-water emulsions, or a water-in-oil liquid emulsions
  • solutions elixirs.
  • composition, shape, and type of dosage forms provided herein will typically vary depending on their use. These variations will be readily apparent to those skilled in the art. See, e.g., Remington 's Pharmaceutical Sciences, 18th ed., Mack Publishing, Easton PA (1990).
  • Typical pharmaceutical compositions and dosage forms comprise one or more excipients.
  • Suitable excipients are well known to those skilled in the art of pharmacy, and non-limiting examples of suitable excipients are provided herein.
  • Lactose-free compositions of the invention can comprise excipients that are well known in the art and are listed, for example, in the U.S. Pharmocopia (USP) SP (XXI)/NF (XVI).
  • lactose-free compositions comprise an active ingredient, a binder/filler, and a lubricant in pharmaceutically compatible and pharmaceutically acceptable amounts.
  • Preferred lactose-free dosage forms comprise an active ingredient, microcrystalline cellulose, pre-gelatinized starch, and magnesium stearate.
  • This invention further encompasses anhydrous pharmaceutical compositions and dosage forms comprising active ingredients, since water can facilitate the degradation of some compounds.
  • water e.g., 5%
  • water is widely accepted in the pharmaceutical arts as a means of simulating long-term storage in order to determine characteristics such as shelf-life or the stability of formulations over time. See, e.g., Jens T. Carstensen, Drug Stability: Principles & Practice, 2d. Ed., Marcel Dekker, NY, NY, 1995, pp. 379-80.
  • water and heat accelerate the decomposition of some compounds.
  • the effect of water on a formulation can be of great significance since moisture and/or humidity are commonly encountered during manufacture, handling, packaging, storage, shipment, and use of formulations.
  • Anhydrous pharmaceutical compositions and dosage forms of the invention can be prepared using anhydrous or low moisture containing ingredients and low moisture or low humidity conditions.
  • Pharmaceutical compositions and dosage forms that comprise lactose and at least one active ingredient that comprises a primary or secondary amine are preferably anhydrous if substantial contact with moisture and/or humidity during manufacturing, packaging, and/or storage is expected.
  • anhydrous pharmaceutical composition should be prepared and stored such that its anhydrous nature is maintained. Accordingly, anhydrous compositions are preferably packaged using materials known to prevent exposure to water such that they can be included in suitable formulary kits. Examples of suitable packaging include, but are not limited to, hermetically sealed foils, plastics, unit dose containers (e.g., vials), blister packs, and strip packs.
  • the dosage forms provided herein may further comprise one or more compounds that reduce the rate by which an active ingredient will decompose.
  • Such compounds which are referred to herein as “stabilizers,” include, but are not limited to, antioxidants such as ascorbic acid, pH buffers, or salt buffers.
  • antioxidants such as ascorbic acid, pH buffers, or salt buffers.
  • typical dosage forms provided herein lie within the range of from about 1 mg to about 1,000 mg per day, given as a single once-a-day dose in the morning but preferably as divided doses throughout the day. More specifically, the daily dose is administered twice daily in equally divided doses.
  • a daily dose range may be from about 5 mg to about 500 mg per day, more specifically, between about 10 mg and about 200 mg per day.
  • the therapy may be initiated at a lower dose, perhaps about 1 mg to about 25 mg, and increased if necessary up to about 200 mg to about 1,000 mg per day as either a single dose or divided doses, depending on the patient's global response.
  • oral dosage forms may be presented as discrete dosage forms, such as, but are not limited to, tablets (e.g., chewable tablets), caplets, capsules, and liquids (e.g., flavored syrups).
  • Such dosage forms contain predetermined amounts of active ingredients, and may be prepared by methods of pharmacy well known to those skilled in the art. See generally Remington 's Pharmaceutical Sciences, 18th ed., Mack Publishing, Easton PA (1990).
  • Typical oral dosage forms provided herein are prepared by combining the active ingredient(s) in an intimate admixture with at least one excipient according to conventional pharmaceutical compounding techniques.
  • Excipients can take a wide variety of forms depending on the form of preparation desired for administration.
  • excipients suitable for use in oral liquid or aerosol dosage forms include, but are not limited to, water, glycols, oils, alcohols, flavoring agents, preservatives, and coloring agents.
  • excipients suitable for use in solid oral dosage forms include, but are not limited to, starches, sugars, micro-crystalline cellulose, diluents, granulating agents, lubricants, binders, and disintegrating agents.
  • tablets and capsules represent the most advantageous oral dosage unit forms, in which case solid excipients are employed. If desired, tablets can be coated by standard aqueous or nonaqueous techniques. Such dosage forms can be prepared by any of the methods of pharmacy. In general, pharmaceutical compositions and dosage forms are prepared by uniformly and intimately admixing the active ingredients with liquid carriers, finely divided solid carriers, or both, and then shaping the product into the desired presentation if necessary.
  • a tablet can be prepared by compression or molding.
  • Compressed tablets can be prepared by compressing in a suitable machine the active ingredients in a free-flowing form such as powder or granules, optionally mixed with an excipient. Molded tablets can be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.
  • the dosage form provided herein is a 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 40 mg, 50 mg, 60 mg, 75 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 400 mg, 500 mg, 750 mg or 1000 mg tablet.
  • excipients that can be used in oral dosage forms provided herein include, but are not limited to, binders, fillers, disintegrants, and lubricants.
  • Binders suitable for use in pharmaceutical compositions and dosage forms include, but are not limited to, corn starch, potato starch, or other starches, gelatin, natural and synthetic gums such as acacia, sodium alginate, alginic acid, other alginates, powdered tragacanth, guar gum, cellulose and its derivatives (e.g., ethyl cellulose, cellulose acetate, carboxymethyl cellulose calcium, sodium carboxymethyl cellulose), polyvinyl pyrrolidone, methyl cellulose, pre-gelatinized starch, hydroxypropyl methyl cellulose, (e.g., Nos. 2208, 2906, 2910), microcrystalline cellulose, and mixtures thereof.
  • natural and synthetic gums such as acacia, sodium alginate, alginic acid, other alginates, powdered tragacanth, guar gum, cellulose and its derivatives (e.g., ethyl cellulose, cellulose acetate, carboxymethyl
  • fillers suitable for use in the pharmaceutical compositions and dosage forms disclosed herein include, but are not limited to, talc, calcium carbonate (e.g., granules or powder), microcrystalline cellulose, powdered cellulose, dextrates, kaolin, mannitol, silicic acid, sorbitol, starch, pre-gelatinized starch, and mixtures thereof.
  • the binder or filler in pharmaceutical compositions of the invention is typically present in from about 50 to about 99 weight percent of the pharmaceutical composition or dosage form.
  • Suitable forms of microcrystalline cellulose include, but are not limited to, the materials sold as AVICEL-PH-101TM, AVICEL-PH-103TM, AVICEL RC-581TM, AVICEL-PH-105TM (available from FMC Corporation, American Viscose Division, Avicel Sales, Marcus Hook, PA), and mixtures thereof.
  • a specific binder is a mixture of microcrystalline cellulose and sodium carboxymethyl cellulose (sodium CMC) sold, for example, as AVICEL RC-581TM.
  • Suitable anhydrous or low moisture excipients or additives include AVICEL-PH-103TM and Starch 1500 LMTM.
  • Disintegrants may be used in the compositions herein to provide tablets that disintegrate when exposed to an aqueous environment. Tablets that contain too much disintegrant may disintegrate in storage, while those that contain too little may not disintegrate at a desired rate or under the desired conditions. Thus, a sufficient amount of disintegrant that is neither too much nor too little to detrimentally alter the release of the active ingredients should be used to form solid oral dosage forms of the invention. The amount of disintegrant used varies based upon the type of formulation, and is readily discernible to those of ordinary skill in the art. Typical pharmaceutical compositions comprise from about 0.5 to about 15 weight percent of disintegrant, specifically from about 1 to about 5 weight percent of disintegrant.
  • Disintegrants that may be used herein include, but are not limited to, agar-agar, alginic acid, calcium carbonate, microcrystalline cellulose, croscarmellose sodium, crospovidone, polacrilin potassium, sodium starch glycolate, potato or tapioca starch, pre-gelatinized starch, other starches, clays, other algins, other celluloses, gums, and mixtures thereof.
  • Lubricants that may be used herein include, but are not limited to, calcium stearate, magnesium stearate, mineral oil, light mineral oil, glycerin, sorbitol, mannitol, polyethylene glycol, other glycols, stearic acid, sodium lauryl sulfate, talc, hydrogenated vegetable oil (e.g., peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil, and soybean oil), zinc stearate, ethyl oleate, ethyl laureate, agar, and mixtures thereof.
  • Additional lubricants include, for example, a syloid silica gel (AEROSIL 200TM, manufactured by W.R.
  • lubricants are typically used in an amount of less than about one weight percent of the pharmaceutical compositions or dosage forms into which they are incorporated.
  • Dosage forms comprising a compound may be administered by controlled release means or by delivery devices that are well known to those of ordinary skill in the art. Examples include, but are not limited to, those described in U. S. Patent Nos. :
  • Such dosage forms can be used to provide slow or controlled-release of one or more active ingredients using, for example, hydropropylmethyl cellulose, other polymer matrices, gels, permeable membranes, osmotic systems, multilayer coatings, microparticles, liposomes, microspheres, or a combination thereof to provide the desired release profile in varying proportions.
  • Suitable controlled-release formulations known to those of ordinary skill in the art, including those described herein, can be readily selected for use with the active ingredients of the invention.
  • the invention thus encompasses single unit dosage forms suitable for oral administration such as, but not limited to, tablets, capsules, gelcaps, and caplets that are adapted for controlled-release.
  • U.S. Patent No. 3,598, 123 discloses the use of sodium bicarbionate as a foaming agent.
  • controlled-release pharmaceutical products have a common goal of improving drug therapy over that achieved by their non-controlled counterparts.
  • the use of an optimally designed controlled-release preparation in medical treatment is characterized by a minimum of drug substance being employed to cure or control the condition in a minimum amount of time.
  • Advantages of controlled-release formulations include extended activity of the drug, reduced dosage frequency, and increased patient compliance.
  • controlled-release formulations can be used to affect the time of onset of action or other characteristics, such as blood levels of the drug, and can thus affect the occurrence of side (e.g., adverse) effects.
  • Controlled-release formulations are designed to initially release an amount of drug (active ingredient) that promptly produces the desired therapeutic effect, and gradually and continually release of other amounts of drug to maintain this level of therapeutic or prophylactic effect over an extended period of time.
  • drug active ingredient
  • Controlled-release of an active ingredient can be stimulated by various conditions including, but not limited to, pH, temperature, enzymes, water, or other physiological conditions or compounds.
  • the invention encompasses methods of treating, preventing and managing diseases or disorders ameliorated by the reduction of levels of TNF-a in a patient which comprise administering to a patient in need of such treatment, prevention or management a therapeutically or prophylactically effective amount of a controlled release oral dosage form provided herein.
  • disorders ameliorated by the inhibition of T F- ⁇ include, but are not limited to: heart disease, such as congestive heart failure, cardiomyopathy, pulmonary edema, endotoxin-mediated septic shock, acute viral myocarditis, cardiac allograft rejection, and myocardial infarction; depression, asthma, inflammation, contact dermatitis, atopic dermatitis, psoriasis, psoriatic arthritis, rheumatoid arthritis, osteoarthritis, cutaneous lupus erythematosis, ankylosing spondylitis, inflammatory skin disease, inflammation due to reperfusion, chronic or acute obstructive pulmonary diseases, chronic or pulmonary inflammatory diseases, autoimmune diseases, inflammatory bowel disease, Crohn's Disease, Behcet's Disease or colitis; solid tumors, including but not limited to, sarcoma, carcinomas, fibrosarcoma, myxosarcoma, liposarcoma,
  • Specific methods provided herein further comprise the administration of an additional therapeutic agent.
  • additional therapeutic agents include, but are not limited to, anti-cancer drugs such as, but are not limited to: alkylating agents, nitrogen mustards, ethylenimines, methylmelamines, alkyl sulfonates, nitrosoureas, triazenes, folic acid analogs, pyrimidine analogs, purine analogs, vinca alkaloids, epipodophyllotoxins, antibiotics, topoisomerase inhibitors and anti-cancer vaccines.
  • anti-cancer drugs such as, but are not limited to: alkylating agents, nitrogen mustards, ethylenimines, methylmelamines, alkyl sulfonates, nitrosoureas, triazenes, folic acid analogs, pyrimidine analogs, purine analogs, vinca alkaloids, epipodophyllotoxins, antibiotics, topoisomerase inhibitors and anti-cancer vaccine
  • Specific additional therapeutic agents include, but are not limited to: acivicin; aclarubicin; acodazole hydrochloride; acronine; adozelesin; aldesleukin;
  • anastrozole anthramycin; asparaginase; asperlin; azacitidine; azetepa; azotomycin; batimastat; benzodepa; bicalutamide; bisantrene hydrochloride; bisnafide dimesylate; bizelesin; bleomycin sulfate; brequinar sodium; bropirimine; busulfan; cactinomycin; calusterone; caracemide; carbetimer; carboplatin; carmustine; carubicin hydrochloride; carzelesin; cedefingol; chlorambucil; cirolemycin; cisplatin; cladribine; crisnatol mesylate; cyclophosphamide; cytarabine; dacarbazine; dactinomycin; daunorubicin hydrochloride; decitabine; dexormaplatin; dezaguanine; deza
  • fenretinide floxuridine; fludarabine phosphate; fluorouracil; flurocitabine; fosquidone; fostriecin sodium; gemcitabine; gemcitabine hydrochloride; hydroxyurea; idarubicin hydrochloride; ifosfamide; ilmofosine; interleukin II (including recombinant interleukin II, or rIL2), interferon alfa-2a; interferon alfa-2b; interferon alfa-nl ; interferon alfa-n3; interferon beta-I a; interferon gamma-I b; iproplatin; irinotecan hydrochloride; lanreotide acetate; letrozole; leuprolide acetate; liarozole hydrochloride; lometrexol sodium;
  • mitindomide mitocarcin; mitocromin; mitogillin; mitomalcin; mitomycin; mitosper; mitotane; mitoxantrone hydrochloride; mycophenolic acid; nocodazole; nogalamycin; ormaplatin; oxisuran; paclitaxel; pegaspargase; peliomycin; pentamustine; peplomycin sulfate; perfosfamide; pipobroman; piposulfan; piroxantrone hydrochloride; plicamycin; plomestane; porfimer sodium; porfiromycin; prednimustine; procarbazine hydrochloride; puromycin; puromycin hydrochloride; pyrazofurin; riboprine; rogletimide; safingol; safingol hydrochloride; semustine; suppressrazene; sparfosate sodium; sparsomycin;
  • spirogermanium hydrochloride spiromustine; spiroplatin; streptonigrin; streptozocin; sulofenur; talisomycin; tecogalan sodium; tegafur; teloxantrone hydrochloride;
  • temoporfin teniposide; teroxirone; testolactone; thiamiprine; thioguanine; thiotepa; tiazofurin; tirapazamine; toremifene citrate; trestolone acetate; triciribine phosphate; trimetrexate; trimetrexate glucuronate; triptorelin; tubulozole hydrochloride; uracil mustard; uredepa; vapreotide; verteporfin; vinblastine sulfate; vincristine sulfate;
  • Other anti-cancer drugs include, but are not limited to: 20-epi-l,25 dihy droxy vitamin D3; 5-ethynyluracil; abiraterone; aclarubicin;
  • acylfulvene acylfulvene; adecypenol; adozelesin; aldesleukin; ALL-TK antagonists; altretamine; ambamustine; amidox; amifostine; aminolevulinic acid; amrubicin; amsacrine;
  • anagrelide anastrozole; andrographolide; angiogenesis inhibitors; antagonist D;
  • antagonist G antarelix; anti-dorsalizing morphogenetic protein- 1; antiandrogen, prostatic carcinoma; antiestrogen; antineoplaston; antisense oligonucleotides; aphidicolin glycinate; apoptosis gene modulators; apoptosis regulators; apurinic acid;
  • ara-CDP-DL-PTBA arginine deaminase; asulacrine; atamestane; atrimustine; axinastatin
  • axinastatin 2 axinastatin 3; azasetron; azatoxin; azatyrosine; baccatin III derivatives; balanol; batimastat; BCR/ABL antagonists; benzochlorins; benzoylstaurosporine; beta lactam derivatives; beta-alethine; betaclamycin B; betulinic acid; bFGF inhibitor;
  • bicalutamide bisantrene; bisaziridinylspermine; bisnafide; bistratene A; bizelesin;
  • breflate bropirimine; budotitane; buthionine sulfoximine; calcipotriol; calphostin C; camptothecin derivatives; canarypox IL-2; capecitabine; carboxamide-amino-triazole; carboxyamidotriazole; CaRest M3; CARN 700; cartilage derived inhibitor; carzelesin; casein kinase inhibitors (ICOS); castanospermine; cecropin B; cetrorelix; chlorlns;
  • chloroquinoxaline sulfonamide cicaprost; cis-porphyrin; cladribine; clomifene analogues; clotrimazole; collismycin A; collismycin B; combretastatin A4;
  • combretastatin analogue conagenin; crambescidin 816; crisnatol; cryptophycin 8;
  • cryptophycin A derivatives curacin A; cyclopentanthraquinones; cycloplatam; cypemycin; cytarabine ocfosfate; cytolytic factor; cytostatin; dacliximab; decitabine; dehydrodidemnin B; deslorelin; dexamethasone; dexifosfamide; dexrazoxane;
  • dexverapamil diaziquone; didemnin B; didox; diethylnorspermine;
  • dihydro-5-azacytidine dihydrotaxol, 9-; dioxamycin; diphenyl spiromustine; docetaxel; docosanol; dolasetron; doxifluridine; droloxifene; dronabinol; duocarmycin SA; ebselen; ecomustine; edelfosine; edrecolomab; eflornithine; elemene; emitefur; epirubicin;
  • epristeride estramustine analogue
  • estrogen agonists include estrogen agonists, estrogen antagonists; etanidazole; etoposide phosphate; exemestane; fadrozole; trasrabine; fenretinide; filgrastim;
  • imiquimod immunostimulant peptides; insulin-like growth factor- 1 receptor inhibitor; interferon agonists; interferons; interleukins; iobenguane; iododoxorubicin; ipomeanol,
  • mopidamol multiple drug resistance gene inhibitor; multiple tumor suppressor 1 -based therapy; mustard anticancer agent; mycaperoxide B; mycobacterial cell wall extract; myriaporone; N-acetyldinaline; N-substituted benzamides; nafarelin; nagrestip;
  • naloxone+pentazocine napavin; naphterpin; nartograstim; nedaplatin; nemorubicin; neridronic acid; neutral endopeptidase; nilutamide; nisamycin; nitric oxide modulators; nitroxide antioxidant; nitrullyn; 06-benzylguanine; octreotide; okicenone;
  • oligonucleotides onapristone; ondansetron; ondansetron; oracin; oral cytokine inducer; ormaplatin; osaterone; oxaliplatin; oxaunomycin; paclitaxel; paclitaxel analogues;
  • paclitaxel derivatives palauamine; palmitoylrhizoxin; pamidronic acid; panaxytriol; panomifene; parabactin; pazelliptine; pegaspargase; peldesine; pentosan polysulfate sodium; pentostatin; pentrozole; perflubron; perfosfamide; perillyl alcohol;
  • phenazinomycin phenylacetate; phosphatase inhibitors; picibanil; pilocarpine hydrochloride; pirarubicin; piritrexim; placetin A; placetin B; plasminogen activator inhibitor; platinum complex; platinum compounds; platinum-triamine complex; porfimer sodium; porfiromycin; prednisone; propyl bis-acridone; prostaglandin J2; proteasome inhibitors; protein A-based immune modulator; protein kinase C inhibitor; protein kinase
  • C inhibitors microalgal; protein tyrosine phosphatase inhibitors; purine nucleoside phosphorylase inhibitors; purpurins; pyrazoloacridine; pyridoxylated hemoglobin polyoxyethylene conjugate; raf antagonists; raltitrexed; ramosetron; ras farnesyl protein transferase inhibitors; ras inhibitors; ras-GAP inhibitor; retelliptine demethylated;
  • sarcophytol A sargramostim; Sdi 1 mimetics; semustine; senescence derived inhibitor 1; sense oligonucleotides; signal transduction inhibitors; signal transduction modulators; single chain antigen binding protein; sizofiran; sobuzoxane; sodium borocaptate; sodium phenylacetate; solverol; somatomedin binding protein; sonermin; sparfosic acid;
  • spicamycin D spiromustine; splenopentin; spongistatin 1; squalamine; stem cell inhibitor; stem-cell division inhibitors; stipiamide; stromelysin inhibitors; sulfinosine; superactive vasoactive intestinal peptide antagonist; suradista; suramin; swainsonine; synthetic glycosaminoglycans; tallimustine; tamoxifen methiodide; tauromustine;
  • telomerase inhibitors tazarotene; tecogalan sodium; tegafur; tellurapyrylium; telomerase inhibitors;
  • temoporfin temozolomide; teniposide; tetrachlorodecaoxide; tetrazomine; thaliblastine; thiocoraline; thrombopoietin; thrombopoietin mimetic; thymalfasin; thymopoietin receptor agonist; thymotrinan; thyroid stimulating hormone; tin ethyl etiopurpurin;
  • ubenimex urogenital sinus-derived growth inhibitory factor; urokinase receptor antagonists; vapreotide; variolin B; vector system, erythrocyte gene therapy; velaresol; veramine; verdins; verteporfin; vinorelbine; vinxaltine; vitaxin; vorozole; zanoterone; zeniplatin; zilascorb; and zinostatin stimalamer.
  • Embodiments herein further encompass a method of treating or preventing diseases or disorders ameliorated by the inhibition of T F- ⁇ in a patient.
  • diseases and disorders include, but are not limited to: heart disease, such as congestive heart failure, cardiomyopathy, pulmonary edema, endotoxin-mediated septic shock, acute viral myocarditis, cardiac allograft rejection, and myocardial infarction; depression, asthma, inflammation (e.g., contact dermatitis, atopic dermatitis, psoriasis, psoriatic arthritis, rheumatoid arthritis, osteoarthritis, cutaneous lupus erythematosis, ankylosing spondylitis, inflammatory skin disease, inflammation due to reperfusion), chronic or acute obstructive pulmonary diseases, chronic or pulmonary inflammatory diseases, autoimmune diseases, inflammatory bowel disease, Crohn's Disease, Behcet's Disease or colitis.
  • the disease or disorder such as congestive heart
  • Specific methods provided herein may comprise the administration of an additional therapeutic agent such as, but not limited to, anti-inflammatory drugs, antihistamines and decongestants.
  • additional therapeutic agents include, but are not limited to: antihistamines including, but not limited to,
  • NSAIDS including, but not limited to, aspirin, salicylates, acetominophen, indomethacin, sulindac, etodolac, fenamates, tolmetin, ketorolac, diclofenac, ibuprofen, naproxen, fenoprofen, ketoprofen, flurbiprofen, oxaprozin, piroxicam, meloxicam, pyrazolon derivatives; and steriods including, but not limited to, cortical steroids and adrenocortical steroids.
  • the dosage forms provided herein may be used in the treatment or prevention of a wide range of diseases and conditions.
  • the magnitude of a prophylactic or therapeutic dose of a particular active ingredient of the invention in the acute or chronic management of a disease or condition may vary with the nature and severity of the disease or condition and the route by which the active ingredient is administered.
  • the dose, and perhaps the dose frequency will also vary according to the age, body weight, and response of the individual patient. Suitable dosing regimens can be readily selected by those skilled in the art with due consideration of such factors.
  • the recommended daily dose range for the conditions described herein lie within the range of from about 1 mg to about 1,000 mg per day, given as a single once-a-day dose preferably as divided doses throughout a day.
  • the daily dose is administered twice daily in equally divided doses.
  • a daily dose range may be from about 5 mg to about 500 mg per day, more specifically, between about 10 mg and about 200 mg per day.
  • the daily dose may be administered in 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 50 mg, or 100 mg dosage forms (Q.D. or B.I.D.).
  • the therapy should be initiated at a lower dose, perhaps about 1 mg to about 25 mg, and increased if necessary up to about 200 mg to about 1,000 mg per day as either a single dose or divided doses, depending on the patient's global response.
  • the daily dose is from 0.01 mg/kg to 100 mg/kg.
  • kits which, when used by the medical practitioner, can simplify the administration of appropriate amounts of active ingredients to a patient.
  • a typical kit of the invention comprises a unit dosage form of a compound provided herein, or a pharmaceutically acceptable solid form or prodrug thereof, and a unit dosage form of a second active ingredient.
  • second active ingredients include, but are not limited to, those listed herein.
  • Kits of the invention can further comprise devices that are used to administer the active ingredient(s).
  • devices include, but are not limited to, syringes, drip bags, patches, and inhalers.
  • Kits of the invention can further comprise pharmaceutically acceptable vehicles that can be used to administer one or more active ingredients.
  • the kit can comprise a sealed container of a suitable vehicle in which the active ingredient can be dissolved to form a particulate-free sterile solution that is suitable for parenteral administration.
  • suitable vehicles include, but are not limited to: Water for Injection USP; aqueous vehicles such as, but not limited to, Sodium Chloride Injection, Ringer's Injection, Dextrose Injection, Dextrose and Sodium Chloride Injection, and Lactated Ringer's Injection;
  • water-miscible vehicles such as, but not limited to, ethyl alcohol, polyethylene glycol, and polypropylene glycol
  • non-aqueous vehicles such as, but not limited to, corn oil, cottonseed oil, peanut oil, sesame oil, ethyl oleate, isopropyl myristate, and benzyl benzoate.
  • EXAMPLE 3 SYNTHESIS OF CYCLOPROPANECARBOXYLIC ACID ⁇ 2-[(7 )-l-(3-ETHOXY-4-METHOXY-PHENYL)-2- METHANE-SULFONYL-ETHYL]-3-OXO-2,3-DIHYDRO-l .H-ISOINDOL-4-YLI-AMIDE
  • the suspension was cooled to 0- 5°C over 0.5-1 hour and kept at 0-5°C for another 1.5-2 hours.
  • the solid was collected by filtration under vacuum, washed with heptane (3x300 mL), and dried to a constant weight in a tray at 30-35°C under a vacuum at 100-120 torr.
  • the yield of methyl 2- methyl-6-nitrobenzoate was 292.0 g (91%), based on 300.0 g of 2-methyl-6-nitrobenzoic acid.
  • the product was found to have a purity of >99% measured by HPLC based on area percentage, and a water content of ⁇ 0.1% measured by Karl Fisher titration.
  • the reaction mixture was refluxed for 6.5-8 hours until the amount of unreacted 2-methyl-6-nitrobenzoate was less than 5-10%.
  • the reaction mixture was cooled to 15-18°C and kept at 15-18°C for 50-60 minutes.
  • the solid was filtered, washed with cold (i.e., 5-10°C) methyl acetate (2x100 mL) until there was less than 3% of methyl 2-bromomethyl-6-nitrobenzoate remained in the solid.
  • the pH of the upper aqueous phase was maintained or adjusted at pH 13-14.
  • the phases were separated and the upper aqueous phase was extracted with DCM (2x4.4 L).
  • the pH of the aqueous phase was maintained at 13-14 throughout the extractions.
  • the DCM extracts were combined and washed with deionized water (3.3 L) until the pH of the aqueous phase reached 11 or less.
  • DCM was removed under vacuum below 35°C.
  • the water content of the residual solid should be ⁇ 0.1% w/w as measured by Karl Fisher titration.
  • the residual solid was dried azeotropically with more DCM.
  • the reaction mixture was gradually heated to an internal temperature of 70- 75°C for two hours until there was less than ⁇ 2% of unreacted methyl 2-bromomethyl-6- nitrobenzoate.
  • the reaction mixture was gradually heated to an internal temperature of 95-100°C for 18 hours.
  • the reaction mixture was cooled to 20-25°C and transferred to an 1-L addition funnel. After purified water (1500 mL) was charged into a 5-L 3-necked flask, the reaction mixture in the addition funnel was added into water in the 5-L 3- necked flask at room temperature over 1-2 hours maintaining an internal temperature below 30°C. The reaction mixture was stirred for 2 hours at room temperature.
  • the reaction mixture was refluxed at 81- 83 °C for about two hours until there was less than 2% of unreacted methyl 2- bromomethyl-6-nitrobenzoate.
  • methanol 200 mL was charged over 5-10 minutes.
  • deionized water (1.40 L) was charged over 0.5-1 hour and stirred at 20-25°C for 30 minutes and at 0-5°C for 1-2 hours.
  • the solid was filtered, washed with deionized water (3x300 mL), and dried to ⁇ 10% of water content as measured by Karl Fisher titration.
  • the solid was suspended in methanol (750 mL) and refluxed for 1-1.5 hours. The suspension was cooled to 0-5°C over 1.5-2 hours and kept at 0-5°C for 1-1.5 hours. The solid was filtered, washed with 0-5°C methanol (2x200 mL) and heptane (200 mL), and then dried at 40-45 °C under vacuum to a constant weight.
  • Example 57.5 10% Pd/C (50% wet, 2.4 g, 4 wt%, from Johnson Matthey, London, UK), ethyl acetate (780 mL) was charged into a Parr-vessel at room temperature under nitrogen. After the mixture was purged with nitrogen three times and with hydrogen three times, the reaction mixture was heated to 40°C and then the heat was removed. The reaction mixture was stirred with hydrogen at a pressure between 40-45 psi over 4-6 hours until there was ⁇ 3% of the hydroxylamine intermediate. The reaction mixture was cooled to 20-25°C. The reaction mixture was filtered through a celite bed (1 inch thickness) and then bed-washed with ethyl acetate (120 mL).
  • Example 5.7.6 and tetrahydrofuran (THF, 1.43 L) was charged into a 3L flask at 20- 25°C under nitrogen. The suspension was heated to 60-65°C until dissolution was achieved. The suspension was filtered at 45-50°C and the solid was rinsed with 95 mL of THF prewarmed at 45-55°C. After about 950-1150 mL of THF was distilled off at normal pressure over 30-60 minutes, absolute ethanol (950 mL) was charged at 55-60°C over 5-10 minutes. About 350-400 mL of solvents was removed at normal pressure until the internal temperature rose to 72-74°C.
  • THF tetrahydrofuran
  • the resulting suspension was refluxed at 72- 75°C for 30-60 minutes, cooled to 20-25°C over 1-2 hours and kept at 20-25°C for another 1-2 hours.
  • the solid was collected by filtration under vacuum, washed with absolute ethanol (240-280 mL) and heptane (240-280 mL), and then dried in tray at 50- 55°C in a vacuum at 130-140 torr to a constant weight.
  • the yield of the off-white crystalline product was (88.0-91.0 g, 92-96 %).
  • Compound A was formulated in 500 mg tablets by direct compression.
  • the drug loading is 10%.
  • the data below show the in vitro evaluation of the release profile and water uptake of expandable polymer systems for gastroretentive system and controlled release solid dosage.
  • the swelling ratios of tablet Formulations 1 to 3 was determined by percent weight gain. Water uptake of the tablets was carried out in 500 mL solution at 37 °C with 10 mM NaAc at pH 4.0, using Distek Dissolution System.
  • Compound A was formulated in 500 mg tablets by direct compression.
  • the drug loading is 10%.
  • the data below show the in vitro evaluation of the release profile and water uptake of expandable polymer systems for gastroretentive system and controlled release solid dosage.
  • Formulation 6 500 mg %
  • Formulation 7 500 mg %
  • the swelling ratios of tablet Formulations 4 to 7 was determined by percent weight gain. Water uptake of the tablets was carried out in 500 mL solution at 37 °C with 0.01 N HC1 solution, using Distek Dissolution System.
  • Compound A was formulated in 250 mg tablets by direct compression.
  • the drug loading is 20%.
  • the data below show the in vitro evaluation of the release profile and water uptake of expandable polymer systems for gastroretentive system and controlled release solid dosage.
  • Formulation 8 250 mg %
  • Formulation 9 250 mg %
  • Formulation 10 250 mg %
  • Formulation 11 250 mg %
  • the swelling ratios of tablet Formulations 8 to 11 was determined by percent weight gain. Water uptake of the tablets was carried out in 500 mL solution at 37 °C with 0.01 N HC1 solution, using Distek Dissolution System.
  • compositions of Formulations 12 to 15 are in weight percent.
  • the drug loading is 20%.
  • Bilayer tablets were prepared to achieve pulsatile drug release and/or immediate release followed by controlled release.
  • An immediate release layer with a controlled release layer was been prepared for the bilayer tablets.
  • the bilayer tablet was prepared as follows: load the gastric retentive portion (750mg) into the die and compress manually; load lOOmg the immediate-release layer (Table 1) on top of it; compress using a Carver Press.
  • Bilayer tablets were prepared to combine the gastric retentive function and extended release profile in one dose unit. Formulations 13, 14 and 16 were each used as the extended release layer. The formulation of the gastric retentive layer is provided as follows in Table 2. The bilayer tablet was prepared as follows: load the gastric retentive portion (500 mg) into the die and compress manually; load 250 mg the extended-release layer (e.g., Formulation 13, 14 or 16) on top of it; compress using a Carver Press. Table 2: Formulation of Gastric-Retentive Layer
  • Bi-layer gastric-retentive tablets were prepared as Formulations 94, 95 and 96 (Table 3). The release profiles of the bi-layer tablets are show in Figure 19.
  • the table below present additional Gastric Retentive tablets comprising Compound A and sodium bicarbonate.
  • the GR tablets are manufactured by compression of dry blend mixture. Alternatively, they can be prepared by roller compaction followed by compression. Coating is optional.
  • the compositions of Formulations 97 to 100 are in weight percent. Formulations 97, 98, and 100 have a total weight of 750 mg.
  • Formulation 99 has a total weight of 600 mg.
  • the data shows the effect dosing under fasting and fed (high fat meal) conditions on the pharmacokinetics of Compound A.
  • the analysis suggests that the effect of skipping a meal and/or dosing with a high fat meal on the pharmacokinetics of apremilast is expected to be minimal.
  • Formulation 98 is administered once daily, this convenient formulation will likely result in increased patient compliance and adherence to therapy while equivalent or better efficacy as compared to the instant release formulation.
  • the dosage form starts to float at about 0.5 - 1 hour. It remains as gel form for up to 4 hours. In contrast, the IR formulation disintegrates within 5 minutes.
  • Table 6 Single Dose Pharmacokinetic Data Under Standard Meal
  • Formulation 101 compared to an instant release formulation administered twice daily is provided in Table 7 below. The data indicates that Formulation 101 has similar pharmacokinetics to the Instant Release Formulation.
  • FIG. 29 shows the once daily administration of either Formulation 98 or Formulation 101 results in similar plasma concentration of Compound A as compared to the twice-daily administration of the instant release formulation.
  • Formulation 98 provides a nearly identical plasma concentration of Compound A as the reference twice-daily instant release formulation, while Formulation 101 provides a plasma concentration that is about 77% of that provided by the reference twice-daily instant release formulation, as provided in Table 8 below.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Inorganic Chemistry (AREA)
  • Nutrition Science (AREA)
  • Physiology (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne des formes pharmaceutiques orales à libération contrôlée de médicaments faiblement solubles, des procédés de fabrication des formes pharmaceutiques et leurs procédés d'utilisation pour le traitement de diverses maladies et/ou troubles.
PCT/US2016/061076 2015-11-11 2016-11-09 Formes pharmaceutiques orales à libération contrôlée de médicaments faiblement solubles et leurs utilisations WO2017083348A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
EP16798345.1A EP3373916A1 (fr) 2015-11-11 2016-11-09 Formes pharmaceutiques orales à libération contrôlée de médicaments faiblement solubles et leurs utilisations

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US14/938,714 2015-11-11
US14/938,714 US9532977B2 (en) 2010-12-16 2015-11-11 Controlled release oral dosage forms of poorly soluble drugs and uses thereof

Publications (1)

Publication Number Publication Date
WO2017083348A1 true WO2017083348A1 (fr) 2017-05-18

Family

ID=57349149

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2016/061076 WO2017083348A1 (fr) 2015-11-11 2016-11-09 Formes pharmaceutiques orales à libération contrôlée de médicaments faiblement solubles et leurs utilisations

Country Status (2)

Country Link
EP (1) EP3373916A1 (fr)
WO (1) WO2017083348A1 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN115192524A (zh) * 2021-04-13 2022-10-18 杭州汉菁生物科技有限公司 一种包载链状难溶药物的聚合型胶束及制备方法和应用
EP3976001A4 (fr) * 2019-05-31 2023-04-26 Sanovel Ilac Sanayi Ve Ticaret Anonim Sirketi Formulations de comprimés d'aprémilast

Citations (28)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3536809A (en) 1969-02-17 1970-10-27 Alza Corp Medication method
US3598123A (en) 1969-04-01 1971-08-10 Alza Corp Bandage for administering drugs
US3845770A (en) 1972-06-05 1974-11-05 Alza Corp Osmatic dispensing device for releasing beneficial agent
US3916899A (en) 1973-04-25 1975-11-04 Alza Corp Osmotic dispensing device with maximum and minimum sizes for the passageway
US4008719A (en) 1976-02-02 1977-02-22 Alza Corporation Osmotic system having laminar arrangement for programming delivery of active agent
US4915952A (en) 1987-02-27 1990-04-10 Alza Corporation Composition comprising drug, HPC, HPMC and PEO
US5059595A (en) 1989-03-22 1991-10-22 Bioresearch, S.P.A. Pharmaceutical compositions containing 5-methyltetrahydrofolic acid, 5-formyltetrahydrofolic acid and their pharmaceutically acceptable salts in controlled-release form active in the therapy of organic mental disturbances
US5073543A (en) 1988-07-21 1991-12-17 G. D. Searle & Co. Controlled release formulations of trophic factors in ganglioside-lipsome vehicle
US5120548A (en) 1989-11-07 1992-06-09 Merck & Co., Inc. Swelling modulated polymeric drug delivery device
US5354556A (en) 1984-10-30 1994-10-11 Elan Corporation, Plc Controlled release powder and process for its preparation
US5451409A (en) 1993-11-22 1995-09-19 Rencher; William F. Sustained release matrix system using hydroxyethyl cellulose and hydroxypropyl cellulose polymer blends
US5591767A (en) 1993-01-25 1997-01-07 Pharmetrix Corporation Liquid reservoir transdermal patch for the administration of ketorolac
US5639476A (en) 1992-01-27 1997-06-17 Euro-Celtique, S.A. Controlled release formulations coated with aqueous dispersions of acrylic polymers
WO1997022335A1 (fr) 1995-12-19 1997-06-26 Abbott Laboratories Formulation a liberation controlee pour medicaments basiques peu solubles
US5674533A (en) 1994-07-07 1997-10-07 Recordati, S.A., Chemical And Pharmaceutical Company Pharmaceutical composition for the controlled release of moguisteine in a liquid suspension
US5733566A (en) 1990-05-15 1998-03-31 Alkermes Controlled Therapeutics Inc. Ii Controlled release of antiparasitic agents in animals
US5945125A (en) 1995-02-28 1999-08-31 Temple University Controlled release tablet
US6210710B1 (en) 1997-04-28 2001-04-03 Hercules Incorporated Sustained release polymer blend for pharmaceutical applications
US20030104062A1 (en) 2000-02-04 2003-06-05 Depomed, Inc. Shell-and-core dosage form approaching zero-order drug release
US20030104053A1 (en) 2001-10-25 2003-06-05 Depomed, Inc. Optimal polymer mixtures for gastric retentive tablets
US6635280B2 (en) 1997-06-06 2003-10-21 Depomed, Inc. Extending the duration of drug release within the stomach during the fed mode
EP0941071B1 (fr) 1996-09-19 2004-01-07 Depomed, Inc. Formes galeniques orales retenues dans l'estomac, pour la liberation controlee de medicaments faiblement solubles et de substance insoluble
US6962940B2 (en) 2002-03-20 2005-11-08 Celgene Corporation (+)-2-[1-(3-Ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-4-acetylaminoisoindoline-1,3-dione: methods of using and compositions thereof
US20100129445A1 (en) 2007-06-04 2010-05-27 Lts Lohmann Therapie-Systeme Ag Gastroretentive system comprising an alginate body
US20100168475A1 (en) 2008-09-10 2010-07-01 Saindane Manohar T Processes for the preparation of aminosulfone compounds
WO2012083017A2 (fr) * 2010-12-16 2012-06-21 Celgene Corporation Formes posologiques pour des médicaments médiocrement solubles administrés par voie orale à libération contrôlée et leurs utilisations
US8263128B2 (en) 1997-08-11 2012-09-11 Bend Research, Inc. Solid pharmaceutical dispersions with enhanced bioavailability
US20160128981A1 (en) * 2010-12-16 2016-05-12 Celgene Corporation Controlled release oral dosage forms of poorly soluble drugs and uses thereof

Patent Citations (30)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3536809A (en) 1969-02-17 1970-10-27 Alza Corp Medication method
US3598123A (en) 1969-04-01 1971-08-10 Alza Corp Bandage for administering drugs
US3845770A (en) 1972-06-05 1974-11-05 Alza Corp Osmatic dispensing device for releasing beneficial agent
US3916899A (en) 1973-04-25 1975-11-04 Alza Corp Osmotic dispensing device with maximum and minimum sizes for the passageway
US4008719A (en) 1976-02-02 1977-02-22 Alza Corporation Osmotic system having laminar arrangement for programming delivery of active agent
US5354556A (en) 1984-10-30 1994-10-11 Elan Corporation, Plc Controlled release powder and process for its preparation
US4915952A (en) 1987-02-27 1990-04-10 Alza Corporation Composition comprising drug, HPC, HPMC and PEO
US5073543A (en) 1988-07-21 1991-12-17 G. D. Searle & Co. Controlled release formulations of trophic factors in ganglioside-lipsome vehicle
US5059595A (en) 1989-03-22 1991-10-22 Bioresearch, S.P.A. Pharmaceutical compositions containing 5-methyltetrahydrofolic acid, 5-formyltetrahydrofolic acid and their pharmaceutically acceptable salts in controlled-release form active in the therapy of organic mental disturbances
US5120548A (en) 1989-11-07 1992-06-09 Merck & Co., Inc. Swelling modulated polymeric drug delivery device
US5733566A (en) 1990-05-15 1998-03-31 Alkermes Controlled Therapeutics Inc. Ii Controlled release of antiparasitic agents in animals
US5639476A (en) 1992-01-27 1997-06-17 Euro-Celtique, S.A. Controlled release formulations coated with aqueous dispersions of acrylic polymers
US5591767A (en) 1993-01-25 1997-01-07 Pharmetrix Corporation Liquid reservoir transdermal patch for the administration of ketorolac
US5451409A (en) 1993-11-22 1995-09-19 Rencher; William F. Sustained release matrix system using hydroxyethyl cellulose and hydroxypropyl cellulose polymer blends
US5674533A (en) 1994-07-07 1997-10-07 Recordati, S.A., Chemical And Pharmaceutical Company Pharmaceutical composition for the controlled release of moguisteine in a liquid suspension
US5945125A (en) 1995-02-28 1999-08-31 Temple University Controlled release tablet
WO1997022335A1 (fr) 1995-12-19 1997-06-26 Abbott Laboratories Formulation a liberation controlee pour medicaments basiques peu solubles
EP0941071B1 (fr) 1996-09-19 2004-01-07 Depomed, Inc. Formes galeniques orales retenues dans l'estomac, pour la liberation controlee de medicaments faiblement solubles et de substance insoluble
US6210710B1 (en) 1997-04-28 2001-04-03 Hercules Incorporated Sustained release polymer blend for pharmaceutical applications
US6217903B1 (en) 1997-04-28 2001-04-17 Hercules Incorporated Sustained release polymer blend for pharmaceutical applications
US6635280B2 (en) 1997-06-06 2003-10-21 Depomed, Inc. Extending the duration of drug release within the stomach during the fed mode
US8263128B2 (en) 1997-08-11 2012-09-11 Bend Research, Inc. Solid pharmaceutical dispersions with enhanced bioavailability
US20030104062A1 (en) 2000-02-04 2003-06-05 Depomed, Inc. Shell-and-core dosage form approaching zero-order drug release
US20030104053A1 (en) 2001-10-25 2003-06-05 Depomed, Inc. Optimal polymer mixtures for gastric retentive tablets
US6723340B2 (en) 2001-10-25 2004-04-20 Depomed, Inc. Optimal polymer mixtures for gastric retentive tablets
US6962940B2 (en) 2002-03-20 2005-11-08 Celgene Corporation (+)-2-[1-(3-Ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-4-acetylaminoisoindoline-1,3-dione: methods of using and compositions thereof
US20100129445A1 (en) 2007-06-04 2010-05-27 Lts Lohmann Therapie-Systeme Ag Gastroretentive system comprising an alginate body
US20100168475A1 (en) 2008-09-10 2010-07-01 Saindane Manohar T Processes for the preparation of aminosulfone compounds
WO2012083017A2 (fr) * 2010-12-16 2012-06-21 Celgene Corporation Formes posologiques pour des médicaments médiocrement solubles administrés par voie orale à libération contrôlée et leurs utilisations
US20160128981A1 (en) * 2010-12-16 2016-05-12 Celgene Corporation Controlled release oral dosage forms of poorly soluble drugs and uses thereof

Non-Patent Citations (14)

* Cited by examiner, † Cited by third party
Title
"Remington: The Science and Practice of Pharmacy, 21 st edition,", 2005, LIPPINCOTT, WILLIAMS AND WILKINS
"Remington's Pharmaceutical Sciences, 18th ed.,", 1990, MACK PUBLISHING
"The MerckManual 17th ed.,", vol. 953, 1999
"The United States Pharmacopeia, 23rd ed.,", 1995, pages: 1843 - 1844
ARORA S ET AL: "Floating drug delivery systems: A review", AAPS PHARMSCITECH, SPRINGER NEW YORK LLC, US, vol. 6, no. 3, 19 October 2005 (2005-10-19), pages 31p, XP009073596, ISSN: 1530-9932, DOI: 10.1208/PT060347 *
EUR JPHARM SCI., vol. 19, no. 5, 2003, pages 345 - 53
JENS T. CARSTENSEN: "Drug Stability: Principles & Practice, 18th ed.,", 1995, MARCEL DEKKER, pages: 379 - 80
KHOSRO ADIBKIA ET AL: "Drug release kinetics and physicochemical characteristics of floating drug delivery systems", EXPERT OPINION ON DRUG DELIVERY, vol. 8, no. 7, 10 July 2011 (2011-07-10), GB, pages 891 - 903, XP055341540, ISSN: 1742-5247, DOI: 10.1517/17425247.2011.574124 *
LEE, J., PHARM. SCI., vol. 89, 2000, pages 850
LIST ET AL., J. CLIN. ONCOL., vol. 8, 1990, pages 1424
MAN ET AL., J. MED. CHEM., vol. 52, 2009, pages 1522 - 1524
MANFRED E. WOLFF: "Burger's Medicinal Chemistry and Drug Discovery, 5th ed.", 1995, pages: 172-178, - 982
QI XIAOLE ET AL: "Floating tablets for controlled release of ofloxacin via compression coating of hydroxypropyl cellulose combined with effervescent agent", INTERNATIONAL JOURNAL OF PHARMACEUTICS, vol. 489, no. 1, 5 May 2015 (2015-05-05), pages 210 - 217, XP029183108, ISSN: 0378-5173, DOI: 10.1016/J.IJPHARM.2015.05.007 *
TIERNEY ET AL.,: "Current Medical Diagnosis & Treatment 37th ed.,", 1998, APPLETON & LANGE, pages: 499

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP3976001A4 (fr) * 2019-05-31 2023-04-26 Sanovel Ilac Sanayi Ve Ticaret Anonim Sirketi Formulations de comprimés d'aprémilast
CN115192524A (zh) * 2021-04-13 2022-10-18 杭州汉菁生物科技有限公司 一种包载链状难溶药物的聚合型胶束及制备方法和应用
CN115192524B (zh) * 2021-04-13 2023-08-29 杭州汉菁生物科技有限公司 一种包载链状难溶药物的聚合型胶束及制备方法和应用

Also Published As

Publication number Publication date
EP3373916A1 (fr) 2018-09-19

Similar Documents

Publication Publication Date Title
EP2651400B2 (fr) Formes posologiques pour des médicaments peu solubles administrés par voie orale à libération contrôlée et leurs utilisations
US11040024B2 (en) Methods of using (+)-2-[1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-4-acetylaminoisoindoline-1,3-dione
US9468605B2 (en) Formulations of (+)-2-[1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-4-acetylaminoisoindoline-1,3-dione
US9532977B2 (en) Controlled release oral dosage forms of poorly soluble drugs and uses thereof
ZA200407651B (en) (+)-2-Ä1-(3-ethoxy-4-methoxyphenyl)2-methylsulfonylethylÜ-4-acetylaminoisoindoline-1,3-dione: methods of using and compositions thereof
WO2003080048A1 (fr) (-)-2-[1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-4-acetylaminoisoindoline-1,3-dione: leurs procedes d'utilisation et leurs compositions
WO2017083348A1 (fr) Formes pharmaceutiques orales à libération contrôlée de médicaments faiblement solubles et leurs utilisations
EP2663292B1 (fr) Formes pharmaceutiques orales d'amide d'acide {2-[(1s)-1-(3-éthoxy-4-méthoxy-phényl]-2-méthanesulfonyl-éthyl]-3-oxo-2,3-dihydro-1h-isoindol-4-yl}-cyclopropanecarboxylique
AU2007231843A1 (en) Tooth Whitening Products

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 16798345

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

WWE Wipo information: entry into national phase

Ref document number: 2016798345

Country of ref document: EP