WO2009033078A2 - Compositions et procédés pour maîtriser les taux de cholestérol - Google Patents

Compositions et procédés pour maîtriser les taux de cholestérol Download PDF

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Publication number
WO2009033078A2
WO2009033078A2 PCT/US2008/075471 US2008075471W WO2009033078A2 WO 2009033078 A2 WO2009033078 A2 WO 2009033078A2 US 2008075471 W US2008075471 W US 2008075471W WO 2009033078 A2 WO2009033078 A2 WO 2009033078A2
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WO
WIPO (PCT)
Prior art keywords
niacin
doses
time period
hdl
agonist
Prior art date
Application number
PCT/US2008/075471
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English (en)
Other versions
WO2009033078A3 (fr
Inventor
Raif Tawakol
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Raif Tawakol
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Filing date
Publication date
Priority claimed from US11/899,284 external-priority patent/US20080058292A1/en
Application filed by Raif Tawakol filed Critical Raif Tawakol
Publication of WO2009033078A2 publication Critical patent/WO2009033078A2/fr
Publication of WO2009033078A3 publication Critical patent/WO2009033078A3/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/06—Fungi, e.g. yeasts
    • 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
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • 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
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/167—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction with an outer layer or coating comprising drug; with chemically bound drugs or non-active substances on their surface
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism

Definitions

  • This invention relates to a method for increasing HDL and HDL-2 levels in patients, and, more particularly, to such a method including the administration of niacin.
  • the present invention describes a method for the treatment of diabetes, insulin resistance, metabolic syndrome, hyperlipidemia, dyslipidemia, cardiovascular disease, atherosclerosis, and hypercholesterolemia.
  • an adipocyte G-protein antagonist a peroxisome proliferator- activated receptor- ⁇ PPAR- ⁇ ) agonist
  • PPAR-7 peroxisome proliferator-activated receptor-7 agonist
  • niacin may moderately increase HDL levels in a subject with early on-set diabetes
  • the fact that niacin increases blood sugar levels prevents the clinical application of niacin to the early on-set diabetic patient population.
  • niacin may be combined with a PPAR- ⁇ agonist and a PPAR- ⁇ agonist to decrease blood sugar levels in a subject with early on-set diabetes while effectively increasing HDL and/or HDL-2b levels.
  • the combination of a niacin, a PPAR- ⁇ agonist, and a PPAR- ⁇ agonist provide a diabetes corrective effect.
  • the HDL-2b increasing effect may be greater than 50%, 75%, 100%. 125%, 150%, 175%, 200%, 225%, 250%, 275%, 300%, 325%, 350%, 375%, 400%, 425%, 450%, 475%, or 500%. Exemplary ranges of HDL-2b increasing effects include from 50% to 600%, 100% to 500%, and 200% to 400%.
  • Adipocyte G-protein antagonists are compounds that inhibit cyclic adenosine monophosphate (cAMP) accumulation in adipose tissue through a
  • adipocyte G-protein antagonists may include decreased production of VLDL (Mahley et al., Williams Textbook of Endocrinology 9 th Edition, Chapter 23, p. 1143), which may be due, at least in part, to a transient inhibitory effect of niacin on lipolysis, a decreased delivery of free fatty acids to the liver, and a decrease in triglyceride synthesis and VLDL- triglyceride transport.
  • Enhanced clearance of VLDL also may occur, possibly owing to enhanced activity of the lipoprotein lipase.
  • the decrease in LDL levels could be due to decreased VLDL production and enhanced hepatic clearance of
  • LDL particle size from the more atherogenic small dense to normal dense LDL, increasing HDL cholesterol, decreasing ApoC-lll levels, increasing ApoC-ll levels, and increasing ApoA-l levels. Additional characteristics and methods of assessing those characteristics are well known in the art, and are discussed in more detail in Torra et al., Curr Opin Lipidol 12: 245-254 (2001), and Henson,
  • the present invention provides a pharmaceutical composition including an adipocyte G-protein antagonist and a non-steroidal anti-inflammatory drug (NSAID) in a single layer of a controlled release solid unit dosage form.
  • the controlled release solid unit dosage may co- release the NSAID and adipocyte G-protein antagonist over a period from 4 to 12 hours.
  • the controlled release solid unit dosage form is an intermediate release solid unit dosage form (e.g. release from about less than about 12 hours and more than 4 hours, or, in some embodiments from about 5 to 9 hours).
  • the controlled release solid unit dosage form may co-release the NSAID and adipocyte G-protein antagonist over a period of about 4, 5, 6, 7, 8, 9, 10, or 11 hours.
  • the composition includes an intermediate release excipient (e.g. Methocel®, with other useful intermediate release excipients discussed in detail below in the section entitled "Pharmaceutical
  • NSAIDs may be selected from: steroidal anti-inflammatory drugs including hydrocortisone and the tike; antihistamine drugs (e.g., chlorpheniramine, triprolidine); antitussive drugs (e.g., dextromethorphan, codeine, carmiphen and carbetapentane); antipruritic drugs (e.g., methidilizine and trimeprizine); anticholinergic drugs (e.g., scopolamine, atropine, homatropine, levodopa); anti-emetic and antinauseant drugs (e.g., cyclizine, meclizine, chlorpromazine, buclizine); anorexic drugs (e.g., benzphetamine, phentermine, chlorphentermine, fenfluramine); central stimulant drugs (e.g., amphetamine, methamphetamine, dextroamphetamine and methylphenidate); antiarrhythmic
  • acetylsalicylic acid includes buffered aspirin, enteric coated aspirin, aspirin salts such as calcium acetylsalicylate, and mixtures of aspirin with acid acceptors.
  • FFA free fatty acid
  • Methods of assaying for HDL and/orHDL-2b levels are well known in the art. Typically, venous blood is drawn in the morning after an overnight fast.
  • Plasma apoA-l and B concentrations may be analyzed by competitive radioimmunoassay (Pharmacia Diagnostics AB).
  • HDL GGE subclasses may be analyzed by a modification of the technique described by Blanche et al., Biochim Biophys Acta. 665:408-419 (1981). In short, HDL is separated as a plasma fraction within the densities of 1.070 and 1.21 kg/L and subject to electrophoresis on polyacrylamide gradient gels (PAA 4/30, Pharmacia). The proteins are stained with amido black and scanned at wavelength 570 nm. The absorption of the gel itself is subtracted from the curves of the HDL samples. The relative areas under the curve may be assessed. The absolute concentration in milligrams of protein per milliliter for each subclass may be derived by multiplying the relative estimates for the HDL GGE subclasses by the total protein concentration of the isolated HDL fraction.
  • the serum sample is combined with a Direct HDL buffer so that lipoproteins other than HDL are selectively removed via a reaction with cholesterol esterase and cholesterol oxidase.
  • Catalase is added to the buffer to remove the hydrogen peroxide by product without the formation of color.
  • Catalase is inhibited with the addition of Direct HDL Activator and the remaining HDL cholesterol is specifically reacted with cholesterol esterase and cholesterol oxidase.
  • the peroxide end product reacts with a 4- aminoantipyrine and N-(2-hydroxy-3-sulfopropyl)-3,5-dimethoxyaniiine to form a colored quinine dye, which is measured spectrophotometrically at 578 nm.
  • the procedures may be performed using Direct HDL Reagent products from Elan Pharmaceuticals in conjunction with an ATAC® 8000 Random Access Chemistry System, with an ATAC® 8000 Random Access Chemistry System.
  • compositions of the present invention may be also be administered as pharmaceutical compositions that include an intravenous (bolus or infusion), intraperitoneal, subcutaneous, and/or intramuscular dosage form.
  • compositions may be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles, and multilamellar vesicles.
  • Liposomes can be formed from a variety of phospholipids, such as cholesterol, stearylamine, or phosphatidylcholines.
  • the controlled release excipient is an intermediate release excipient.
  • An intermediate release excipient is a controlled release excipient (discussed above) that is provided in sufficient amounts to allow administration of active ingredients over a period of less than about 12 hours and more than about 4 hours. In an exemplary embodiment, the period is from about 5 to 9 hours. In some embodiments, the administration of active ingredients is from about 5 to 8 hours or from about 6 to 8 hours. In another exemplary embodiment, the administration of active ingredients is approximately 7 hours.
  • Tablets may include in admixture, about 5-30% high viscosity hydroxypropyl methyl cellulose, about 2-15% of a water-soluble pharmaceutical binder, about 2-20% of a hydrophobic component such as a waxy material, e.g., a fatty acid, etc.
  • a hydrophobic component such as a waxy material, e.g., a fatty acid, etc.
  • the dosage of niacin administered in the intermediate release solid unit form, the methods for increasing HDL levels or HDL-2b levels in a subject, and the methods for reducing flushing is from about 20 to 2000 mg.
  • the amount of niacin is from about 50 to 2000 mg.
  • the amount of niacin is from about 50 to 1000 mg.
  • the amount of niacin is from about 50 to 500 mg.
  • the amount of niacin is from about 50 to 400 mg.
  • the amount of niacin is from about 50 to 375 mg.
  • a starter pack that includes dosages of aspirin and niacin useful in increasing niacin dosage administration to a patient while minimizing flushing and/or liver damage.
  • Exemplary dosages include: about 62.5 mg niacin and about 81 mg of aspirin; about 125 mg of niacin and about 161 mg of aspirin; about 250 mg of niacin and about 161 mg of aspirin; about 375 mg of niacin and about 200 mg of aspirin, about 500 mg of niacin and about 250 mg of aspirin, about 500 mg of niacin and about 325 mg of aspirin, about 750 mg niacin and about 375 mg of aspirin, and about 750 mg of niacin and about 350 mg of aspirin.
  • Maintenance dosages may subsequently be administered including up to about 750 mg of niacin and about 161 mg of aspirin not to exceed about 1125 mg of niacin in a day.
  • the composition further includes an NSAID.
  • NSAID aspirin
  • Exemplary dosage levels for the NSAID aspirin are discussed above in the context of intermediate release solid unit forms that include niacin and an NSAID and are equally applicable here.
  • the dosage levels discussed above in the context of niacin levels in the intermediate release solid unit forms are equally applicable here for the first amount of an adipocyte G-protein antagonist where the adipocyte G-protein antagonist is niacin.
  • dosages of other adipocyte G-protein antagonists may be determined.
  • the dosage of rosiglitazone is from about 1 to 20 mg. In another exemplary embodiment, the dosage of rosiglitazone is from about 1-10 mg. In another exemplary embodiment, the dosage of rosiglitazone is from about 1 to 8 mg. In another exemplary embodiment, the dosage of rosiglitazone is from 2 to 8 mg. In another exemplary embodiment, the dosage of rosiglitazone selected from about 2 mg, 4 mg, and 8 mg.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Epidemiology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Natural Medicines & Medicinal Plants (AREA)
  • Mycology (AREA)
  • Obesity (AREA)
  • Alternative & Traditional Medicine (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Hematology (AREA)
  • Diabetes (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Biotechnology (AREA)
  • Botany (AREA)
  • Medical Informatics (AREA)
  • Microbiology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

La présente invention concerne un procédé pour réduire les bouffées congestives chez un patient et pour augmenter les taux de HDL et/ou HDL-2b chez un patient, par administration de compositions au patient uniquement deux fois par jour, de 30 à 60 minutes après le déjeuner et de 30 à 60 minutes après le dîner. Dans certains modes de réalisation, les compositions comprennent un antagoniste de protéine G d'adipocyte, un agoniste de PPAR-α et un agoniste de PPAR-γ avec des quantités efficaces pour conférer un effet thérapeutique synergique augmentant le HDL et/ou un effet thérapeutique synergique augmentant le HDL-2b.
PCT/US2008/075471 2007-09-05 2008-09-05 Compositions et procédés pour maîtriser les taux de cholestérol WO2009033078A2 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US11/899,284 2007-09-05
US11/899,284 US20080058292A1 (en) 2003-10-29 2007-09-05 Method for increasing HDL and HDL-2b levels
US96779707P 2007-09-07 2007-09-07
US60/967,797 2007-09-07

Publications (2)

Publication Number Publication Date
WO2009033078A2 true WO2009033078A2 (fr) 2009-03-12
WO2009033078A3 WO2009033078A3 (fr) 2009-08-20

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PCT/US2008/075465 WO2009033072A1 (fr) 2007-09-05 2008-09-05 Compositions et procédés pour maîtriser les taux de cholestérol

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014011926A1 (fr) 2012-07-11 2014-01-16 Elcelyx Therapeutics, Inc. Compositions comportant des statines, des biguanides et d'autres agents pour réduire un risque cardiométabolique

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP3622948A1 (fr) 2018-09-11 2020-03-18 I.P.S. International Products & Services S.r.l. Formulations multicouches à double débit de libération d'un ou plusieurs principes actifs

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6469035B1 (en) * 1997-07-31 2002-10-22 Eugenio A. Cefali Methods of pretreating hyperlipidemic individuals with a flush inhibiting agent prior to the start of single daily dose nicotinic acid therapy to reduce flushing provoked by nicotinic acid
US20040097593A1 (en) * 1999-11-08 2004-05-20 Partha Neogi Compounds for treatment of inflammation, diabetes and related disorders
US20050148556A1 (en) * 2003-10-29 2005-07-07 Raif Tawakol Compositions and methods for increasing HDL and HDL-2b levels

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20070087048A1 (en) * 2001-05-31 2007-04-19 Abrams Andrew L Oral dosage combination pharmaceutical packaging
ATE428411T1 (de) * 2003-11-07 2009-05-15 Jj Pharma Inc Hdl-verstärkende kombinationstherapie-komplexe
US20050267091A1 (en) * 2004-05-25 2005-12-01 Roger Berlin Compositions containing policosanol and niacin and/or niacin derivatives and their pharmaceutical uses

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6469035B1 (en) * 1997-07-31 2002-10-22 Eugenio A. Cefali Methods of pretreating hyperlipidemic individuals with a flush inhibiting agent prior to the start of single daily dose nicotinic acid therapy to reduce flushing provoked by nicotinic acid
US20040097593A1 (en) * 1999-11-08 2004-05-20 Partha Neogi Compounds for treatment of inflammation, diabetes and related disorders
US20050148556A1 (en) * 2003-10-29 2005-07-07 Raif Tawakol Compositions and methods for increasing HDL and HDL-2b levels

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014011926A1 (fr) 2012-07-11 2014-01-16 Elcelyx Therapeutics, Inc. Compositions comportant des statines, des biguanides et d'autres agents pour réduire un risque cardiométabolique

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WO2009033072A1 (fr) 2009-03-12
WO2009033078A3 (fr) 2009-08-20

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