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WO2012106581A1 - Inhibiteur de fxr, agent séquestrant d'acide biliaire en tant que polythérapie pour la réduction du cholestérol - Google Patents

Inhibiteur de fxr, agent séquestrant d'acide biliaire en tant que polythérapie pour la réduction du cholestérol Download PDF

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Publication number
WO2012106581A1
WO2012106581A1 PCT/US2012/023742 US2012023742W WO2012106581A1 WO 2012106581 A1 WO2012106581 A1 WO 2012106581A1 US 2012023742 W US2012023742 W US 2012023742W WO 2012106581 A1 WO2012106581 A1 WO 2012106581A1
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Prior art keywords
fxr
bile acid
antagonist
subject
acid sequestrant
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English (en)
Inventor
Michael Davidson
Godfrey GETZ
Catherine REARDON
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University of Chicago
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University of Chicago
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    • 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

Definitions

  • the present invention relates generally to the field of lipid metabolism. In certain aspects, it concerns methods and compositions for enhancing reverse cholesterol transport, reducing atherosclerosis, and/or lowering cholesterol involving both a Farnesoid X Receptor antagonist and a bile acid sequestrant.
  • a lipid disorder such as high blood cholesterol and triglycerides
  • increases the risk for atherosclerosis and thus for heart disease, stroke, high blood pressure, and other pathological conditions.
  • atherosclerosis is the leading cause of heart disease.
  • Lowering the levels of cholesterol and triglycerides is a way to reduce the risk for cardiovascular diseases and conditions. While a number of drugs are being used for this purpose, more Americans die from cardiovascular diseases than cancer. Therefore, there remains a need for additional therapeutics to lower cholesterol as a way to prevent and/or treat cardiovascular diseases and conditions.
  • Embodiments overcome a major deficiency in the art by providing methods and pharmaceutical compositions related to the treatment of high cholesterol, atherosclerosis and/or cardiovascular diseases.
  • embodiments generally include a method for modulating lipid metabolism comprising administering to a subject an effective amount of a bile acid sequestrant and a FXR antagonist.
  • lipids are modulated by the lowering of their levels.
  • the lipid is cholesterol, such as Low Density Lipoprotein-Cholesterol (LDL-C).
  • the subject is determined to be in need of having lipid levels modulated.
  • a subject is evaluated for the level of lipids.
  • the bile acid sequestrant and/or the FXR antagonist are administered to the subject after the subject has been evaluated for cholesterol levels.
  • the subject has been determined to be at risk for a cardiovascular disease based on the evaluation.
  • the LDL-C levels are determined to be at least 100 mg/dl.
  • bile acid sequestrant refers to a compound that is capable of sequestering bile acids and preventing their reabsorption from the gut, thus disrupting the enterohepatic circulation of bile acids and reducing bile acid levels.
  • FXR antagonist refers to a compound that blocks or dampens agonist- mediated responses of the farnesoid X receptor, or that otherwise inhibits the function of the farnesoid X receptor.
  • FXR inhibitors refers to FXR antagonists and methods for reducing the expression of the farnesoid X receptor. In specific embodiments the FXR antagonist directly inhibits binding to the farnesoid X receptor.
  • FXR inhibitor is useful for increasing reverse cholesterol transport, decreasing LDL-C, and reducing the risk of atherosclerosis in a subject in need thereof.
  • the bile acid sequestrant and the FXR antagonist are formulated into a pharmaceutical composition when administered to a subject in need thereof.
  • the bile acid sequestrant and FXR antagonist are administered to a human, especially a patient having atherosclerosis, cardiovascular disease, or other conditions associated with atherosclerosis or high blood cholesterol.
  • a bile acid sequestrant is administered to a patient in need thereof who is already given a FXR antagonist; or a FXR antagonist is administered to a patient in need thereof who is already given a bile acid sequestrant.
  • a bile acid sequestrant and/or a FXR antagonist are administered to a subject in need thereof intravenously, intradermally, intraarterially, intraperitoneally, intralesionally, intracranially, intraarticularly, intraprostaticaly, intrapleurally, intratracheally, intranasally, intravitreally, intravaginally, intrarectally, topically, intratumorally, intramuscularly, intraperitoneally, subcutaneously, subconjunctival, intravesicularlly, mucosally, intrapericardially, intraumbilically, intraocularally, orally, topically, locally, by inhalation, by injection, by infusion, by continuous infusion, by localized perfusion bathing target cells directly, via a catheter, and/or via a lavage.
  • compositions comprising a bile acid sequestrant and a FXR antagonist.
  • embodiments concern a composition that is a nutritional composition or one that can be ingested.
  • the pharmaceutical composition of a bile acid sequestrant and a FXR antagonist further comprises a pharmaceutically acceptable carrier.
  • the pharmaceutical composition takes the form of solutions, suspensions, tablets, pills, capsules, sustained release formulations or powders and contain about 10% to 95% of active ingredient, preferably about 25% to about 70%.
  • the pharmaceutical composition comprises X amount of bile acid sequestrant and Y amount of FXR antagonist.
  • the bile acid sequestrant is colesevelam, cholestyramine, colestilan, colextran, BTG 511, filicol, DMP 504, GT31-104, SK&F 97426A, soystatin, or colestipol or a combination thereof.
  • the bile acid sequestrant is a natural compound, including but not limited to saponins and chitosan derivatives.
  • natural compound refers to a compound or substance produced by a living, organism found in nature. In some embodiments, the natural compound is isolated or purified.
  • serin in some embodiments, refers to amphipathic glycosides containing one or more hydrophilic glycoside moieties combined with a lipophilic triterpene derivative. It will further be appreciated by those of ordinary skill in the art that other saponins may also be useful in the embodiments described.
  • ileal bile acid transport inhibitors include but are not limited to SC-435, 264W94, 2164U90, or benzothiepines.
  • the FXR antagonist is a natural compound, preferably a guggulipid, a stigmasterol, a tuberatolide, lithocholate, oleanolic acid or a combination thereof.
  • Tuberatolides include but are not limited to tuberatolide A, tuberatolide B, 2'-epi-tuberatolide B, Yezoquinolide, (R)- Sargachromenol, and (S)-Sargachromenol.
  • the FXR antagonist is a synthetic compound.
  • the FXR antagonist is CDRI 80/574, QRX-401, or a substituted-isoxazole derivative.
  • Substituted-isoxazole derivatives include but are not limited to 3- ⁇ 2-Chloro-4-[3-(2,6-dichlorophenyl)-5- naphthalen-2-ylisoxazol-4-ylmethoxy]benzoylamino ⁇ benzoic acid and 3- ⁇ 4-Biphenyl-4-yl-3- (2,6-dichlorophenyl)-isoxazol-4-ylmethoxy]-2-chlorobenzoylamino ⁇ benzoate.
  • methods and/or compositions include an FXR antagonist that is a guggulipid, its active component guggulsterone, or a derivative thereof, in combination with a bile acid sequestrant that is colesevelam.
  • the colsevelam is administered as part of a diet on a regular basis.
  • Guggulipid, its active component guggulsterone, or a derivative thereof may be given before, after, and or concurrently with the colsevelam.
  • Embodiments concerning other FXR antagonists or bile acid sequestrants may also be similarly administered.
  • the FXR inhibitor is a FXR anti-sense and/or a FXR iRNA.
  • methods of inhibiting expression of FXR in a cell include contacting the cell with a complex comprising an FXR anti- sense or FXR iRNA, wherein the iRNA-inducing agent is complementary to at least a portion of the mRNA.
  • the FXR antagonist binds FXR.
  • Embodiments discussed in the context of methods and/or compositions of the invention may be employed with respect to any other method or composition described herein. Thus, an embodiment pertaining to one method or composition may be applied to other methods and compositions of the invention as well.
  • an "effective amount” is used to indicate that the compounds are administered at an amount sufficient to treat a condition in a subject in need thereof.
  • the condition is, but is not limited to, high cholesterol, atherosclerosis, gallstones, or conditions associated therewith.
  • an "effective amount” is an amount that can reduce symptoms of the condition in a majority of subject by at least about 20% when compared to untreated subjects.
  • delivery of an iRNA-inducing agent reduces expression of the target transcript to a level that confers a therapeutic effect.
  • Delivery of an iRNA-inducing agent suitably reduces expression of the target transcript at least about 25%, at least about 50%>, at least about 80%>, at least about 90%>, at least about 95%, at least about 98%>, at least about 99% or 100%, relative to expression of the transcript in an appropriate control cell.
  • the percentage reduction in expression can be calculated by the following equation:
  • iRNA inducing agents include short interfering RNA ("siRNA”), short hairpin RNA (“shRNA”), and iRNA-inducing vectors, each of which is defined below. Selection of appropriate target sequences for iRNA may take into account factors such as synthetic considerations, avoidance of targeting unwanted transcripts, and other considerations, as described by Manoharan (2004), which is incorporated herein by reference in its entirety.
  • a "short, interfering RNA,” or “siRNA,” comprises an RNA duplex that is about 19 to about 27 base pairs in length and optionally further comprises one or two single-stranded overhangs.
  • siRNA can be chemically synthesized, or can be transcribed in vitro from a DNA template, or in vivo from an RNA precursor.
  • An siRNA may be formed from two RNA molecules that hybridize, or may alternatively be generated from a single RNA molecule that includes a self-hybridizing portion. It is generally preferred that free 5' ends of siRNA molecules have phosphate groups, and free 3' ends have hydroxyl groups.
  • the duplex portion of an siRNA may, but typically does not, contain one or more unpaired nucleotides.
  • One strand of an siRNA includes a portion that hybridizes with a target transcript.
  • one strand of the siRNA is precisely complementary with a region of the target transcript, meaning that the siRNA hybridizes to the target transcript without a single mismatch.
  • one or more mismatches between the siRNA and the targeted portion of the target transcript may exist.
  • An siRNA used in accordance with the invention is suitably hybridizable to a target transcript and capable of inducing its degradation.
  • short hairpin RNA refers to an RNA molecule comprising at least two complementary portions hybridized or capable of hybridizing to form a double- stranded (duplex) structure of sufficient length to mediate RNAi (typically about 19-27 base pairs in length), and at least one single-stranded portion, typically between approximately 1 and 10 nucleotides in length, that forms a loop structure.
  • the duplex portion may, but typically does not, contain one or more unpaired nucleotides.
  • shRNAs are precursors of siRNAs and are, in general, similarly capable of inhibiting expression of a target transcript.
  • an RNAi-inducing vector is a vector whose presence within a cell results in transcription of one or more RNAs that self-hybridize or hybridize to each other to form an shRNA or siRNA.
  • the term generally encompasses any construct comprising a polynucleotide operably linked to expression signal(s) so that one or more RNA molecules that hybridize or self-hybridize to form an siRNA or shRNA are transcribed when the vector is present within a cell.
  • the vector provides a template for intracellular synthesis of the RNA-inducing agent or precursors thereof.
  • RNAi-inducing vector is considered to be targeted to a transcript if presence of the vector within a cell results in production of one or more RNAs that hybridize to each other or self-hybridize to form an siRNA or shRNA that is targeted to the transcript, i.e., if presence of the vector within a cell results in production of one or more siRNAs or shRNAs targeted to the transcript.
  • Genetic constructs for the delivery of iRNA molecules are described, for example, in U.S. Pat. No. 6,573,099, which is incorporated herein by reference.
  • a further example of the use of shRNA expression plasmids to reduce gene expression in vivo in rats has been described by Zhang et al. (2003), which is also incorporated herein by reference.
  • the iRNA-inducing agent is suitably stabilized by chemical modification.
  • iRNAs may be crosslinked to increase half-life in the body.
  • a 3' OH terminus of one of the strands of double-stranded siRNA can be modified, or the two strands can be crosslinked and modified at the 3' OH terminus.
  • the siRNA derivative can contain a single crosslink or multiple crosslinks.
  • stability may be enhanced by including nucleotide analogs at one or more free ends in order to reduce digestion, e.g., by exonucleases.
  • deoxynucleotides e.g., pyrimidines such as deoxythymidines
  • siRNA agents for use in accordance with certain embodiments of the invention may comprise one or more moieties that are not nucleotides or nucleotide analogs. Further suitable chemical modifications are described by, e.g., Manoharan (2004), incorporated herein by reference in its entirety.
  • micro RNA may be delivered to cells according to the invention.
  • miRNA refers to single- stranded, non-coding RNA molecules of about 19 to about 27 base pairs which regulate gene expression in a sequence specific manner.
  • FIG. 1 illustrates the effects of colesvelam on reverse cholesterol transport in wild type mice and FXR knockout mice. DETAILED DESCRIPTION OF THE INVENTION
  • FXR Farnesoid X Receptor
  • BSEP bile salt export pump
  • FXR knockout mice FXR ⁇ ⁇
  • the knockout mice had increased plasma triglyceride and HDL-cholesterol levels (Lambert et al, 2003; Yale et al, 2000; Hanniman et al, 2005; Zhang et al, 2006)).
  • Bile acids such as chenodeoxycholic acid, which is a potent FXR agonist, lowers triglycerides in humans; bile acid sequestrants, which reduce hepatic bile acid levels, increase triglyceride levels (Davidson, 2006).
  • the synthetic FXR agonist GW4064 has been shown to lower triglyceride levels in animal models (Zhang et al, 2006). FXR affects lipid metabolism largely by down regulating SREBP-lc gene expression (Claudel et al, 2005; Lee et al, 2006). This is mediated in part through the FXR-mediated induction of a small heterodimer partner (SHP), an atypical member of the nuclear receptor superfamily because it lacks a DNA-binding domain, which can inactivate the liver X receptor-a (LXRa), a positive regulator of the SREBP-lc gene (Watanabe et al, 2004).
  • SHP small heterodimer partner
  • LXRa liver X receptor-a
  • FXR induces apoC-II expression (Kast et al, 2001) and represses apoC-III expression (Claudel et al, 2003), which activate and inhibit lipoprotein lipase respectively. Therefore, induction of the FXR target genes would result in marked reduction in plasma triglycerides by repressing triglyceride synthesis and increasing triglyceride clearance.
  • FXR upregulation appears to have a negative effect HDL metabolism and on reverse cholesterol transport (RCT), the process by which cholesterol in peripheral tissues is effluxed to HDL for transport to the liver.
  • RCT reverse cholesterol transport
  • Activation of FXR results in decreased expression of apoA-I (Claudel et al, 2002), the major apoprotein in HDL, and hepatic lipase (Sirvent et al, 2004), which is involved in the catabolism of HDL.
  • FXR inhibits LXRa activity, at least in part by induction of SHP expression (Watanabe et al, 2004).
  • LXRa inhibition would decrease expression of ABCA-1 (Kalaany and Mangelsdorf, 2006), which is essential for the efflux of free cholesterol into nascent HDL from macrophages (Zannis et al, 2006). Since HDL-C is a primary source of cholesterol for bile acid synthesis, FXR appears to downregulate reverse cholesterol transport by repressing the expression of hepatic SR-BI (Malerod et al, 2005), a receptor that mediates selective uptake of cholesteryl esters from HDL. FXR also downregulates ApoA-I and ABCA-1 which have all been shown to be necessary for RCT (Zhang et al, 2003; Wang et al, 2007; Zhang et al, 2005).
  • Colesevelam a bile acid sequestrant, is likely to decrease FXR activity by reducing bile acid levels in hepatocytes by interrupting enterohepatic recirculation. Downregulation of FXR may potentially lead to increased synthesis of apoA-I, ABCA1 and hepatic lipase, which should significantly increase HDL levels. However, FXR inhibition also increases the expression of SR-BI, phospholipid transfer protein (PLTP), and CETP (probably mediated by reduced inhibition of LXR), which would decrease HDL levels.
  • SR-BI phospholipid transfer protein
  • CETP probably mediated by reduced inhibition of LXR
  • compositions described herein comprise an effective amount of a bile acid sequestrant and/or a FXR antagonist and/or additional agent dissolved or dispersed in a pharmaceutically acceptable carrier.
  • pharmaceutically acceptable refers to molecular entities and compositions that do not produce an adverse, allergic or other untoward reaction when administered to an animal, such as, for example, a human, as appropriate.
  • compositions that contains at least a bile acid sequestrant and/or a FXR antagonist or additional active ingredient will be known to those of skill in the art in light of the present disclosure, as exemplified by Remington's Pharmaceutical Sciences, 18th Ed. Mack Printing Company, 1990, incorporated herein by reference. Moreover, for animal ⁇ e.g., human) administration, it will be understood that preparations should meet sterility, pyrogenicity, general safety and purity standards as required by FDA Office of Biological Standards.
  • pharmaceutically acceptable carrier includes any and all solvents, dispersion media, coatings, surfactants, antioxidants, preservatives ⁇ e.g., antibacterial agents, antifungal agents), isotonic agents, absorption delaying agents, salts, preservatives, drugs, drug stabilizers, gels, binders, excipients, disintegration agents, lubricants, sweetening agents, flavoring agents, dyes, such like materials and combinations thereof, as would be known to one of ordinary skill in the art (see, for example, Remington's Pharmaceutical Sciences, 18th Ed. Mack Printing Company, 1990, pp. 1289-1329, incorporated herein by reference). Except insofar as any conventional carrier is incompatible with the active ingredient, its use in the pharmaceutical compositions is contemplated.
  • Embodiments may comprise different types of carriers depending on whether it is to be administered in solid, liquid or aerosol form, and whether it need to be sterile for such routes of administration as injection.
  • the present invention can be administered intravenously, intradermally, transdermally, intrathecally, intraarterially, intraperitoneally, intranasally, intravaginally, intrarectally, topically, intramuscularly, subcutaneously, mucosally, orally, topically, locally, inhalation ⁇ e.g., aerosol inhalation), injection, infusion, continuous infusion, localized perfusion bathing target cells directly, via a catheter, via a lavage, in cremes, in lipid compositions (e.g., liposomes), or by other method or any combination of the forgoing as would be known to one of ordinary skill in the art (see, for example, Remington's Pharmaceutical Sciences, 18th Ed. Mack Printing Company, 1990, incorporated herein by reference).
  • Compounds may be formulated into a composition in a free base, neutral or salt form.
  • Pharmaceutically acceptable salts include the acid addition salts, e.g., those formed with the free amino groups of a proteinaceous composition, or which are formed with inorganic acids such as for example, hydrochloric or phosphoric acids, or such organic acids as acetic, oxalic, tartaric or mandelic acid. Salts formed with the free carboxyl groups can also be derived from inorganic bases such as for example, sodium, potassium, ammonium, calcium or ferric hydroxides; or such organic bases as isopropylamine, trimethylamine, histidine or procaine.
  • solutions Upon formulation, solutions will be administered in a manner compatible with the dosage formulation and in such amount as is therapeutically effective.
  • the formulations are easily administered in a variety of dosage forms such as formulated for parenteral administrations such as injectable solutions, or aerosols for delivery to the lungs, or formulated for alimentary administrations such as drug release capsules and the like.
  • compositions that are suitable for administration may be provided in a pharmaceutically acceptable carrier with or without an inert diluent.
  • the carrier should be assimilable and includes liquid, semi-solid, i.e., pastes, or solid carriers. Except insofar as any conventional media, agent, diluent or carrier is detrimental to the recipient or to the therapeutic effectiveness of a the composition contained therein, its use in administrable composition for use in practicing the methods of the present invention is appropriate.
  • carriers or diluents include fats, oils, water, saline solutions, lipids, liposomes, resins, binders, fillers and the like, or combinations thereof.
  • composition may also comprise various antioxidants to retard oxidation of one or more component. Additionally, the prevention of the action of microorganisms can be brought about by preservatives such as various antibacterial and antifungal agents, including but not limited to parabens ⁇ e.g., methylparabens, propylparabens), chlorobutanol, phenol, sorbic acid, thimerosal or combinations thereof.
  • preservatives such as various antibacterial and antifungal agents, including but not limited to parabens ⁇ e.g., methylparabens, propylparabens), chlorobutanol, phenol, sorbic acid, thimerosal or combinations thereof.
  • the composition is combined with the carrier in any convenient and practical manner, i.e., by solution, suspension, emulsification, admixture, encapsulation, absorption and the like. Such procedures are routine for those skilled in the art.
  • the composition is combined or mixed thoroughly with a semi-solid or solid carrier.
  • the mixing can be carried out in any convenient manner such as grinding.
  • Stabilizing agents can be also added in the mixing process in order to protect the composition from loss of therapeutic activity, i.e., denaturation in the stomach.
  • stabilizers for use in an the composition include buffers, amino acids such as glycine and lysine, carbohydrates such as dextrose, mannose, galactose, fructose, lactose, sucrose, maltose, sorbitol, mannitol, etc.
  • methods may concern the use of a pharmaceutical lipid vehicle compositions that include a bile acid sequestrant and a FXR antagonist, one or more lipids, and an aqueous solvent.
  • lipid will be defined to include any of a broad range of substances that is characteristically insoluble in water and extractable with an organic solvent. This broad class of compounds is well known to those of skill in the art, and as the term "lipid” is used herein, it is not limited to any particular structure. Examples include compounds which contain long-chain aliphatic hydrocarbons and their derivatives. A lipid may be naturally occurring or synthetic (i.e., designed or produced by man). However, a lipid is usually a biological substance.
  • Biological lipids are well known in the art, and include for example, neutral fats, phospholipids, phosphoglycerides, steroids, terpenes, lysolipids, glycosphingolipids, glycolipids, sulphatides, lipids with ether and ester-linked fatty acids and polymerizable lipids, and combinations thereof.
  • neutral fats phospholipids, phosphoglycerides, steroids, terpenes, lysolipids, glycosphingolipids, glycolipids, sulphatides, lipids with ether and ester-linked fatty acids and polymerizable lipids, and combinations thereof.
  • lipids are also encompassed by the compositions and methods described herein.
  • One of ordinary skill in the art would be familiar with the range of techniques that can be employed for dispersing a composition in a lipid vehicle.
  • the composition comprising a bile acid sequestrant and a FXR antagonist may be dispersed in a solution containing a lipid, dissolved with a lipid, emulsified with a lipid, mixed with a lipid, combined with a lipid, covalently bonded to a lipid, contained as a suspension in a lipid, contained or complexed with a micelle or liposome, or otherwise associated with a lipid or lipid structure by any means known to those of ordinary skill in the art.
  • the dispersion may or may not result in the formation of liposomes.
  • the actual dosage amount of a composition that is administered to an animal patient can be determined by physical and physiological factors such as body weight, severity of condition, the type of disease being treated, previous or concurrent therapeutic interventions, idiopathy of the patient and on the route of administration. Depending upon the dosage and the route of administration, the number of administrations of a preferred dosage and/or an effective amount may vary according to the response of the subject. The practitioner responsible for administration will, in any event, determine the concentration of active ingredient(s) in a composition and appropriate dose(s) for the individual subject.
  • compositions may comprise, for example, at least about 0.1% of an active compound.
  • the an active compound may comprise between about 2% to about 75% of the weight of the unit, or between about 25% to about 60%, for example, about 2%, about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%), about 60%), about 65%, about 70%, about 75%, and any range derivable therein.
  • the amount of active compound(s) in each therapeutically useful composition may be prepared is such a way that a suitable dosage will be obtained in any given unit dose of the compound.
  • a dose may also comprise from about 1 microgram/kg/body weight, about 5 microgram/kg/body weight, about 10 microgram/kg/body weight, about 50 microgram/kg/body weight, about 100 microgram/kg/body weight, about 200 microgram/kg/body weight, about 350 microgram/kg/body weight, about 500 microgram/kg/body weight, about 1 milligram/kg/body weight, about 5 milligram/kg/body weight, about 10 milligram/kg/body weight, about 50 milligram/kg/body weight, about 100 milligram/kg/body weight, about 200 milligram/kg/body weight, about 350 milligram/kg/body weight, about 500 milligram/kg/body weight, to about 1000 mg/kg/body weight or more per administration, and any range derivable therein.
  • a range of about 5 mg/kg/body weight to about 100 mg/kg/body weight, about 5 microgram/kg/body weight to about 500 milligram/kg/body weight, etc. can be administered, based on the numbers described above.
  • one of more agents is administered as part of a diet.
  • a subject is administered or intakes about, at least about, or at most about 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7. 3.8, 3.9, 4.0, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9,
  • the agent is about, at most about, or at least about 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4,
  • one or more agents is a nutritional or dietary supplement. In further embodiments, it is provided in powder, pill, or liquid format.
  • compositions of the present invention are formulated to be administered via an alimentary route.
  • Alimentary routes include all possible routes of administration in which the composition is in direct contact with the alimentary tract.
  • the pharmaceutical compositions disclosed herein may be administered orally, buccally, rectally, or sublingually.
  • these compositions may be formulated with an inert diluent or with an assimilable edible carrier, or they may be enclosed in hard- or soft- shell gelatin capsule, or they may be compressed into tablets, or they may be incorporated directly with the food of the diet.
  • the active compounds may be incorporated with excipients and used in the form of ingestible tablets, buccal tables, troches, capsules, elixirs, suspensions, syrups, wafers, and the like (Mathiowitz et ah, 1997; Hwang et ah, 1998; U.S. Pat. Nos. 5,641,515; 5,580,579 and 5,792, 451, each specifically incorporated herein by reference in its entirety).
  • the tablets, troches, pills, capsules and the like may also contain the following: a binder, such as, for example, gum tragacanth, acacia, cornstarch, gelatin or combinations thereof; an excipient, such as, for example, dicalcium phosphate, mannitol, lactose, starch, magnesium stearate, sodium saccharine, cellulose, magnesium carbonate or combinations thereof; a disintegrating agent, such as, for example, corn starch, potato starch, alginic acid or combinations thereof; a lubricant, such as, for example, magnesium stearate; a sweetening agent, such as, for example, sucrose, lactose, saccharin or combinations thereof; a flavoring agent, such as, for example peppermint, oil of wintergreen, cherry flavoring, orange flavoring, etc.
  • a binder such as, for example, gum tragacanth, acacia, cornstarch, gelatin or combinations thereof
  • an excipient such as, for
  • the dosage unit form When the dosage unit form is a capsule, it may contain, in addition to materials of the above type, a liquid carrier. Various other materials may be present as coatings or to otherwise modify the physical form of the dosage unit. For instance, tablets, pills, or capsules may be coated with shellac, sugar, or both. When the dosage form is a capsule, it may contain, in addition to materials of the above type, carriers such as a liquid carrier. Gelatin capsules, tablets, or pills may be enterically coated. Enteric coatings prevent denaturation of the composition in the stomach or upper bowel where the pH is acidic. See, e.g., U.S. Pat. No. 5,629,001.
  • the basic pH therein dissolves the coating and permits the composition to be released and absorbed by specialized cells, e.g., epithelial enterocytes and Peyer's patch M cells.
  • a syrup of elixir may contain the active compound sucrose as a sweetening agent methyl and propylparabens as preservatives, a dye and flavoring, such as cherry or orange flavor.
  • any material used in preparing any dosage unit form should be pharmaceutically pure and substantially non-toxic in the amounts employed.
  • the active compounds may be incorporated into sustained-release preparation and formulations.
  • compositions of the present invention may alternatively be incorporated with one or more excipients in the form of a mouthwash, dentifrice, buccal tablet, oral spray, or sublingual orally- administered formulation.
  • a mouthwash may be prepared incorporating the active ingredient in the required amount in an appropriate solvent, such as a sodium borate solution (Dobell's Solution).
  • the active ingredient may be incorporated into an oral solution such as one containing sodium borate, glycerin and potassium bicarbonate, or dispersed in a dentifrice, or added in a therapeutically- effective amount to a composition that may include water, binders, abrasives, flavoring agents, foaming agents, and humectants.
  • the compositions may be fashioned into a tablet or solution form that may be placed under the tongue or otherwise dissolved in the mouth.
  • Additional formulations which are suitable for other modes of alimentary administration include suppositories.
  • Suppositories are solid dosage forms of various weights and shapes, usually medicated, for insertion into the rectum. After insertion, suppositories soften, melt or dissolve in the cavity fluids.
  • traditional carriers may include, for example, polyalkylene glycols, triglycerides or combinations thereof.
  • suppositories may be formed from mixtures containing, for example, the active ingredient in the range of about 0.5% to about 10%, and preferably about 1% to about 2%.
  • the composition of the present invention may be administered via a parenteral route.
  • parenteral includes routes that bypass the alimentary tract.
  • the pharmaceutical compositions disclosed herein may be administered for example, but not limited to intravenously, intradermally, intramuscularly, intraarterially, intrathecally, subcutaneous, or intraperitoneally U.S. Pat. Nos. 6,537,514, 6,613,308, 5,466,468, 5,543,158; 5,641,515; and 5,399,363 (each specifically incorporated herein by reference in its entirety).
  • Solutions of the active compounds as free base or pharmacologically acceptable salts may be prepared in water suitably mixed with a surfactant, such as hydroxypropylcellulose.
  • Dispersions may also be prepared in glycerol, liquid polyethylene glycols, and mixtures thereof and in oils. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms.
  • the pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions (U.S. Patent 5,466,468, specifically incorporated herein by reference in its entirety).
  • the carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (i.e., glycerol, propylene glycol, and liquid polyethylene glycol, and the like), suitable mixtures thereof, and/or vegetable oils.
  • a coating such as lecithin
  • surfactants for example
  • the prevention of the action of microorganisms can be brought about by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like.
  • isotonic agents for example, sugars or sodium chloride.
  • Prolonged absorption of the injectable compositions can be brought about by the use in the compositions of agents delaying absorption, for example, aluminum monostearate and gelatin.
  • aqueous solutions for parenteral administration in an aqueous solution
  • the solution should be suitably buffered if necessary and the liquid diluent first rendered isotonic with sufficient saline or glucose.
  • aqueous solutions are especially suitable for intravenous, intramuscular, subcutaneous, and intraperitoneal administration.
  • sterile aqueous media that can be employed will be known to those of skill in the art in light of the present disclosure.
  • one dosage may be dissolved in isotonic NaCl solution and either added hypodermoclysis fluid or injected at the proposed site of infusion, (see for example, "Remington's Pharmaceutical Sciences” 15th Edition, pages 1035- 1038 and 1570-1580).
  • Sterile injectable solutions are prepared by incorporating the active compounds in the required amount in the appropriate solvent with various of the other ingredients enumerated above, as required, followed by filtered sterilization.
  • dispersions are prepared by incorporating the various sterilized active ingredients into a sterile vehicle which contains the basic dispersion medium and the required other ingredients from those enumerated above.
  • the preferred methods of preparation are vacuum-drying and freeze- drying techniques which yield a powder of the active ingredient plus any additional desired ingredient from a previously sterile-filtered solution thereof.
  • a powdered composition is combined with a liquid carrier such as, e.g., water or a saline solution, with or without a stabilizing agent.
  • the active compound i.e. the bile acid sequestrant and/or the FXR antagonist
  • the active compound may be formulated for administration via various miscellaneous routes, for example, topical (i.e., transdermal) administration, mucosal administration (intranasal, vaginal, etc.) and/or inhalation.
  • compositions for topical administration may include the active compound formulated for a medicated application such as an ointment, paste, cream or powder.
  • Ointments include all oleaginous, adsorption, emulsion and water-solubly based compositions for topical application, while creams and lotions are those compositions that include an emulsion base only.
  • Topically administered medications may contain a penetration enhancer to facilitate adsorption of the active ingredients through the skin. Suitable penetration enhancers include glycerin, alcohols, alkyl methyl sulfoxides, pyrrolidones and luarocapram.
  • compositions for topical application include polyethylene glycol, lanolin, cold cream and petrolatum as well as any other suitable absorption, emulsion or water-soluble ointment base.
  • Topical preparations may also include emulsifiers, gelling agents, and antimicrobial preservatives as necessary to preserve the active ingredient and provide for a homogenous mixture.
  • Transdermal administration of the present invention may also comprise the use of a "patch".
  • the patch may supply one or more active substances at a predetermined rate and in a continuous manner over a fixed period of time.
  • the pharmaceutical compositions may be delivered by eye drops, intranasal sprays, inhalation, and/or other aerosol delivery vehicles.
  • aerosol refers to a colloidal system of finely divided solid of liquid particles dispersed in a liquefied or pressurized gas propellant.
  • the typical aerosol of the present invention for inhalation will consist of a suspension of active ingredients in liquid propellant or a mixture of liquid propellant and a suitable solvent.
  • Suitable propellants include hydrocarbons and hydrocarbon ethers.
  • Suitable containers will vary according to the pressure requirements of the propellant.
  • Administration of the aerosol will vary according to subject's age, weight and the severity and response of the symptoms.
  • kits such as therapeutic kits.
  • a kit may comprise one or more pharmaceutical composition as described herein and optionally instructions for their use.
  • Kits may also comprise one or more devices for accomplishing administration of such compositions.
  • a subject kit may comprise a pharmaceutical composition and catheter for accomplishing direct intraarterial injection of the composition into a cancerous tumor.
  • a subject kit may comprise pre-filled ampoules of a protein isoform specific antibody construct, optionally formulated as a pharmaceutical, or lyophilized, for use with a delivery device.
  • Kits may comprise a container with a label. Suitable containers include, for example, bottles, vials, and test tubes.
  • the containers may be formed from a variety of materials such as glass or plastic.
  • the container may hold a composition which includes an antibody that is effective for therapeutic or non-therapeutic applications, such as described above.
  • the label on the container may indicate that the composition is used for a specific therapy or non-therapeutic application, and may also indicate directions for either in vivo or in vitro use, such as those described above.
  • the kit of the invention will typically comprise the container described above and one or more other containers comprising materials desirable from a commercial and user standpoint, including buffers, diluents, filters, needles, syringes, and package inserts with instructions for use.
  • a novel assay was previously developed to assess the effects of various therapeutic approaches on RCT in murine models (Zhang et ah, 2003; Wang et ah, 2007; zhang et al, 2005).
  • This assay involves injecting H-cholesterol-labeled macrophages ⁇ i.e., the murine macrophage cell line J774) intraperitoneally into mice.
  • the radiolabeled cholesterol in the macrophages is effluxed, presumably to nascent HDL particles. Cholesterol efflux from the macrophages is detected by the appearance of the radiolabeled cholesterol in the plasma, liver, and feces.
  • This technique was utilized to show that an LXR agonist increases the rate of RCT from macrophages to feces in vivo.
  • wild type mice and FXR knockout mice were fed with control diet or diet with colesevelam for 2 weeks prior to intraperitoneal injection with J774 cells loaded with acetylated LDL and H-cholesterol.
  • the feces was collected at 48 hours and radioactivity in the feces were determined.
  • the change in radioactivity in the feces reflects an increase in reverse cholesterol transport (RCT).
  • the apoB/CETP transgenic murine model will be used to examine the combined effect of colesevelam and FXR antagonists on macrophage RCT.
  • colesevelam treatment was shown to increase the amount of radioactivity in the feces by 4.5 fold, which is 2.5 times more than in wild type mice.
  • the assay will be repeated in the absence of colesevelam to confirm that co-treatment is necessary for the enhancement of RCT.
  • the treatment groups will be: 1. Control diet with or without colesevelam in FXR-/- mice
  • Guggulipid is a natural product of the gum resin of the tree Commiphora mukul that has been used to lower plasma lipids in humans (Uriza and Moore, 2003) and mice (Urizar et al, 2002). Its active component is guggulsterone and has been shown to be an antagonist of bile acid activation of FXR (Urizar et al, 2002; Wu et al, 2002). However it may also activate other steroid receptors such as mineralcorticoid receptor (Burris et al, 2005).
  • mice will have 5 animals and each group will be studied twice (total number per group is 10).
  • the mice will be switched to the control or drug-containing diets for approximately 2 weeks.
  • the control diet is a powdered cereal based diet (Harlan Teklad 2916).
  • Colesevelam will be mixed into the diet to a final concentration of 2% and guggulsterone at 0.05% (100 mg/kg body weight) (Urizar et al, 2002).
  • the mice will be subjected to the in vivo RCT assay described below.
  • In vivo RCT assay In vivo RCT assay:
  • J774 cells will be grown in RPMI media that is radiolabeled by incubation with 5 ⁇ 3H-cholesterol and loaded with cholesterol by incubation with 50 ⁇ / ⁇ 1 acetylated LDL for 48 hours, followed by a 16 hour equilibration period in DMEM with 0.2% BSA. The cells will be extensively washed and total radioactivity in the cells will be determined by scintillation counting. Between 8-10 x 106 cholesterol-loaded cells in 1 ml will be injected into the peritoneal cavity of the mice. The mice will be housed individually and feces will be collected 48 hours post-injection. Blood (50 ⁇ ) is obtained at 6, 24 and 48 hours after injection.
  • mice All samples will be stored at -20°C until analyzed. At 48 hours, the mice will be perfused transcardially with cold PBS for 2 minutes. The liver will be removed and flash frozen in liquid nitrogen or stored at 4°C in R ALater. The intestine will also also removed, cells will be scraped from the intestinal lumen and stored as described for the liver.
  • the lipids in the feces and liver will be extracted and amount of radioactivity expressed as a % of the initial total radioactivity injected into the mice. Aliquots of the plasma will be counted in a scintillation counter and counts expressed as % total injected radioactivity per ml plasma.
  • Plasma levels of cholesterol and triglycerides will be measured enzymatically using kits from Roche Diagnostics. Since FXR agonists also influence glucose homeostasis, plasma glucose levels are also measured.
  • Total RNA will be isolated from the liver and intestine by the Trizol method. Real time PCR will be used to measure hepatic transcript levels for FXR target genes (CYP7A1, BSEP, SHP, SR-BI) and genes involved in HDL metabolism (ABCA-1, SR-BI). The intestinal transcripts for the bile acid transporters and FGF-15 will be measured.
  • FXR target genes CYP7A1, BSEP, SHP, SR-BI
  • ABCA-1, SR-BI genes involved in HDL metabolism
  • Results will expressed as mean ⁇ SEM. Data is analyzed using Stat View 5.0.1 software by ANOVA analysis. The significance level will be set at p ⁇ 0.05. Expected Results:
  • Colesevelam enhances the removal of cholesterol from lipid laden macrophages in FXR KO mice as well as in conjunction with the FXR antagonists guggulipid and stigmasterol.
  • the cholesterol lowering effect of colesevelam is synergistically enhanced with combination as compared to monotherapy.

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Abstract

Cette invention concerne une composition contenant à la fois un agent séquestrant d'acide biliaire et un antagoniste du récepteur farnesoïde X, et un procédé d'administration de la composition à un sujet pour moduler le métabolisme lipidique, spécifiquement, pour augmenter le transport du cholestérol, pour diminuer le cholestérol à lipoprotéines de faible densité (LDL-C), et/ou pour réduire le risque d'athérosclérose chez le patient. Cette composition peut être utilisée pour traiter un patient atteint d'une maladie cardiovasculaire, d'une athérosclérose et/ou de calculs biliaires.
PCT/US2012/023742 2011-02-03 2012-02-03 Inhibiteur de fxr, agent séquestrant d'acide biliaire en tant que polythérapie pour la réduction du cholestérol Ceased WO2012106581A1 (fr)

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IT202200011705A1 (it) * 2022-06-01 2023-12-01 Prec Bio Therapeutics S R L Derivati del colesterolo e loro usi

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WO2016164413A1 (fr) * 2015-04-07 2016-10-13 Intercept Pharmaceuticals, Inc. Compositions pharmaceutiques pour thérapie combinée
EA036757B1 (ru) * 2015-04-07 2020-12-17 Интерсепт Фармасьютикалз, Инк. Фармацевтические композиции для комбинированной терапии
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