WO2006039268A2 - Formulations pharmaceutiques renfermant des molecules tpgs de vitamine e solubilisant des medicaments lipophiles sans inhibition importante de l'ecoulement et utilisation de telles formulations - Google Patents

Formulations pharmaceutiques renfermant des molecules tpgs de vitamine e solubilisant des medicaments lipophiles sans inhibition importante de l'ecoulement et utilisation de telles formulations Download PDF

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WO2006039268A2
WO2006039268A2 PCT/US2005/034587 US2005034587W WO2006039268A2 WO 2006039268 A2 WO2006039268 A2 WO 2006039268A2 US 2005034587 W US2005034587 W US 2005034587W WO 2006039268 A2 WO2006039268 A2 WO 2006039268A2
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Prior art keywords
tpgs
efflux
molecular weight
composition
compounds
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PCT/US2005/034587
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English (en)
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WO2006039268A3 (fr
Inventor
John Anthony Hyatt
George Chester Zima
Kevin Joseph Edgar
Lisa Tonner Navarro
Claus-Michael Lehr
Eva-Maria Collnot
Andy Hugh Singleton
Christiane Baldes
Ulrich Friedrich Schafer
Michael Fitzpatrick Wempe
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Eastman Chemical Company
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Priority to EP05803721A priority Critical patent/EP1793806A2/fr
Priority to JP2007534708A priority patent/JP2008514714A/ja
Publication of WO2006039268A2 publication Critical patent/WO2006039268A2/fr
Publication of WO2006039268A3 publication Critical patent/WO2006039268A3/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—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
    • 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
    • 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
    • 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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • 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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • 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
    • A61P3/02—Nutrients, e.g. vitamins, minerals

Definitions

  • the invention relates to increasing the bioavailability of lipophilic drugs, and more specifically, to solubilizing lipophilic drugs using bioenhancers that achieve a desired degree of efflux inhibition.
  • Water-soluble vitamin E-active polyethylene glycol esters of tocopheryl acid such as succinates were developed to provide water-soluble molecules having high vitamin E ' activity via either oral or parenteral administration.
  • TPGS polyethylene glycol acid succinate of ⁇ -tocopherol
  • TPGS d- ⁇ -tocopheryl polyethylene glycol succinate
  • U.S. Pat. No. 2,680,749 discloses TPGS molecules in which the polyethylene glycols have average molecular weights of 400, 1000, and those varying between
  • TPGS molecules in which the polyethylene glycol chains have an average molecular weight (MW) of about 1000 are currently used in oral pharmaceutical applications to enhance the bioavailability of various drugs. Due to the amphiphi ⁇ c nature of TPGS 1000, incorporating TPGS 1000 into pharmaceutical formulations enhances oral bioavailability by solubilizing some hydrophobic drugs. TPGS 1000 is also believed to influence one or more transporter proteins, one example of which is P-glycoprotein (P-gp), an enzyme that acts as a cellular efflux pump. Therefore, TPGS 1000 may contribute to oral bioavailability enhancement by influencing efflux of some drugs.
  • P-gp P-glycoprotein
  • efflux inhibition results in increased oral bioavailability of certain drugs, it is also desirable in some circumstances to avoid efflux inhibition or to control the degree to which efflux inhibition occurs.
  • administration of an efflux inhibitor in a pharmaceutical formulation may result in the need for additional testing to determine whether the efflux inhibitor has an impact on the oral bioavailability (absorption, metabolism, distribution, or clearance) of other coadministered drugs or dietary substances.
  • Controlling the degree of efflux inhibition can also be desirable where a number of substances subject to efflux need to be considered. It would be an advance in the art to provide pharmaceutical formulations that contain a solubility-enhancing TPGS molecule to enhance the bioavailability of lipophilic drugs, while avoiding efflux inhibition altogether or achieving a desired level of efflux inhibition.
  • One aspect of the invention is based on the unexpected discovery that the efflux inhibition effect of TPGS varies with the molecular weight of the polyethylene glycol (PEG) portion of the molecule.
  • PEG polyethylene glycol
  • TPGS molecules having a PEG molecular weight of no more than about 600 exhibit a significant solubilizing effect when coadministered with lipophilic drugs, without exhibiting significant efflux inhibition.
  • TPGS molecules having a PEG molecular weight of at least about 3400 exhibit a significant solubilizing effect when coadministered with lipophilic drugs, without exhibiting significant efflux inhibition. Properties that provide useful solubiiizing agents without efflux inhibition characteristics will allow formulators a choice to simultaneously obtain solubilizing effects with efflux inhibition of a desired degree, or a product having solubilizing effects but lacking substantial efflux inhibition.
  • the numerical value in the TPGS designation refers to the molecular weight of the PEG from which it was made.
  • TPGS 1000 contains a PEG side chain with an average molecular weight of 1000. This, can be converted to the number of ethylene glycol monomers in the chain by subtracting 18 amu and dividing by 44.
  • a PEG MW of 1000 average molecular weight is the product of condensation of approximately 22.3 ethylene glycol monomers, meaning that "n" is -22.
  • Fig. 2 depicts the dependence of the inhibitory effect on the length of the
  • Fig. 3 depicts the dependence of permeability coefficient (in both the basoiateral to apical and apical to basolateral directions) of Caco-2 monolayers to Rhodamine 123 in the presence of Vitamin E TPGS upon the molecular weight of the PEG portion of Vitamin E TPGS.
  • Rho 123 on the x-axis refers to Rhodamine 123 alone as a negative control.
  • the x-axis indicates the molecular weight of the PEG.
  • “3400” is actually data for PEG MW 3350, that has been rounded up for purposes of the figure.
  • Y-axis indicates the permeability coefficient in each direction.
  • Fig. 4 depicts the Caco-2 monolayer permeability (apical to basoiateral direction only) of Rhodamine 123 in the presence of Vitamin E TPGS in which the PEG Chain has varying molecular weights.
  • Rho 123 on the x- axis refers to Rhodamine 123 alone as a negative control.
  • the x-axis indicates the molecular weight of the PEG.
  • "3400" is actually data for PEG MW 3350, that has been rounded up for purposes of the figure.
  • lipophilic compounds shall mean compounds having solubility in water that is in the "sparingly soluble” range, or lower. (Persons of ordinary skill in the art will understand that, for compounds that are “sparingly soluble in water,” the quantity of water needed to dissolve one gram of the compound will be in the range beginning at about 30 mL and ending at about 100 mL Compounds having solubility lower than "sparingly soluble” in water will require greater volumes of water to dissolve the compounds).
  • TPGS TPGS compound
  • TPGS analog shall refer to any compound depicted by Figure 1. ' ⁇
  • the terms "effectively solubilizing" a compound or having a “solubilizing effect” on such compound shall mean having the effect of increasing the solubility in water of the compound at least about two-fold (i.e., reducing by at least about half the amount of water required to dissolve one gram of the compound).
  • the term "compound for pharmaceutical use” refers to any substance which, when administered to a human or animal under conditions effective to cause absorption to the bloodstream, or into target cells, tissues, or organs, causes a therapeutic or prophylactic effect.
  • pharmaceuticals include, but are not limited to, anesthetics, hypnotics, sedatives and sleep inducers, antipsychotics, antidepressants, antiallergics, antianginals, antiarthritics, antiasthmatics, antidiabetics, antidiarrheal drugs, anticonvulsants, antigout drugs, antihistamines, antipruritics, emetics, antiemetics, antispasmondics, appetite suppressants, neuroactive substances, neurotransmitter agonists, antagonists, receptor blockers and reuptake modulators, beta-adrenergic blockers, calcium channel blockers, disulfarim and disulfarim-Iike drugs, muscle relaxants, analgesics, anti
  • lipophilic compound for pharmaceutical use refers to a lipophilic compound that is also a compound for pharmaceutical use.
  • lipophilic compounds for pharmaceutical use include, but are not limited to, itraconazole, astemizole, saquinavir, amprenavir, paciitaxel, docetaxel, doxorubicin, ibuprofen, posaconazole, tacrolimus, danazol, estrogen, lopinavir, tamoxifen, nevirapine, efavirenz, delaviridine, nelfinavir, raloxifene, erythromycin, carbamazepine, ketoconazole, indinavir, progesterone, ritonavir, etc.
  • the term "pharmaceutically effective amount of a lipophilic compound for pharmaceutical use” shall mean an amount of that compound that exhibits the intended pharmaceutical, prophylactic or therapeutic effect when administered.
  • the term "increasing bioavailability" or “increased bioavailability” of one or more compound(s) administered shall mean, in reference to the effect of administering a TPGS analog, that the TPGS analog results in an increase in the portion of the. dose of the compound(s) administered that reaches one or more targeted systemic fluids, organs, tissues or cells as compared to administration without the TPGS analog.
  • Increased bioavailability can include any mechanism that that has a desired effect on cellular efflux, cellular influx, or clearance.
  • “Clearance” includes any type of elimination of one or more compounds from cells, blood, plasma, tissues or organs (e.g.
  • intestinal clearance hepatic clearance
  • renal clearance and pulmonary clearance each describe elimination of compounds from the blood). Clearance may be described via the observed differences of renal excretion and elimination by all other processes including influx and efflux mechanisms (e.g. gastrointestinal clearance, excretory clearance, biliary clearance and enterohepatic cycling, metabolic clearance).
  • systemic fluids include, but are not limited to: blood; cerebrospinal fluid; lymph; and any other tissue fluids (including increased amounts in tissues that are bathed by such fluids, such as the brain, tissue of one or more visceral organs, connective tissue, muscle, fat, or one or more tissues in the skin).
  • the increase is systemic, as in the case of an increase measurable anywhere in the blood.
  • the increase is more localized, as is the case with some embodiments involving topical administration in which the increase is measured only in areas near the administration.
  • An increase in portion of the dosage that reaches a fluid or tissue measurable by any reliable means is within this definition, including but not limited to increases identified by measuring the total systemic drug concentration over time after administration.
  • concentrations are determined by measuring the tissue or fluids themselves, or by measuring fractions thereof (for example, without limitation, serum or plasma in the case of blood).
  • increases for compounds that are excreted metabolized and/or un-metabolized in . urine are determined by measuring levels of compounds or metabolites of the compounds in urine and will reflect an increase in systemic concentrations.
  • an increase in compound bioavailability is defined as an increase in the Area Under the Curve (AUC).
  • AUC is an integrated measure of systemic compound concentrations over time in units of mass-time/volume and is measured from the time compound is administered (time zero) to infinity (when no compound(s) remaining in the body can be measured).
  • Information regarding monitoring substances are known to persons of ordinary skill in the art and may be found in references such as M. Rowland and T. N. Tozer, Clinical Pharmacokinetics Concepts and Applications (third Ed., 1995), Lippincott Willams and Wilkins, Philadelphia. •
  • P app refers to apparent permeability coefficient as defined in the Inhibition Protocol set forth herein.
  • P a ppBA refers to the permeability coefficient in the basolateral to apical direction determined using the Inhibition Protocol set forth herein.
  • P app AB refers to the permeability coefficient in the apical to basolateral direction determined using the Inhibition Protocol set forth herein.
  • the terms "compound for use as an efflux inhibitor” shall mean a compound that reduces P app BA to no more than about 50% of the P app BA observed in the absence of the compound as determined using the Inhibition Protocol set forth in this application.
  • a “compound not for use as an efflux inhibitor” shall mean a compound that does not reduce P app BA or that reduces P app BA to an amount greater than 50% of P app BA observed in the absence of the compound, as determined using the Inhibition Protocol.
  • the compound is a compound that reduces the efflux of drugs and other substances out of a cell, into the gut, or organ (brain, liver, kidney, etc.) due to any mechanism, including, but not limited to the action of enzymes or transporter proteins such as P-glycoprotein (P-gp), Breast Cancer Resistance Protein (BCRP), multi-drug resistant-associated proteins (MRP's), cytochrome P450's, UDP- glucuronosyltransferases and. sulfotransferases, etc., as demonstrated using the Inhibition Protocol set forth herein.
  • the compound is one that causes increased bioavailability as defined above.
  • molecular weight shall refer, in connection with a single molecule, to the molecular weight of that molecule. With respect to a polydisperse preparation containing polymer molecules of differing molecular weights, molecular weight shall refer to weight-average molecular weight (M w ).
  • M w weight-average molecular weight
  • the invention includes TPGS and compositions comprising TPGS.
  • the TPGS contains a PEG that has a selected molecular weight or is within a selected range of molecular weights. The molecular weight is selected to provide a TPGS having a desired degree of efflux inhibition, or lack thereof.
  • the polyethylene glycol molecular weight is less than or equal to about 900. In some embodiments, the polyethylene glycol molecular weight is less than or equal to about 800. In some embodiments, the polyethylene glycol molecular weight is less than or equal to about 700. In some embodiments, the polyethylene glycol molecular weight is less than or equal to about 600. In some embodiments, the polyethylene glycol molecular weight is less than or equal to about 500.
  • the polyethylene glycol molecular weight is less than or equal to about 400. In some embodiments, the polyethylene glycol molecular weight is less than or equal to about 300. In some embodiments, the polyethylene glycol molecular weight is less than or equal to about 200. In some embodiments, the polyethylene glycol molecular weight is greater than or equal to about
  • the polyethylene glycol molecular weight is greater than or equal to about 1600. In some embodiments, the polyethylene glycol molecular weight is greater than or equal to about 1700. In some embodiments, the polyethylene glycol molecular weight is greater than or equal to about 1800. In some embodiments, the polyethylene glycol molecular weight is greater than or equal to about 1900. In some embodiments, the polyethylene glycol molecular weight is less than or equal to about -2000. In some embodiments, the polyethylene glycol molecular weight is greater than or equal to about 2100. In some embodiments, the polyethylene glycol molecular weight is greater than or equal to about 2200. In some embodiments, the polyethylene glycol molecular weight is greater than or equal to about 2300.
  • the polyethylene glycol molecular weight is greater than or equal to about 2400. In some embodiments, the polyethylene glycol molecular weight is greater than or equal to about 2500. In some embodiments, the polyethylene glycol molecular weight is greater than or equal to about 2600. In some embodiments, the polyethylene glycol molecular weight is less than or equal to about 3000. in some embodiments the polyethylene glycol molecular weight is greater than or equal to 3350: In some embodiments, the polyethylene glycol molecular weight is greater than or equal to about 3500. In some embodiments, the polyethylene glycol molecular weight is less than or equal to about 4000. In some embodiments, the polyethylene glycol molecular weight is greater than or equal to about 4500.
  • the polyethylene glycol molecular weight is less than or equal to about 5000. in some embodiments, the polyethylene glycol molecular weight is greater than or equal to about 5500. In some embodiments, the polyethylene glycol molecular weight is less than or equal to about 6000. In some embodiments, the polyethylene glycol molecular weight is less than or equal to about 7000. In some embodiments, the polyethylene glycol molecular weight is less than or equal to about 8000. In some embodiments, the polyethylene glycol molecular weight is less than or equal to about 9000. In some embodiments, the polyethylene glycol molecular weight is less than or equal to about 10000. in some embodiments, the polyethylene glycol molecular weight is less than or equal to about 11000.
  • the polyethylene glycol molecular weight is less ⁇ than or equal to about 12000. In some embodiments, the polyethylene glycol molecular weight is less than or equal to about 13000. In some embodiments, the polyethylene glycol molecular weight is less than or equal to about 14000. In some embodiments, the polyethylene glycol molecular weight is less than or equal to about 15000. In some embodiments, the polyethylene glycol molecular weight is less than or equal to about ' 16000. In some embodiments, the polyethylene glycol molecular weight is less than or equal to about 17000. In some embodiments, the polyethylene glycol molecular weight is less than or equal to about 18000.
  • the polyethylene glycol molecular weight is less than or equal to about 19000. In some embodiments, the polyethylene glycol molecular weight is less than or equal to about 20000. In some embodiments, the polyethylene glycol molecular weight is less than or equal to about 22000. In some embodiments, the polyethylene glycol molecular weight is less than or equal to about 24000. In some embodiments, the polyethylene glycol molecular weight is less than or equal to about 26000. In some embodiments, the polyethylene glycol molecular weight is less than or equal to about 28000. In some embodiments, the polyethylene glycol molecular weight is less than or equal to about 30000. In some embodiments, the polyethylene glycol molecular weight is less than or equal to about 32000.
  • the polyethylene glycol molecular weight is less than or equal to about 34000. In some embodiments, the polyethylene glycol molecular weight is less than or equal to about 36000. In some embodiments, the polyethylene glycol molecular weight is less than or equal to about 38000. In some embodiments, the polyethylene glycol molecular weight is less than or equal to about 41000.
  • Embodiments also exist in which the molecular weight of the polyethylene glycol is in specific ranges, for example 50-150, 100-200, 150-250, 200-300, 250-350, 300- 400, 350-450, 400-500, 450-550, 500-600, 550-650, 600-700, 650-750, 700-800, 750-850, 800-900, 850-950, 1000-1100, 1050-1150, 1100-1200, 1150-1250, 1200-1300, 1250-1350, 1300-1400, 1350-1450, 1400-1500, 1450-1550, 1500-1600, 1550-1650, 1600-1700, 1650-1750, 1700-1800, 1750-1850, 1800-1900, 1850-1950, 1900-2000, 1950-2050, 2000-2100, 2050-2150, 2100-2200, 2150-2250, 2200-2300, 2250-2350, 2300-2400, ' 2350-2450, 2400-2500, 2450-2550, 2500-2600, 2550-2650,
  • Embodiments also exist in which PEG is in a larger range made by combining two or more of any of the foregoing ranges.
  • the invention includes single PEG molecules as well as groups of PEG molecules such as polydisperse pluralities of PEG molecules.
  • “molecular weight" for such pluralities refers to M w .
  • TPGS has the ability to form micelles in water, thereby helping to solubilize lipophilic compounds in water.
  • CMC critical micellar concentration
  • the TPGS contains a PEG of a molecular weight differing from that of TPGS 1000 but has a CMC that is no more than ten times the CMC of TPGS 1000.
  • Information regarding CMC's are known to persons of ordinary skill in the art and may be found in references such as P.W. Atkins, Physical Chemistry (Fourth Edition, 1990), W.H.
  • the TPGS contains a PEG of a molecular weight differing from that of TPGS 1000 but has a CMC that is no more than five times the CMC of TPGS 1000. In some embodiments, the TPGS contains a PEG of a molecular weight differing from that of TPGS 1000 but has a CMC that is no more than double the CMC of TPGS 1000. In some embodiments, the TPGS contains a PEG of a molecular weight differing from that of TPGS 1000 but has a CMC that is no more than 150% of the CMC of TPGS 1000. In some embodiments, the TPGS contains a PEG.
  • the CMC of TPGS is 0.02 ⁇ 0.02 Wt % at all PEG molecular weights between 200 and 6000.
  • the TPGS contains a PEG of a molecular weight differing from that of TPGS 1000 but has a CMC that is the same as the CMC of TPGS 1000.
  • the invention includes embodiments having any of the foregoing CMCs at each of the ranges of molecular weights (and combinations ranges of molecular weights) disclosed herein.
  • the TPGS is a "compound for use as an efflux inhibitor” as defined herein. In some embodiments the TPGS is a "compound not for use as an efflux inhibitor” as defined herein. In some embodiments in which the TPGS is a compound not for use as an efflux inhibitor, P app BA of the TPGS is greater than about 60% of P app BA in the absence of the TPGS as determined using the Inhibition Protocol. In some embodiments of compounds not for use as an efflux inhibitor, the P app BA of the TPGS is greater than about 65% of P app BA of in the absence of the TPGS as determined using the inhibition Protocol.
  • the P app BA of the TPGS is greater than about 70% of P app BA in the absence of the TPGS as determined using the Inhibition Protocol. In some embodiments of compounds not for use as an efflux inhibitor, the P app BA of the TPGS is greater than about 75% of P app BA of in the absence of the TPGS as determined using the Inhibition Protocol. In some embodiments of compounds not for use as an efflux inhibitor, the P app BA of the TPGS is greater than about 80% of P app BA in the absence of the TPGS as determined using the Inhibition Protocol.
  • the P apP BA of the TPGS is greater than about 85% of P app BA in the absence of the TPGS as determined using the Inhibition Protocol. In some embodiments of compounds not for use as an efflux inhibitor, the P app BA of the TPGS is greater than about 90% of P app BA in the absence of the TPGS as determined using the Inhibition Protocol. In some embodiments of compounds not for use as an efflux inhibitor, the P app BA of the TPGS is greater than about 95% of P app BA in the absence of the TPGS as determined using the Inhibition Protocol.
  • the invention also includes compositions that contain a TPGS of the present invention. Embodiments of such compositions exist involving all TPGS compounds described in this application as well as all combinations of such compounds.
  • the composition contains one or more lipophilic compounds along with a TPGS of the present invention.
  • the lipophilic compound is a lipophilic compound for pharmaceutical use.
  • the compositions contain a pharmaceutically effective amount of a lipophilic compound for pharmaceutical use.
  • the TPGS in some embodiments is present above its CMC and thus increases the solubility of the lipophilic compound in water.
  • the TPGS is a compound that effectively solubilizes the lipophilic compound in water.
  • the invention further includes compositions that contain a plurality of TPGS molecules wherein the TPGS molecules are all within a single MW range disclosed above or within any combination or plurality of MW ranges.
  • compositions of the present invention contain one or more additional desirable components or compounds.
  • additional desirable compounds include, but are not limited to, additional active pharmaceutical ingredients as well as excipients, diluents, and carriers such as fillers and extenders (e.g., starch, sugars, mannitol, and silicic derivatives); binding agents ⁇ e.g., carboxymethyl cellulose and other cellulose derivatives, alginates, gelatin, and polyvinyl-pyrrolidone); moisturizing agents (e.g., glycerol); disintegrating agents (e.g., calcium carbonate and sodium bicarbonate); agents for retarding dissolution (e.g., paraffin); resorption accelerators (e.g., quaternary ammonium compounds); surface active agents (e.g., cetyl alcohol, glycerol monostearate); adsorptive carriers (e.g., kaolin and bentonite); emulsifiers; preservatives;
  • additional active pharmaceutical ingredients
  • Examples of carriers include, without limitation, any liquids, liquid crystals, solids or semi-solids, such as water or saline, gels, creams, salves, solvents, diluents, fluid ointment bases, ointments, pastes, implants, liposomes, micelles, giant micelles, and the like, which are suitable for use in the compositions.
  • ingredients particularly mentioned above are merely examples and that some embodiments of formulations comprising the compositions of the present invention include other suitable components and agents..
  • the invention further includes packages, vessels, or any other type of container that contain a TPGS of the present invention or any composition comprising a TPGS of the present invention.
  • the package, vessel or container contains, is labeled with, or is otherwise accompanied by instructions to use the TPGS or TPGS composition to enhance or to increase solubility of one or more lipophilic compounds in water and indicates in any manner that the TPGS or TPGS composition has a specified degree of effect on efflux or otherwise causes a specified degree of increased bioavailability. Any degree of efflux inhibition or other increased bioavailability may be indicated.
  • the indication is that the TPGS or TPGS composiion does not inhibit efflux, has a diminished, limited, or insignificant inhibitory effect on efflux or increased bioavailability, or otherwise provides some indication regarding a lack of efflux inhibition or lack of increased bioavailability or a reduced degree of efflux inhibition or other increased bioavailability (for example, identifying that the efflux inhibition is no greater than a certain level).
  • the invention further includes various methods that use the TPGS and TPGS compositions described above. Any of the foregoing molecules and compositions (and combinations of such molecules and compositions) that are effective to produce a desired result can be used with each of such methods.
  • compositions are administered in any form by any means.
  • forms of administration include but are not limited to injections, solutions, creams, gels, implants, ointments, emulsions, suspensions, microspheres, powders, particles, microparticles,. nanoparticles, liposomes, pastes, patches, capsules, suppositories, tablets, transdermal delivery devices, sprays, suppositories, aerosols, or other means familiar to one of ordinary skill in the art.
  • the compositions are combined with other components. Examples include but are not limited to coatings, depots, matrices for time release and osmotic pump components.
  • Examples of methods of administration include, but are not limited to, oral administration (e.g., ingestion, buccal or sublingual administration), anal or rectal administration, topical application, aerosol application, inhalation, intraperitoneal " administration, intravenous administration, transdermal administration, intradermal administration, subdermal administration, intramuscular administration, intrauterine administration, vaginal administration, administration into a body cavity, surgical administration (for example, at the location of a tumor or internal injury), administration into the lumen or parenchyma of an organ, and parenteral administration.
  • oral administration e.g., ingestion, buccal or sublingual administration
  • anal or rectal administration topical application
  • aerosol application inhalation
  • intraperitoneal " administration intravenous administration
  • transdermal administration intradermal administration
  • subdermal administration subdermal administration
  • intramuscular administration intramuscular administration
  • intrauterine administration vaginal administration
  • administration into a body cavity for example, at the location of a tumor or internal injury
  • parenteral administration
  • compositions of the present invention are administered to persons or animals to provide substances in any dose range that will produce desired physiological or pharmacological results. Dosage will depend upon the substance or substances administered, the therapeutic endpoint desired, the desired effective concentration at the site of action or in a body fluid, and the type of administration. Information regarding appropriate doses of substances are known to persons of ordinary skill in the art and may be found in references such as LS. Goodman and A. Gilman, eds, The Pharmacological Basis of Therapeutics, Macmillan Publishing, New York, and Katzung, Basic & Clinical Pharmacology, Appleton & Lang, Norwalk, Conn., (6th Ed. 1995).
  • the invention further includes any method of admixture or coadministration, including the above methods, in which the method further includes the step of identifying a desired degree (or lack thereof) of efflux inhibition on the part of the TPGS.
  • the method includes selecting from among several TPGS molecules (having different PEG molecular weights) that are compounds for use as an efflux inhibitor to identify the desired level of efflux inhibition.
  • the method includes selecting from among two or more TPGS molecules (having different PEG molecular weights) that are compounds not for use as an efflux inhibitor to identify the desired level of efflux inhibition.
  • the term "Inhibition Protocol” or “inhibition protocol” refers to the following test.
  • the test is carried out using Caco-2 (C2BBe1 or HTB- 37) monolayers which are known to be a good in vitro model for gastrointestinal epithelial cells.
  • DMEM Duibecco's modified Eagle's medium
  • FBS fetal bovine serum
  • Cells are grown at a temperature of ⁇ 37°C in an atmosphere of -85% relative humidity and -5% CO 2 . Cells are seeded on top of Transwell® inserts (pore size 0.4 ⁇ m, 1.13 cm 2 ) at a density of -60,000 cells/cm 2 . Caco-2 monolayers are used -21-25 days after seeding. Transepithelial electrical resistance (TEER) are measured and monolayers only with a TEER> 350 ⁇ *cm 2 , with background subtracted, are used for transport studies.
  • TEER Transepithelial electrical resistance
  • Rhodamine 123 (RHO) transport is assessed in absorptive (apical to basolateral, Ap->BI) and secretory (BI->Ap) directions.
  • KRB Krebs Ringer Buffer
  • P ap pBA/P ap pAB efflux ratio
  • P app BA/P ap pAB efflux ratio
  • Significance of difference in the P app values were determined by one-way analysis of variances (ANOVA) followed by Neumann-Keuls-Student post- hoc tests.
  • Examples 1(a) to (n) illustrate the ability of TPGS 400 to solubilize lipophilic drugs. These examples use the following commercially available products.
  • Vitamin E TPGS 400 (Available from Eastman Chemical Company, Kingsport, Tennessee)
  • CoEnzyme Q10 powder, a dietary supplement were then added to the bottle.
  • the bottle was sealed then placed in an oven.
  • the oven temperature was set at 75 degrees Celsius. After six hours the sample was removed and mixed thoroughly using a vortexer. The sample was returned to the oven and after eighteen hours the oven was turned off. The sample was allowed to cool to room temperature then removed. The blend was free flowing and dark red in appearance. After three days the sample began to crystallize.
  • the Inhibition Protocol was performed with TPGS 1000.
  • Rhodamine 123 is known to be affected by efflux transport in normal Caco-2 cells.
  • the Inhibition Protocol was performed with TPGS in which the PEG had a molecular weight of 2000.
  • the Inhibition Protocol was performed with TPGS in which the PEG had a molecular weight of 4000.
  • TPGS 4000 does not effectively inhibit efflux transport of Rhodamine 123 in Caco-2 monolayers.
  • the Inhibition Protocol was performed with TPGS in which the PEG had a molecular weight of 200.
  • the Inhibition Protocol was performed with TPGS in which the PEG had a molecular weight of 600.
  • TPGS 600 does not effectively inhibit efflux transport of Rhodamine 123 in Caco-2 monolayers.
  • the Inhibition Protocol was performed with TPGS in which the PEG had a molecular weight of 3350.
  • TPGS 3350 does not effectively inhibit efflux transport of Rhodamine 123 in Caco-2 monolayers.
  • Example 8 Rhodamine 123 Efflux in Caco-2 monolayers in the presence of TPGS-6000
  • the Inhibition Protocol was performed with TPGS in which the PEG had a molecular weight of 6000.
  • the Inhibition Protocol was performed with TPGS in which the PEG had a " molecular weight of 400.
  • TPGS 400 does not effectively inhibit efflux transport of Rhodamine 123 in Caco-2 monolayers.
  • TPGS analogs were synthesized by methods similar to those used to synthesize TPGS 1000, differing only in the molecular weight of the polyethylene glycol (PEG) chain. Solutions were prepared of various known concentrations of these derivatives in water. Surface tension of these solutions were measured, and plotted against the concentration of the TPGS. These plots all showed a linear decline of surface tension with TPGS concentration, until an inflection point above which the surface tension held steady with increasing concentration of the TPGS. The concentration at this inflection point is defined as the critical miceliar concentration (CMC) of the particular TPGS in water. The following is a table of the measured CMC's versus the molecular weight of the PEG chain.
  • CMC critical miceliar concentration

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Abstract

L'invention concerne des composés et des compositions permettant d'accroître la biodisponibilité de médicaments lipophiles et, plus précisément, des médicaments lipophiles de dispersion, au moyen de bioactivateurs n'engendrant pas d'inhibition de l'écoulement ou engendrant un degré souhaité d'inhibition de l'écoulement. L'invention concerne également des procédés de fabrication et d'utilisation de ces compositions.
PCT/US2005/034587 2004-09-30 2005-09-29 Formulations pharmaceutiques renfermant des molecules tpgs de vitamine e solubilisant des medicaments lipophiles sans inhibition importante de l'ecoulement et utilisation de telles formulations WO2006039268A2 (fr)

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EP05803721A EP1793806A2 (fr) 2004-09-30 2005-09-29 Formulations pharmaceutiques renfermant des molecules tpgs de vitamine e solubilisant des medicaments lipophiles sans inhibition importante de l'ecoulement et utilisation de telles formulations
JP2007534708A JP2008514714A (ja) 2004-09-30 2005-09-29 有意な流出阻害を示さない、親油性薬物を可溶化するビタミンｅｔｐｇｓ分子を含む医薬製剤及びこのような医薬製剤の使用

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Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006115713A2 (fr) * 2005-04-26 2006-11-02 Eastman Chemical Company Melanges eutectiques contenant un derive d'une vitamine hydrosoluble
US8722093B2 (en) 2009-02-23 2014-05-13 NanoRx, Inc. Policosanol nanoparticles
US20140220140A1 (en) * 2011-09-09 2014-08-07 The University Of Liverpool Compositions of efavirenz
US9034383B2 (en) 2010-08-23 2015-05-19 NanoRx, Inc. Policosanol nanoparticles
WO2021123949A1 (fr) 2019-12-20 2021-06-24 Idorsia Pharmaceuticals Ltd Compositions pharmaceutiques comprenant du n-[1-(5-cyano-pyridin-2-ylméthyl)-1h-pyrazol-3-yl]-2-[4-(1-trifluorométhyl-cyclopropyl)-phényl]-acétamide
WO2021123108A1 (fr) * 2019-12-20 2021-06-24 Intervet International B.V. Composition pharmaceutique de pyrazole

Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997035587A1 (fr) * 1996-03-22 1997-10-02 Glaxo Group Limited Compositions contenant un inhibiteur de la protease du vih tel que le vx 478 et un compose hydrosoluble de vitamine e tel que la vitamine e-tpgs
WO1998008490A1 (fr) * 1996-09-01 1998-03-05 Pharmos Corporation Coprecipites solides augmentant la biodisponibilite de substances lipophiles
WO2000061189A2 (fr) * 1999-04-02 2000-10-19 National Research Council Of Canada Compositions hydrosolubles de composes lipophiles bioactifs
US20010029264A1 (en) * 1998-03-10 2001-10-11 Mcchesney-Harris Lisa L. Novel methods and compositions for delivery of taxanes
WO2003013474A1 (fr) * 2001-08-09 2003-02-20 Jagotec Ag Preparations nanoparticulaires constituees de fenofibrate
US20030191179A1 (en) * 1999-10-25 2003-10-09 Supergen, Inc. Methods for administration of paclitaxel
EP1464341A1 (fr) * 2003-04-03 2004-10-06 Visufarma S.R.L. Formulation hydrosoluble comprénant de l'ubiquinone pour utilisation oculaire

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997035587A1 (fr) * 1996-03-22 1997-10-02 Glaxo Group Limited Compositions contenant un inhibiteur de la protease du vih tel que le vx 478 et un compose hydrosoluble de vitamine e tel que la vitamine e-tpgs
WO1998008490A1 (fr) * 1996-09-01 1998-03-05 Pharmos Corporation Coprecipites solides augmentant la biodisponibilite de substances lipophiles
US20010029264A1 (en) * 1998-03-10 2001-10-11 Mcchesney-Harris Lisa L. Novel methods and compositions for delivery of taxanes
WO2000061189A2 (fr) * 1999-04-02 2000-10-19 National Research Council Of Canada Compositions hydrosolubles de composes lipophiles bioactifs
US20030191179A1 (en) * 1999-10-25 2003-10-09 Supergen, Inc. Methods for administration of paclitaxel
WO2003013474A1 (fr) * 2001-08-09 2003-02-20 Jagotec Ag Preparations nanoparticulaires constituees de fenofibrate
EP1464341A1 (fr) * 2003-04-03 2004-10-06 Visufarma S.R.L. Formulation hydrosoluble comprénant de l'ubiquinone pour utilisation oculaire

Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006115713A2 (fr) * 2005-04-26 2006-11-02 Eastman Chemical Company Melanges eutectiques contenant un derive d'une vitamine hydrosoluble
WO2006115713A3 (fr) * 2005-04-26 2007-06-28 Eastman Chem Co Melanges eutectiques contenant un derive d'une vitamine hydrosoluble
US8722093B2 (en) 2009-02-23 2014-05-13 NanoRx, Inc. Policosanol nanoparticles
US9034383B2 (en) 2010-08-23 2015-05-19 NanoRx, Inc. Policosanol nanoparticles
US20140220140A1 (en) * 2011-09-09 2014-08-07 The University Of Liverpool Compositions of efavirenz
US9498438B2 (en) * 2011-09-09 2016-11-22 The University Of Liverpool Compositions of efavirenz
WO2021123949A1 (fr) 2019-12-20 2021-06-24 Idorsia Pharmaceuticals Ltd Compositions pharmaceutiques comprenant du n-[1-(5-cyano-pyridin-2-ylméthyl)-1h-pyrazol-3-yl]-2-[4-(1-trifluorométhyl-cyclopropyl)-phényl]-acétamide
WO2021123108A1 (fr) * 2019-12-20 2021-06-24 Intervet International B.V. Composition pharmaceutique de pyrazole
CN115103668A (zh) * 2019-12-20 2022-09-23 爱杜西亚药品有限公司 包含n-[1-(5-氰基-吡啶-2-基甲基)-1h-吡唑-3-基]-2-[4-(1-三氟甲基-环丙基)-苯基]-乙酰胺的药物组合物
EP4282475A3 (fr) * 2019-12-20 2024-02-28 Intervet International B.V. Composition pharmaceutique à base de pyrazole

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