WO2002043742A1 - Cyclodextrines et elimination de l"atherosclerose - Google Patents

Cyclodextrines et elimination de l"atherosclerose Download PDF

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Publication number
WO2002043742A1
WO2002043742A1 PCT/AU2001/001547 AU0101547W WO0243742A1 WO 2002043742 A1 WO2002043742 A1 WO 2002043742A1 AU 0101547 W AU0101547 W AU 0101547W WO 0243742 A1 WO0243742 A1 WO 0243742A1
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cholesterol
cyclodextrin
cyclodextrins
phospholipid vesicles
efflux
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PCT/AU2001/001547
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English (en)
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WO2002043742A8 (fr
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Len Kritharides
Roger Dean
Wendy Jessup
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The Heart Research Institute Ltd
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Priority to AU2002223303A priority Critical patent/AU2002223303A1/en
Publication of WO2002043742A1 publication Critical patent/WO2002043742A1/fr
Publication of WO2002043742A8 publication Critical patent/WO2002043742A8/fr

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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
    • 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
    • A61K31/66—Phosphorus compounds
    • A61K31/683—Diesters of a phosphorus acid with two hydroxy compounds, e.g. phosphatidylinositols
    • A61K31/685—Diesters of a phosphorus acid with two hydroxy compounds, e.g. phosphatidylinositols one of the hydroxy compounds having nitrogen atoms, e.g. phosphatidylserine, lecithin
    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7135—Compounds containing heavy metals
    • A61K31/714—Cobalamins, e.g. cyanocobalamin, i.e. vitamin B12
    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
    • A61K31/716—Glucans
    • A61K31/724—Cyclodextrins
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Definitions

  • This invention relates to a method of removing free cholesterol, cholesteryl esters, 7- ketocholesterol and 7-ketocholesteryl esters from human monocytes, particularly human foam cell macrophages and a method of treating atherosclerosis by removing cholesterol and cholesteryl esters from human monocytes, particularly human foam cell macrophages.
  • Atherosclerotic lesion development is preceded by intimal penetration of blood-borne mononuclear cells which subsequently undergo transformation into macrophage foam cells in fatty streak lesions. These cells are characterised by massive accumulation of cholesteryl esters, present predominantly as cytoplasmic lipid droplets which occupy a large proportion of the cell volume.
  • the foam cell macrophage is an early and persistent feature of atherosclerosis.
  • Macrophages cannot metabolise cholesterol and excess accumulated cholesterol must be released spontaneously or transferred to an extra-cellular cholesterol acceptor such as high density lipoprotein (HDL).
  • HDL high density lipoprotein
  • This phenotypic reversion involves firstly the export of cholesterol associated with the plasma membrane to an extracellular acceptor and secondly hydrolysis of cytoplasmic cholesteryl esters, mediated by neutral cholesterol ester hydrolases, to replenish plasma membrane cholesterol levels. Provided that sufficient extracellular capacity to remove cholesterol from the plasma membrane exists, the above processes can continue until all excess cholesteryl esters are hydrolysed.
  • Natural cholesterol acceptors include HDL and apoA-1. It is an apparent paradox that while both HDL and apoA-1 are detectable in atherosclerotic lesions, foam cells are also formed and persist. This suggests that such natural cholesterol acceptors are unable to adequately stimulate cholesterol export from macrophages in lesions. Pharmacological agents which have the capacity to replace or augment natural endogenous cholesterol acceptors should therefore be effective as antiatherosclerotic agents.
  • Cyclodextrins are cyclic polymers of glucose. They present a hydrophilic exterior and a hydrophobic interior capable of solubilizing a range of hydrophobic molecules. Beta- cyclodextrins (containing 7 glucose molecules) avidly bind cholesterol and have been shown to promote cholesterol efflux from cells in vitro. As small, water-soluble molecules, they can rapidly penetrate and exit from lesion tissues and are therefore excellent candidates as novel agents for cholesterol removal in vivo. Some cyclodextrins have a high affinity for cholesterol (e.g. trimethyl cyclodextrin) and others have a considerably lower affinity for cholesterol (e.g. hydroxypropyl cyclodextrin (discussed in Kritharides et al. (1996) J Biol Chem 271:27450-27455)). Chemical substitution on the glucose rings affects the affinity of individual cyclodextrins for sterol binding.
  • Cyclodextrins may cause the net removal of cholesterol from cells in one of two ways. Cyclodextrins with a high affinity for cholesterol can directly remove cholesterol from the plasma membrane and retain it in the extracellular medium, acting as so-called cholesterol "sinks”. Second, lower concentrations of high affinity cyclodextrins, or cyclodextrins with a lower affinity for cholesterol can act as vehicles or "shuttles" to remove cholesterol from the plasma membrane, and deliver it to a second acceptor of larger capacity but lower efficiency such as a phospholipid vesicle.
  • a method of depleting human monocytes of cholesterol by treatment with a cyclodextrin having a low cholesterol affinity and phospholipid vesicles According to a second aspect of the present invention there is provided a method of depleting human monocytes of cholesteryl esters by treatment with a cyclodextrin having a low cholesterol affinity and phospholipid vesicles.
  • the low affinity cyclodextrin is hydroxypropyl cyclodextrin.
  • the present invention also provides a method for depleting human monocytes of cholesteryl esters by treatment with a cyclodextrin having a high cholesterol affinity and phospholipid vesicles, said cyclodextrin having a high cholesterol affinity being added in an amount to achieve a low concentration in said treatment.
  • concentration of the high affinity cyclodextrin will be less than 1 mg/ml during treatment, more preferably between 0.2 and 0.5mg/ml and the concentration of phospholipid vesicles will be 0.2mg/ml.
  • a method of treating atherosclerosis in an individual by treating said individual with a cyclodextrin having a low affinity for cholesterol.
  • the method further includes treating the individual with a low affinity cyclodextrin in the presence of phospholipid vesicles.
  • the treatment comprises administering a composition containing the low affinity cyclodextrin to the individual, such as by intravenous administration.
  • the composition may also contain phospholipid vesicles.
  • it is possible that the individual may have sufficient levels of phospholipid vesicles in their bloodstream to not require further administration of phospholipid vesicles.
  • the present invention provides a method for treating atherosclerosis in an individual by treating said individual with a cyclodextrin having a high affinity for cholesterol, said cyclodextrin being present with phospholipid vesicles and in a concentration below that at which said cyclodextrin can remove free cholesterol from cells in the absence of phospholipid vesicles.
  • the human monocytes are preferably human foam cell macrophages.
  • the present invention also encompasses a composition for treating atherosclerosis comprising cyclodexrin and phospholipid vesicles.
  • the cyclodextrin is a cyclodextrin having a low affinity for cholesterol.
  • the present inventors have also found that 7-ketocholesterol and 7-ketocholesteryl esters may be removed from human monocytes by treatment with cyclodextrins and phospholipid vesicles.
  • the present invention provides a method for depleting human monocytes of 7-ketocholesterol by treatment with cyclodextrin and phospholipid vesicles.
  • the cyclodextrin has a low affinity for cholesterol.
  • the invention also provides for a method for depleting human monocytes of 7- ketocholesteryl esters by treatment with cyclodextrin and phospholipid vesicles.
  • the cyclodextrin has a low affinity for cholesterol.
  • a method of producing novel cyclodextrins for use in treating atherosclerosis comprises the steps of: designing novel cyclodextrins; and testing said novel cyclodextrins for their ability to deplete human monocytes of cholesteryl esters in the presence of phospholipid vesicles.
  • the method of producing novel cyclodextrins would comprise the step of designing novel cyclodextrins having a low affinity for cholesterol.
  • the method of producing novel cyclodextrins would further comprise the step of designing a cyclodextrin which has the ability to act as a shuttle or vehicle for the removal cholesterol from human monocytes by transferring said cholesterol to an extracellular acceptor.
  • cyclodextrins are preferably beta-cyclodextrins.
  • Figure 1 illustrates the ability of cyclodextrins and phospholipid vesicles to efflux cholesterol from human foam cell macrophages
  • Figure 2 illustrates the synergy between hydroxpropyl cyclodextrin and phospholipid vesicles in the efflux of cholesterol from human foam cell macrophages
  • Figure 3 illustrates the synergistic ability of cyclodextrins and phospholipid vesicles to remove cholesteryl esters from human foam cell macrophages;
  • Figure 4 illustrates the relationship between the concentration of trimethyl cyclodextrin and its ability to deplete human foam cell macrophages of cholesteryl esters
  • Figure 5 illustrates the relationship between the concentration of hydroxypropyl cyclodextrin and its ability to remove cholesteryl esters from human foam cell macrophages
  • Figure 6 illustrates the time-dependent efflux of cholesterol from human foam cell macrophages by hydroxypropyl and trimethyl cyclodextrins
  • Figure 7 demonstrates the synergistic efflux of cholesterol from human foam cell macrophages by hydroxpropyl cyclodextrin and phospholipid vesicles after oxysterol enrichment
  • Figure 8 shows the comparative efflux of cholesterol and 7-ketocholesterol by hydroxypropyl cyclodextrin and phospholipid vesicles.
  • cyclodextrins can facilitate the removal of cholesterol from mouse macrophages.
  • the present applicant believes that there may be little correlation between cholesterol removal in mouse cells and successfully obtaining cholesterol removal from equivalent human cells.
  • the applicant has defined a specific application of cyclodextrins to act as efficient shuttles of cholesterol from human foam cell macrophages to secondary acceptors, by a process that also enhances cholesteryl ester mobilisation.
  • the identity of specific cyclodextrins that are efficient shuttles cannot be predicted from their cholesterol binding efficiency.
  • the present application relates to a method of depletion of cholesterol and cholesteryl esters from human monocytes, in particular human foam cell macrophages, by treating the monocytes with a combination of a cyclodextrin having a low affinity for cholesterol and phospholipid vesicles.
  • the cyclodextrin is a beta- cyclodextrin, and more preferably the cyclodextrin is hydroxypropyl cyclodextrin.
  • the treatment of human monocytes with the combination of a cyclodextrin having a high affinity for cholesterol and phospholipid vesicles may also be used to deplete the monocytes of cholesteryl esters, hi this case, preferably the high cholesterol affinity cyclodextrin is added in a low concentration, such as less than lmg/ml (more preferably between 0.2 and 0.5 mg/ml) in combination with 0.2 mg/ml phospholipid vesicles.
  • the present invention further relates to the depletion of 7-ketocholesterol and 7- ketocholesteryl esters from human monocytes using a combination of cyclodextrin and phospholipid vesicles.
  • the present invention is applicable to the treatment of atherosclerosis in individuals, wherein the individuals are administered a composition including a cyclodextrin having a low affinity for cyclodextrin.
  • the composition may be administered intravenously, or via any other suitable method, such as orally for example.
  • the composition may include an appropriate concentration of phospholipid vesicles, or alternatively it is possible that the individual being treated possesses sufficient levels of endogenous phospholipid vesicles in their system so as to not require the administration of additional phospholipid vesicles.
  • the present invention may also be used in the treatment of atherosclerosis in an individual by treating the individual with a composition containing a cyclodextrin having a high affinity for cholesterol and phospholipid vesicles wherein the cyclodextrin is provided in a concentration below that at which the cyclodextrin can remove free cholesterol from cells in the absence of phospholipid vesicles.
  • novel cyclodextrins for the treatment of atherosclerosis.
  • the production of such cyclodextrins would likely involve designing candidate cyclodextrins and testing these candidates for their ability to deplete human monocytes of cholesteryl esters in the presence of phospholipid vesicles.
  • the method of producing novel cyclodextrins may further comprise the step of designing a candidate cyclodextrin which has the ability to act as a shuttle or vehicle for the removal cholesterol from human monocytes by transferring said cholesterol to an extracellular acceptor.
  • PC Materials -Egg phosphatidylcholine (PC), penicillin/streptomycin, essentially fatty acid free bovine serum albumin (BSA), and silica gel on polyester thin layer chromatography (TLC) plates were from Sigma Aldrich.
  • Beta cyclodextrins (CDs) were from Cyclolabs (Hungary) and Sigma Aldrich.
  • RPMI 1640 media and glutamine were obtained from Gibco, tissue culture plates and consumables were purchased from Falcon.
  • [ 3 H] -cholesterol (lmCi/ml) was purchased from Amersham Pharmacia Biotech. Solvents were purchased from EM Science. Buffy coats and whole human sera from normal donors were supplied by the Red Cross blood bank of NSW.
  • Acyl-CoA:cholesterol acyltransferase (ACAT) inhibitor Sandoz 58035 (S- 58035) was a gift from Drs. Nordmann and Nodelson at Sandoz Pharmaceuticals.
  • LDL lipoprotein-deficient serum
  • PBS phosphate buffered saline
  • Acetylation of LDL (AcLDL) was achieved with acetic anhydride.
  • HMDM Human monocyte derived macrophages
  • Cholesterol efflux - Phospholipid vesicles were prepared from egg PC by repeated sonication, and incubated with HMDM in RPMI at concentrations described (typically between 100-200 ⁇ g/ml). CDs were dissolved in RPMI, and typical experiments used 1.0 mg/ml of CD.
  • HMDM HMDM were washed an incubated in 1ml of efflux medium.
  • efflux media contained RPMI control, PLN, hydroxypropyl- ⁇ -cyclodextrin (hp-CD) with or without PLN, or trimethyl- ⁇ -CD (tm-CD) with or without PLN. These media were incubated with HMDM for up to 24 hours, at which time cells and media were extracted from triplicate cultures.
  • hp-CD hydroxypropyl- ⁇ -cyclodextrin
  • tm-CD trimethyl- ⁇ -CD
  • Mass cholesterol efflux was expressed as nmol cholesterol/culture, nmol/mg cell protein, and percent efflux, which was calculated as cholesterol in media at the time of extraction divided by the sum of cholesterol in media plus total cholesterol in cells at that time.
  • aliquots (100 ⁇ l) of efflux medium were removed at specified times, centrifuged to remove non-adherent cells and debris, 80 ⁇ l aliquots analyzed by scintillation counter, and % efflux expressed relative to that in cells extracted at tO. Lipid Analysis - HMDM monolayers were washed with PBS, lysed with 600 ⁇ l of ice-cold
  • lipids were extracted from 400 ⁇ l aliquots of cell lysate into niethanol and hexane. 4 ml of the hexane phase was collected, evaporated, and redissolved in HPLC mobile phase comprising acetonitrile/isopropanol/water (44/54/2, v/v/v) or acetonitrile/isopropanol (30/70, v/v). HPLC quantification of free (FC) and esterified cholesterol (CE), respectively was performed. Extraction of efflux media in all experiments confirmed there were no CE in the media and that CE decline was not explained by cell lysis.
  • FC free
  • CE esterified cholesterol
  • Protein Estimation Protein content of cell lysates and of LDL samples was determined in triplicate for each cell culture or sample, and was measured using the bicinchoninic acid (BCA) method (Sigma) with BSA as standard.
  • BCA bicinchoninic acid
  • cyclodextrins cyclodextrins
  • human foam cell macrophages were loaded with acetylated low density lipoproteins (50 ⁇ g ml AcLDL) for 96 hours and subsequently with fresh efflux media for 24 hours.
  • Efflux media contained RPMI, 1.0 mg/ml hydroxpropyl cyclodextrin (hp-CD), 1.0 mg/ml trimethyl cyclodextrin (tm-CD), 200 ⁇ g/ml phospholipid vesicles (PLV), or 1.0 mg/ml hp-CD together with 200 ⁇ g/ml PLN.
  • hp-CD in isolation, hp-CD at concentrations between 0.01-1.0 mg/ml did not achieve significant efflux, but each of these concentrations facilitated synergistic cholesterol efflux in the presence of 200 ⁇ g/ml PLN ( Figure 2A). In the presence of a fixed concentration of hp-CD (1.0 mg/ml) efflux also increased with increasing concentrations of PLN ( Figure 2).
  • cholesteryl ester Within foam cell macrophages, excess cell cholesterol is stored as cholesteryl ester. Depletion of cholesteryl ester is characteristic of cholesterol efflux achieved by physiological acceptors such as HDL and apo A-I. Whether synthetic agents can achieve this in human cells which have very slow rates of cholesteryl ester hydrolysis is unclear, and it is unknown if cholesteryl ester depletion is equally achieved by CDs working as “sinks” (direct depletion) and as “shuttles"(synergistic efflux).
  • CDs acting as "sinks” 1.0 mg/ml tm-CD alone
  • CDs acting as "shuttles” 1.0 mg/ml hp-CD + 200 ⁇ g ml PLN
  • EXAMPLE 4 Lower concentrations of a high affinity cyclodextrin can promote cholesteryl ester removal in combination with phospholipid vesicles Apparent synergistic efflux could be restored for tm-CD by decreasing concentrations and diminished for hp-CD by increasing concentrations.
  • Low concentrations of tm-CD (0.01-0.1 mg/ml) did cause a decrease in cholesteryl esters in association with synergistic efflux, but 1.0 mg/ml tm-CD with PLN usually did not cause cholesteryl ester depletion, or caused less cholesteryl ester depletion than the lower concentration of tm-CD with PLN.
  • tm-CD on its own caused an apparent modest rise in the cholesteryl ester content which was most clearly evident at lmg/ml tm-CD but which could sometimes be observed at lower concentrations which caused only minor net cholesterol efflux.
  • apoA-1 -mediated cholesterol efflux is impaired from macrophages loaded with oxidized LDL (which contains 7-ketocholesterol, 7-KC), or with 7-KC-enriched acetylated LDL (7-KC-AcLDL), relative to that from cells loaded with AcLDL.
  • oxidized LDL which contains 7-ketocholesterol, 7-KC
  • 7-KC-AcLDL 7-KC-enriched acetylated LDL
  • human foam cell macrophages were loaded with variable amounts of 7-KC- AcLDL and tested for efflux.
  • Human foam cell macrophages were loaded with 50 ⁇ g/ml AcLDL for 48 hours, washed and incubated with 25 ⁇ g/ml AcLDL+ 25 ⁇ g/ml 7-KC-AcLDL for 48 hours to achieve enrichment with free cholesterol, cholesteryl esters, and physiological concentrations of 7-KC and its esters.
  • cell free cholesterol was 9.9 ⁇ 0.2nmol culture, cholesteryl esters 8.0+0.5 nmol/culture, 7-KC 0.4+0.1 nmol/culture and 7-KCE 1.1+0.1 nmol culture (7- KC+7-KCE representing 7.9% of total cell sterol).
  • Lipid-rich human foam cell macrophages were washed and incubated with fresh media containing 200 ⁇ g/ml PLV alone (single solid circle), or 0-200 ⁇ g/ml PLV + hp-CD 1.0 mg/ml (open circles) for 24 hours. Cholesterol efflux produced by 200 ⁇ g/ml PLV alone was 17.3+2.0% (3.2+0.4 nmol/well), efflux achieved by 1.0 mg/ml hp-CD alone was 2.3+1.9%, and that by hp-CD +PLV was 46.8+2.1%.
  • Hp-CD and PLV achieved clear and substantial synergistic cholesterol efflux from cells loaded with 7-KC-AcLDL. Similar overall cholesterol efflux was achieved under optimal efflux conditions (1.0 mg/ml hp-CD and PLV 0.1-0.2 mg/ml, Figure 7), consistently between 45-50% to that observed in oxysterol-free cells. The efflux achieved by the combination hp- CD+PLV was much greater than the sum of efflux achieved by each agent added separately, and clearly showed a dependence upon the concentration of PLV.
  • Efflux of cholesterol and 7-KC to control media apo A-I (25 ⁇ g/ml), PLV (200 ⁇ g/ml), hp-CD (1.0 mg/ml), or both hp-CD+PLV was measured after 24 hours.
  • % cholesterol efflux to hp- CD+PLV for low-7-KC cells was 49.5+0.1% and for high-7-KC cells was 33.8+1.6% (panel A).
  • %7-KC efflux to hp-CD+PLV for low-7-KC cells was 67.3+12.4% and for high-7-KC cells was 54.1+2.2%.
  • hp-CD+PLV but not PLV alone, efficiently promoted cholesterol efflux from human foam cell macrophages.

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Abstract

L"invention concerne un procédé de déplétion de monocytes humains de cholestérol, d"esters de cholestéryle, d"esters de 7-kétocholestérol et de 7-kétocholestéryle, ce procédé consistant à traiter ces monocytes à l"aide d"une cyclodextrine possédant une faible affinité pour le cholestérol et, en même temps, de vésicules phospholipidiques.
PCT/AU2001/001547 2000-11-29 2001-11-29 Cyclodextrines et elimination de l"atherosclerose WO2002043742A1 (fr)

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Cited By (6)

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WO2007119103A1 (fr) * 2005-10-17 2007-10-25 Robert Bender Macrophages marques et procedes d'utilisation de ceux-ci
US7291590B2 (en) * 2003-06-12 2007-11-06 Queen's University At Kingston Compositions and methods for treating atherosclerosis
WO2007135523A2 (fr) * 2006-05-19 2007-11-29 Viroblock S.A. Composition destinée à inactiver un virus enveloppé
US7674772B2 (en) 2006-03-31 2010-03-09 Queen's University At Kingston Compositions and methods for treating atherosclerosis
WO2015087017A1 (fr) 2013-12-13 2015-06-18 Roquette Freres Compositions a base de methyl-cyclodextrines pour le traitement et/ou la prevention de maladies par augmentation du taux de cholesterol-hdl
US11279774B2 (en) 2019-01-03 2022-03-22 Underdog Pharmaceuticals, Inc. Cyclodextrin dimers, compositions thereof, and uses thereof

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Cited By (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7291590B2 (en) * 2003-06-12 2007-11-06 Queen's University At Kingston Compositions and methods for treating atherosclerosis
WO2007119103A1 (fr) * 2005-10-17 2007-10-25 Robert Bender Macrophages marques et procedes d'utilisation de ceux-ci
US7674772B2 (en) 2006-03-31 2010-03-09 Queen's University At Kingston Compositions and methods for treating atherosclerosis
US8889398B2 (en) 2006-05-19 2014-11-18 Viroblock Sa Composition for inactivating an enveloped virus
WO2007135523A3 (fr) * 2006-05-19 2008-06-26 Viroblock S A Composition destinée à inactiver un virus enveloppé
EA016073B1 (ru) * 2006-05-19 2012-01-30 Вайэроблок С.А. Композиция для инактивации оболочечного вируса (варианты), средства на ее основе для приготовления лекарства против вирусного заболевания, для приготовления больших количеств биосовместимого дезинфицирующего средства и для приготовления покрытия, содержащий ее набор для инактивации оболочечного вируса и способ инактивации оболочечного вируса
WO2007135523A2 (fr) * 2006-05-19 2007-11-29 Viroblock S.A. Composition destinée à inactiver un virus enveloppé
WO2015087017A1 (fr) 2013-12-13 2015-06-18 Roquette Freres Compositions a base de methyl-cyclodextrines pour le traitement et/ou la prevention de maladies par augmentation du taux de cholesterol-hdl
WO2015087016A1 (fr) 2013-12-13 2015-06-18 Roquette Freres Compositions a base de methyl-cyclodextrines pour le traitement et/ou la prevention de maladies par augmentation du taux de cholesterol-hdl
FR3014694A1 (fr) * 2013-12-13 2015-06-19 Roquette Freres Compositions a base de methyl-cyclodextrines pour le traitement et/ou la prevention de maladies par augmentation du taux de cholesterol-hdl
US10022392B2 (en) 2013-12-13 2018-07-17 Roquette Freres Compositions based on methyl cyclodextrins for the treatment and/or prevention of diseases by increasing the HDL cholesterol level
EP3581188A1 (fr) 2013-12-13 2019-12-18 Roquette Freres Compositions a base de methyl-cyclodextrines pour le traitement et/ou la prévention de maladies du snc par augmentation du taux de cholestérol-hdl
US11266680B2 (en) 2013-12-13 2022-03-08 Roquette Freres Compositions based on methyl cyclodextrins for the treatment and/or prevention of diseases by increasing the HDL cholesterol level
US11279774B2 (en) 2019-01-03 2022-03-22 Underdog Pharmaceuticals, Inc. Cyclodextrin dimers, compositions thereof, and uses thereof

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AU2002223303A1 (en) 2002-06-11
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