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    • 专利摘要:
    The present invention relates to a new use of a pharmaceutical composition comprising at least one methyl-cyclodextrin having a degree of molar substitution (MS) of between 0.05 and 1.5 in the treatment and / or prevention of diseases likely to be treated and / or prevented by an increase in HDL cholesterol. It also relates to its use in the treatment and / or prevention of atherosclerosis or complications related to atheroma, Alzheimer's disease, or Niemann-Pick type C disease. The pharmaceutical compositions of the invention can also be used to further promote the lowering of triglycerides and circulating fatty acids and to reduce or prevent atheroma plaques.
    公开号:FR3014694A1
    申请号:FR1362633
    申请日:2013-12-13
    公开日:2015-06-19
    发明作者:Marc Salome；Daniel Wils；Xavier Parissaux；Francois Mach；Fabrizio Montecucco
    申请人:Roquette Freres SA；
    IPC主号:
    专利说明:

    [0001] COMPOSITIONS BASED ON METHYL-CYCLODEXTRINS FOR THE TREATMENT AND / OR PREVENTION OF DISEASES BY INCREASING THE CHOLESTEROL-HDL RATE
    [0002] The present invention relates to pharmaceutical compositions for increasing the HDL-cholesterol level in an individual. The present invention more specifically relates to the use of a pharmaceutical composition in the treatment and / or prevention of diseases that can be treated and / or prevented by an increase in the level of HDL cholesterol, or in the treatment and / or the prevention of atherosclerosis or complications related to atheroma, Alzheimer's disease, and Niemann-Pick type C disease. BACKGROUND OF THE INVENTION Cholesterol is a lipid of the sterol family playing a central role in many biochemical processes. It is a major component of animal cell membranes that contributes to their stability and maintenance of their structure by intercalating between phospholipids. Indeed, cholesterol stiffens the membrane by preventing its gelation because it avoids the crystallization of fatty acids and also decreases the membrane permeability to water-soluble molecules. By intercalating in the membranes, cholesterol also allows the formation of lipid rafts which are essential areas for the anchoring of functional proteins. Moreover, cholesterol is also found in neurons where it allows the synthesis of neurotransmitters by exocytosis and thus the propagation of the nervous message. It is directly involved in the formation of beta-amyloid peptides, and therefore in the pathogenesis of Alzheimer's disease. An association between atherosclerosis and Alzheimer's disease has also been demonstrated (Mikael Simons et al., "Cholesterol depletion inhibited the generation of b-amyloid in hippocampal neuron", Proc Natl Acad Sci USA, Vol. 95, pp. 6460-6464, May 1998, Neurobiology.) The metabolism of cholesterol is also a precursor of many molecules such as steroid hormones (cortisol, cortisone and aldosterone), sex steroid hormones (progesterone, estrogen and testosterone), vitamin D3, heme A, prenylated or farnesylated proteins, ubiquinone or coenzyme Q10, dolichol, NF kappa B nuclear factor, Tau protein and bile salts. Cholesterol is transported in the blood by transport systems with very different roles, namely LDL lipoproteins (low density lipoproteins) and HDL lipoproteins (high density lipoproteins).
    [0003] HDL-cholesterol is considered protective against cardiovascular disease and is often referred to as "good cholesterol". LDL carrying cholesterol penetrate the arterial wall and are then captured by monocytes and macrophages residing in this arterial wall as well as by smooth muscle cells. This results in an excessive lipid load of macrophages and smooth muscle cells which then turn into foam cells at the origin of the atherosclerosis processes and corresponding to the first stage of atheroma plaque formation. This is called "bad cholesterol".
    [0004] Atheroma is defined by the World Health Organization as an "association of intimal reworking of the large and medium-sized arteries consisting of focal accumulation of lipids, complex carbohydrates, blood and calcium deposits, with reworking of the media ". Atheroma is at the root of most cardiovascular diseases and is the leading cause of morbidity and mortality in industrialized countries. Atheroma begins with the formation of a "lipidic streak", a simple fat deposit, linear and without consequences for the flow, located between the endothelium and the media of the artery. Over time, this streak can grow, load into lipids, fibrogen, platelets and other blood cells and calcium to form the "atheroma plaque". It becomes more or less important and can decrease the size of the artery sufficiently to reduce its flow. There are two types of complications: the first, of long evolution, is due to its slow growth, hindering more and more the passage of the blood until completely preventing it by obstruction. The second, rapid and responsible for acute complications, is the lesion or rupture of the endothelium: the gap formed is then obstructed by aggregation of blood platelets and the formation of a blood clot that can quickly completely obstruct the vessel. This clot can also come off and clog further downstream. The plaque can also come off partially and also clog the artery, or more rarely, release its contents and make a cholesterol embolism. Finally, the dilation of the arterial wall induced by the increase in volume of the plate can lead to the formation of aneurysm, with risk of rupture.
    [0005] The most used pharmaceutical class to prevent atheroma are statins, which aim to reduce LDL-cholesterol and circulating lipids, in addition to a suitable diet. However, the interest and usefulness of statins have for some time been strongly criticized by some researchers and clinicians who claim that statins, after analysis of controversial statistical tests because contradictory, do not provide patients with the expected therapeutic benefit. In addition to this, the harmful and sometimes dramatic side effects that have been identified have led in some cases to withdrawal from the market. The other drug treatments proposed today are: platelet aggregation inhibitors such as aspirin or clopidogrel, which are supposed to reduce the formation of clots from the atheroma plaque; antihypertensive drugs such as angiotensin converting enzyme inhibitors.
    [0006] The pharmaceutical treatments that currently exist are therefore only intended to reduce the risks associated with atheroma. None of the existing drugs on the market directly attack the atheromatous plaque. When life-threatening is at stake, the treatment is surgical or endovascular. It aims to restore the arterial lumen, to irrigate the territory deprived of oxygen or to suppress the arterial aneurysm. These techniques include angioplasty, endoberectomy, bridging.
    [0007] Finally, the main means of fight against atheroma and its complications still remains behavioral today: stopping smoking, development of physical activity, control of blood pressure, correction of dyslipidemia, balance of diabetes , diet.
    [0008] Thus, it is clear that there is clearly and for a long time an unmet need for treatment and / or prevention of atheroma. Various approaches have been tried, but no new solution has been adopted. In particular, HDL-cholesterol began to be studied in 1975 when researchers highlighted the relationship between high HDL-cholesterol levels and decreased incidence of cardiovascular disease (Rye KA 2013. High density lipoprotein structure, function, and metabolism: a new Thematic Series, J. Lipid Res 54: (8) 2031-2033). The positive results of these studies have encouraged the development of treatments aimed at increasing HDL-cholesterol levels, among which are the inhibitors of the CETP enzyme (cholesterol ester transfer protein), which were the very first agents. developed and evaluated on a large scale, specifically for this purpose. However, none of these treatments reduced the occurrence of cardiovascular events.
    [0009] Finally, there is still no drug on the market capable of effectively inducing an increase in the HDL-cholesterol level in the patient, in particular because the mechanisms involved are still far from being elucidated. In particular, there is no drug on the market able to fight effectively and efficiently against diseases that can be treated and / or prevented by an increase in HDL cholesterol. In addition, there is a continuing need for a drug capable of combating atherosclerosis, particularly against the formation of atheroma plaque.
    [0010] SUMMARY OF THE INVENTION It is of the merit of the Applicant to have discovered that methyl-cyclodextrin-based pharmaceutical compositions having a particular degree of molar substitution of between 0.05 and 1.5 make it possible to induce a rate increase. HDL cholesterol, in particular plasma HDL cholesterol, and are therefore extremely useful for the treatment or prevention of diseases that can be treated and / or prevented by an increase in HDL cholesterol, especially atherosclerosis. or complications related to atheroma, Alzheimer's disease, or Niemann-Pick type C disease. The object of the present invention is therefore to provide a pharmaceutical composition comprising at least one methyl-cyclodextrin having a degree of molar substitution between 0.05 and 1.5 for its use in the treatment and / or prevention of diseases that can be treated and / or prevented by an increase in HDL cholesterol. Another object of the present invention is to provide a pharmaceutical composition comprising at least one methyl-cyclodextrin having a degree of molar substitution of between 0.05 and 1.5 for its use in the treatment and / or prevention of atherosclerosis or complications related to atheroma, Alzheimer's disease or Nieman-Pick type C disease. Preferably, the compositions of the invention are used in the treatment and / or prevention of atherosclerosis or complications related to an atheroma. Atheroma-related complications typically include ischemia, eg myocardial ischemia, coronary artery disease, angina pectoris, acute coronary syndrome, myocardial infarction, mesenteric infarction, stroke. - brain, aneurysm, or arterial disease of the lower limbs and their consequences (consequences related to hypopoxia / ischemia, eg diabetes secondary to atherosclerosis). The methyl-cyclodextrin used in the pharmaceutical compositions of the invention preferably has a molar degree of substitution of between 0.2 and 1.2, and even more preferentially of between 0.4 and 0.9. Advantageously, the degree of molar substitution is between 0.6 and 0.8. In a particular embodiment, the methyl-cyclodextrin is a methyl-β-cyclodextrin. In another particular embodiment, the methyl-cyclodextrin is substituted on the hydroxyl borne by the C2 carbon of the glucopyranose units, or by the C3 and / or C6 carbons of the glucopyranose units or by a combination of the C2, C3 and / or or C6, preferably C2 and C6, glucopyranose units. Preferably, the methyl-cyclodextrin compositions comprise one or more methyl-β-cyclodextrins selected from the group consisting of hydroxyl-substituted methyl-β-cyclodextrins carried by the C2 carbon of the glucopyranose units, the methyl-β-cyclodextrins substituted on the the hydroxyl borne by the C3 and / or C6 carbons of the glucopyranose units, the hydroxyl-substituted methyl-β-cyclodextrins carried by the C2, C3 and / or C6 carbons, preferably C2 and C6 of the glucopyranose units and the said methyls; -P-cyclodextrins having a degree of molar substitution of between 0.6 and 0.8. Advantageously, the methyl-cyclodextrin compositions comprise at least 50, 60 or 75% of methyl substituted on the hydroxyl borne by the C2 carbon of the glucopyranose units. Optionally, the compositions comprising at least one methyl-cyclodextrin also comprise a cyclodextrin, in particular p -cyclodextrin, unsubstituted and / or a cyclodextrin, in particular p-cyclodextrin, substituted with sulfobutyl ether (SBE-) and hydroxypropyl (HP) groups. ), preferably with a degree of molar substitution of between 0.05 and 1.5. The pharmaceutical compositions used in the context of the present invention may further comprise at least one additional active agent.
    [0011] The additional active agent is preferably an active agent used in the treatment of atherosclerosis or complications related to an atheroma, preferentially a statin, a platelet antiaggregant or anticoagulant agent, preferably selected from aspirin, clopidogrel new oral anticoagulants such as dabigatran, apixaban, rivaroxaban, and anti-vitamin K - an antihypertensive agent, preferably selected from the angiotensin converting enzyme inhibitors such as perindopril, captopril, enalapril, lisinopril or ramipril, angiotensin II receptor antagonists such as losartan, valsartan, or candesartan, and / or among beta-blockers such as acebutolol, labetalol, nadolol, oxprenolol, penbutolol, pindolol, or propranolol, or a combination thereof.
    [0012] Preferably, the additional active agent is an angiotensin II receptor antagonist, such as losartan, valsartan, or candesartan. The pharmaceutical compositions according to the invention are capable of being administered orally, parenterally, or cutaneously or mucosally.
    [0013] In a particular embodiment, the compositions of the invention are furthermore used to promote a decrease in the level of triglycerides and circulating fatty acids. In another particular embodiment, the compositions of the invention are used to reduce or prevent atheroma plaques.
    [0014] In yet another particular embodiment, the compositions used in the invention are free of phospholipid vesicles. DETAILED DESCRIPTION OF THE INVENTION The inventors have identified a new use of a pharmaceutical composition comprising at least one methyl-cyclodextrin having a molar degree of substitution of between 0.05 and 1.5 in the treatment and / or prevention of diseases. likely to be treated and / or prevented by an increase in HDL cholesterol and / or by a reduction or prevention of atheroma plaques. In particular, the inventors have surprisingly discovered that the composition of the invention has the effect of increasing the HDL-cholesterol level in an individual, and furthermore, of decreasing the level of triglycerides and of circulating fatty acids and to reduce atheromatous plaques. The inventors have thus demonstrated that the composition of the invention, thanks to its different properties, can notably be used in the treatment and / or prevention of diseases related to overloading, and / or storage, and / or accumulation. of cholesterol in the tissues, as well as their consequences. In particular, these diseases include atherosclerosis or complications related to atheroma, Alzheimer's disease, and Niemann-Pick type C disease. The invention therefore relates to a pharmaceutical composition comprising at least one methyl-cyclodextrin having a degree of molar substitution between 0.05 and 1.5 for its use in the treatment and / or prevention of diseases that can be treated and / or prevented by an increase in HDL-cholesterol, in particular atherosclerosis or complications related to atheroma, Alzheimer's disease and Niemann-Pick type C disease. It also relates to a pharmaceutical composition comprising at least one methyl-cyclodextrin having a degree of molar substitution of between 0.05 and 1, 5 for its use in the treatment and / or prevention of diseases that can be treated and / or prevented by the reduction of atheromatous plaques or by the prevention of atheroma plaque formation.
    [0015] The invention also relates to a pharmaceutical composition comprising at least one methyl-cyclodextrin having a degree of molar substitution between 0.05 and 1.5 for its use in the treatment and / or prevention of atherosclerosis or complications related to atheroma, Alzheimer's disease and Niemann-Pick type C.
    [0016] The invention also relates to methods or methods employing a pharmaceutical composition comprising at least one methyl-cyclodextrin as defined in the present invention for its administration in a therapeutically effective amount in an individual suffering from a disease likely to be treated and / or prevented by an increase in HDL-cholesterol and / or by a reduction or prevention of atheroma plaques, particularly atherosclerosis or complications related to atheroma, Alzheimer's disease and Niemann-Pick type C. The invention also relates to the use of a pharmaceutical composition comprising at least one methyl-cyclodextrin as defined in the present application for the preparation of a medicament for treating and / or preventing diseases susceptible of be treated and / or prevented by an increase in HDL cholesterol and / or by a reduction or prevention of atherosclerosis, preferably atherosclerosis or complications related to atheroma, Alzheimer's disease and Niemann-Pick type C disease. Methyl-cyclodextrins Cyclodextrins are cyclic oligosaccharides derived from the enzymatic degradation of 'starch. The three most common natural cyclodextrins consist of 6, 7 or 8 α-D-glucopyranose units in chair configuration interconnected by α-1,4 bonds. They are more commonly referred to as , (3, or Cyclodextrin, respectively.) Their three-dimensional structure appears as a truncated cone outside of which are the hydroxyl groups representing the highly hydrophilic part of the cyclodextrins. inside the cone or the cavity of the cyclodextrins is constituted by the hydrogen atoms carried by the C3 and C5 carbons as well as by the oxygen atoms participating in the glycosidic bond, thus conferring on them an apolar character. hydrophilic and a hydrophobic cavity are generally used for their ability to encapsulate the hydrophobic compounds and, therefore, for their role as protector and solubilizer of hydrophobic active substances.They are thus classically found in the fields of food processing, but also in galenic where they are used as an excipient in administered pharmaceutical formulations orally or in cosmetic formulations administered topically. In order to improve the aqueous solubility of natural cyclodextrins, numerous derivatives have been synthesized by grafting various groups on the hydroxyl functions. The glucopyranose units of the cyclodextrins in fact each comprise 3 reactive hydroxyl groups, which are borne by the C2, C3 and C6 carbons. Examples of derivatives include hydroxypropyl cyclodextrins, methylcyclodextrins and "sulfated" cyclodextrin derivatives. Frômming and Szetli have shown in the case of methyl-cyclodextrins that the increase in the degree of methylation promotes solubilization up to a degree of molar substitution equal to 2, and that beyond the solubilization decreased. Some authors have also been interested in cyclodextrins and their derivatives other than by their role of pharmaceutical excipient.
    [0017] For example, the patent application WO 02/43732 describes the role of cyclodextrins or hydroxypropyl-cyclodextrins in the metabolism of cholesterol, and especially to promote the efflux of cholesterol macrophages. In this application, the authors recall that there are two mechanisms of actions of cyclodextrins. High affinity cyclodextrins for cholesterol act directly by complexing the membrane cholesterol of macrophages. In contrast, low affinity cyclodextrins for cholesterol act as a catalyst for efflux of cholesterol from the cell membrane to an extracellular acceptor which is a phospholipid vesicle. In the latter case, the efflux of cholesterol can be done only in the presence of another element which is an exogenous acceptor phospholipid vesicle. Thus, if pharmacological effects on cholesterol are mentioned in the prior art, the therapeutic value of cyclodextrins remains highly questionable.
    [0018] Indeed, high affinity cyclodextrins, due to their activity in the complexation of cholesterol, would have required to be administered in considerable quantities, which would not have been pharmaceutically acceptable and which would have generated toxicity problems due to the fact that large amount of solubilized cholesterol.
    [0019] As for the low affinity cyclodextrins, the need to co-administer them with phospholipid vesicles makes it a technology that is far too complex in the light of current knowledge, in particular because the phospholipid vesicles are very unstable The use of methyl-cyclodextrins among other active agents have been suggested in the treatment of atherosclerosis (WO 2006/032905). In particular, this patent application suggests that the methyl-cyclodextrins are capable of inhibiting the bonds between the oxidized LDLs and the monocytes. The use of methyl-β-cyclodextrins has been suggested in methods for modulating the inflammatory response by altering plasma cholesterol levels (US 2008/0032925). The methyl-β-cyclodextrin used in this application is a methyl β-cyclodextrin marketed by Sigma Aldrich and which has a degree of molar substitution well above 1.5.
    [0020] In the present invention, the inventors use particular cyclodextrin compositions as an active ingredient for the purpose of significantly increasing the plasma HDL-cholesterol level while minimizing the toxicity-related disadvantages in a patient. The compositions of the invention make it possible to rule out the toxicity problems by virtue of their particular characteristic, namely a degree of substitution, in particular of methylation, which is relatively low as well as a low affinity for cholesterol. Surprisingly, and despite their low affinity for cholesterol, the methylcyclodextrins, and particularly the methyl-β-cyclodextrins, used in accordance with the present invention, do not require the addition of phospholipid vesicles to exert their effect. The results obtained by the inventors suggest a different mode of action for these particular methyl-cyclodextrins, which would not go through the complexation of cholesterol, nor by the catalysis of a transport to vesicles of phospholipids. Quite original, these methyl-cyclodextrins seem to promote the efflux of cholesterol in the form of HDL cholesterol, and not in a form complexed with cyclodextrins, or vesicles of phospholipids. The present invention therefore relates to a new use of a pharmaceutical composition comprising at least one methyl-cyclodextrin having a degree of molar substitution of between 0.05 and 1.5 in the treatment and / or prevention of diseases that can be treated. and / or prevented by an increase in HDL cholesterol and / or by a reduction or prevention of atheroma plaques. The invention also relates to a new use of a pharmaceutical composition comprising at least one methyl-cyclodextrin having a molar degree of substitution of between 0.05 and 1.5 in the treatment and / or prevention of atherosclerosis or complications related to atheroma, Alzheimer's disease and Niemann-Pick type C disease. "Molar degree of substitution (MS)" means the number of hydroxyls substituted, in particular by a methyl group, per glucopyranose unit. It should be noted that the degree of molar substitution (MS) is different from the degree of molecular substitution (DS) which corresponds to the number of hydroxyls substituted, in particular by a methyl group, per molecule of cyclodextrin and which therefore takes into account the number of units. glucopyranoses constituting methyl-cyclodextrin.
    [0021] MS can be determined in the present invention by Nuclear Magnetic Resonance of proton (NMR), or by mass spectrometry (Electrospray ionization mass spectrometry (ESI-MS) or matrix assisted laser desorption / ionization mass spectrometry). (MALDI-MS)). Although these techniques are well known to those skilled in the art, optimal conditions for determining the MS of the methyl-cyclodextrins according to the invention are in particular well described in the reference thesis of JACQUET Romain. "Hydrophilic cyclodextrins: characterization and study of their enantioselective and complexing properties. Use of liquid chromatography and mass spectrometry ". Thesis of chemistry and physicochemistry of compounds of biological interest. University of Orleans, 2006. available on: http: // tel. archive s -ouv erte s .fr / docs / 00/18/55/42 / PDF / jacquet.pdf (accessed 27.11.2013). In particular Chapter 2, Part B (pages 59 to 83). Preferably, the MS is determined by NMR, according to the following method: the measurements are carried out at 25 ° C. on a 250 MHz DPX device Advance (Bruker, Rheinstetten, Germany). Calibration is performed with signal D20. The samples of methylcyclodextrin according to the invention, and of native cyclodextrin, that is to say unmethylated, are prepared at a concentration of 5 mg in 0.75 ml of D20. The solutions are evaporated to dryness under a stream of nitrogen and then reconstituted in 0.75 ml of D20. This operation is repeated twice to ensure a total exchange of the protons of the hydroxyl functions. The MS is calculated from the difference in integration between the spectrum of the native cyclodextrin and that of the methyl-cyclodextrin according to the invention. A typical spectrum is shown in FIG. 1. It should be noted that the methyl cyclodextrin used according to the invention, although possibly corresponding to a pure product, generally corresponds to a mixture of methyl cyclodextrins of different structures. This is the case, for example, with the product marketed by the Applicant under the name KLEPTOSE® CRYSMEB, which exhibits, in particular, the physico-chemical properties as determined in the aforementioned JACQUET Romain thesis, in particular in Chapter 2, Part B (pages 59 at 83).
    [0022] As a result, the measured MS is in this case an average of the substitutions that take place on all the glucopyranose units of the whole mixture of methylcyclodextrins.
    [0023] This mixture may especially contain residual native cyclodextrin, that is to say unmethylated, but which are generally in negligible amounts, in particular less than 1% by dry weight relative to the total dry weight of the methyl-cyclodextrin preferably less than 0.5%, more preferably less than 0.1%.
    [0024] In the context of the invention, the compositions comprise at least one methylcyclodextrin having a degree of molar substitution of between 0.05 and 1.5. Advantageously, the methyl-cyclodextrin has an MS of between 0.1 and 1.4, preferably between 0.1 and 1.3, preferably between 0.2 and 1.2, preferably between 0.3 and 1.1, preferentially between 0.3 and 1, preferably between 0.5 and 0.9, preferably between 0.6 and 0.8, for example 0.7. Preferably, at least 50% of the methyl groups of the methyl-cyclodextrin used in the context of the present invention are located at the level of the hydroxyl borne by the C2 carbon of the glucopyranose unit, preferably between 60 and 80%, typically from the order of 75%.
    [0025] At the same time, the other methyl groups are generally located mainly at the level of the hydroxyl borne by the C3 and / or C6 carbon of the glucopyranose unit. Those skilled in the art know how to determine the distribution of the methyl groups on the hydroxyls of the glucopyranose unit of methyl-cyclodextrin, for example by NMR.
    [0026] Advantageously, the methyl-cyclodextrin used in the context of the present invention comprises 7 α-D-glucopyranose units. It is therefore a methyl-β-cyclodextrin. In a particular embodiment, the methyl-cyclodextrin is a methyl-β-cyclodextrin and has an MS of between 0.05 and 1.5, preferably between 0.1 and 1.4, preferably between 0.1 and 1. , 3, preferably between 0.2 and 1.2, preferentially between 0.3 and 1.1, preferably between 0.4 and 1, preferably between 0.5 and 0.9, preferably between 0.6 and 0.8. for example 0.7.
    [0027] The methyl-cyclodextrin may be substituted on the hydroxyl carried by the carbon C2 of the glucopyranose units, or by the C3 and / or C6 carbons of the glucopyranose units, or by a combination of the C2, C3 and / or C6 carbons, preferably C2 and C6 glucopyranose units.
    [0028] In another particular embodiment, the methyl-cyclodextrin is a methylcyclodextrin, preferably a methyl-β-cyclodextrin, of which at least 50% of the methyl groups are located at the hydroxyl borne by the carbon C2 of the unit. glucopyranose, preferably between 60 and 80%, typically of the order of 75%, and has an MS of between 0.05 and 1.5, preferably between 0.1 and 1.4, preferably between 0.1 and 1 , 3, preferably between 0.2 and 1.2, preferentially between 0.3 and 1.1, preferably between 0.4 and 1, preferably between 0.5 and 0.9, preferably between 0.6 and 0.8. for example 0.7.
    [0029] In a preferred embodiment, the methyl-cyclodextrin composition comprises one or more methyl-β-cyclodextrins selected from the group consisting of hydroxyl-substituted methyl-β-cyclodextrins carried by the C2 carbon of the glucopyranose, methyl, and -P-cyclodextrins substituted on the hydroxyl borne by the C3 and / or C6 carbon glucopyranose units, methyl-β-cyclodextrins substituted on the hydroxyl borne by the C2, C3 and / or C6 carbons, preferably C2 and C6 glucopyranose units and having an MS of between 0.05 and 1.5, preferably between 0.1 and 1.4, preferably between 0.1 and 1.3, preferably between 0.2 and 1.2, preferentially between 0.3 and 1.1, preferably between 0.4 and 1, preferably between 0.5 and 0.9, preferably between 0.6 and 0.8, for example 0.7. Preferably, the methyl-cyclodextrin composition comprises at least 50, 60 or 75% of methyl substituted on the hydroxyl borne by the C2 carbon of the glucopyranose units. As mentioned above, the methyl-cyclodextrin according to the invention may be a mixture. The mass spectrometric analysis of the product KLEPTOSE® CRYSMEB, which is a methyl-β-cyclodextrin, reveals in particular that it is a polydisperse product, comprising seven groups of methyl-cyclodextrins, which are distinguished by their DS. This DS, which in theory can vary from 0 to 21 for a methyl-β-cyclodextrin, varies from 2 to 8 in the KLEPTOSE® CRYSMEB product.
    [0030] Advantageously, the compositions of the invention comprise a mixture of methylcyclodextrins comprising at least 50, 60, 70, 80 or 90% of methyl-cyclodextrins having an MS of between 0.2 and 1.2. Preferably at least 40, 50, 60, 70, 80 or 90% of methyl-cyclodextrins have an MS of between 0.3 and 1.1. Preferably at least 30, 40, 50, 60, 70, 80 or 90% of methyl cyclodextrins have an MS of between 0.5 and 0.9. Even more preferably, at least 25, 30, 40, 50, 60, 70, 80 or 90% of methyl-cyclodextrins have an MS of between 0.6 and 0.8. The methyl-cyclodextrin compositions can optionally be prepared by adding different methyl-cyclodextrins having defined MS to obtain compositions as defined in the present invention or they can be obtained as a result of the synthesis thereof. Thus, in another particular embodiment, the composition of methylcyclodextrins, preferably of methyl-β-cyclodextrins, exhibits the substitution profile, expressed in molar percentages, according to: o 0 to 5% of methyl-β-cyclodextrins comprise 2 groups methyls (DS of 2); o 5 to 15% of methyl-β-cyclodextrins comprise 3 methyl groups (DS of 3); 20 to 25% of methyl-β-cyclodextrins comprise 4 methyl groups (DS of 4); 25 to 40% of methyl-β-cyclodextrins comprise 5 methyl groups (DS of 5); 15 to 25% of methyl-β-cyclodextrins comprise 6 methyl groups (DS of 6); 5 to 15% of methyl-β-cyclodextrins comprise 7 methyl groups (DS of 7); o 0 to 5% of methyl-β-cyclodextrins comprise 8 methyl groups (DS of 8); the total sum being generally of the order of 100%, although the composition may optionally contain traces of methyl-cyclodextrins of different DS, as well as traces of native cyclodextrin, that is to say unmethylated.
    [0031] The substitution profile can be determined by any technique well known to those skilled in the art, for example by ESI-MS or MALDI-TOF-MS. The optimal conditions for determining the substitution profile by these two methods are notably discussed in Romain JACQUET's thesis cited above, in Chapter 2, Part B, points 11.3 and 11.2 (pages 67 to 82) and in Appendix II. In a preferred embodiment, the composition of methyl-cyclodextrins, preferably of methyl-β-cyclodextrins, is such that at least 50% of the methyl groups are located at the hydroxyl borne by the C2 carbon of the glucopyranose units. , preferably between 60 and 80%, typically of the order of 75%, and which has the substitution profile, expressed in molar percentages, according to: o 0 to 5% of methyl-β-cyclodextrins comprise 2 methyl groups (DS of 2); o 5 to 15% of methyl-β-cyclodextrins comprise 3 methyl groups (DS of 3); 20 to 25% of methyl-β-cyclodextrins comprise 4 methyl groups (DS of 4); 25 to 40% of methyl-β-cyclodextrins comprise 5 methyl groups (DS of 5); 15 to 25% of methyl-β-cyclodextrins comprise 6 methyl groups (DS of 6); 5 to 15% of methyl-β-cyclodextrins comprise 7 methyl groups (DS of 7); o 0 to 5% of methyl-β-cyclodextrins comprise 8 methyl groups (DS of 8); the total sum being generally of the order of 100%, although the composition may optionally contain traces of methyl-cyclodextrins of different DS, as well as traces of native cyclodextrin, that is to say unmethylated.
    [0032] It is also entirely possible to envisage varying in proportions or isolating molecules or groups of molecules of methyl-cyclodextrins, in particular according to their DS.
    [0033] Thus, in another particular embodiment, the methyl-cyclodextrin is a methyl-β-cyclodextrin which has a DS chosen from an integer ranging from 2 to 8, in particular 2, 3, 4, 5, 6, 7 or 8.
    [0034] In another preferred embodiment, the methyl-cyclodextrin is a methyl-β-cyclodextrin in which at least 50% of the methyl groups are located at the hydroxyl borne by the C2 carbon of the glucopyranose units, preferably between 60 and 80%. , typically of the order of 75%, and which has a DS chosen from an integer ranging from 2 to 8, in particular 2, 3, 4, 5, 6, 7 or 8.
    [0035] In another particular embodiment, the methyl-cyclodextrin, in particular methyl-β-cyclodextrin, has an MS of between 0.1 and 0.3, in particular between 0.2 and 0.3. In another particular embodiment, the methyl-cyclodextrin, in particular the methyl-β-cyclodextrin, has an MS of between 0.3 and 0.5. In another particular embodiment, the methyl-cyclodextrin, in particular the methyl-β-cyclodextrin, has an MS of between 0.5 and 0.6. In another particular embodiment, the methylcyclodextrin, in particular methyl-β-cyclodextrin, has an MS of between 0.6 and 0.7. In another particular embodiment, the methyl-cyclodextrin, in particular the methyl-β-cyclodextrin, has an MS of between 0.7 and 0.8. In another particular embodiment, the methyl-cyclodextrin, in particular methyl-β-cyclodextrin, has an MS of between 0.8 and 0.9. In another particular embodiment, the methylcyclodextrin, in particular methyl-β-cyclodextrin, has an MS of between 0.9 and 1.1. In another particular embodiment, the methyl-cyclodextrin, in particular methyl-β-cyclodextrin, has an MS of between 1.1 and 1.2.
    [0036] Generally, the methyl-cyclodextrin used according to the invention has a reducing sugar content of less than 1% by dry weight, preferably less than 0.5%. The composition of methyl-β-cyclodextrins according to the invention can be obtained by the process described in US Pat. No. 6,602,860 B1. An example of such a composition is marketed by the Roquette Frères group under the trade name KLEPTOSE® CRYSMEB and has a degree of molar substitution of 0.7 methyl per unit glucose.
    [0037] Optionally, the composition according to the present invention may further comprise a cyclodextrin, in particular (3-cyclodextrin, unsubstituted and / or a cyclodextrin, in particular (3-cyclodextrin, substituted by sulfobutyl ether (SBE-), hydroxyethyl, hydroxypropyl (HP-), carboxymethyl, carboxyethyl, acetyl, triacetyl, succinyl, ethyl, propyl, butyl, sulphates, preferably sulphobutyl and hydroxypropyl, preferably with a molar degree of substitution between 0.05 and 1.5. methyl-cyclodextrin according to the invention, in particular methyl-β-cyclodextrin, may be substituted by additional groups, in particular chosen from those listed before, It may therefore for example be a sulfated methyl- (3-cyclodextrin) In a separate embodiment, the present invention also considers the use for the treatment of diseases according to the present invention of other cyclodextrins, preferably (3-cyclodextrin), having a degree of molar substitution according to the present invention, that is to say between 0.05 and 1.5, preferably between 0.1 and 1, 4, preferentially between 0.1 and 1.3, preferentially between 0.2 and 1.2, preferably between 0.3 and 1.1, preferably between 0.4 and 1, preferably between 0.5 and 0.9, preferably between 0.6 and 0.8, for example 0.7. These cyclodextrin derivatives, preferably (3-cyclodextrin, are substituted by a group chosen from sulphobutyl ethers (SBE-) and hydroxypropyls (HP-). Preferably, these substitutions are predominantly borne by the C2 carbon of the glucopyranose units, typically at 50%, 60%, 70% or 80%.
    [0038] Application In the context of the present invention, the pharmaceutical compositions comprising at least one methyl-cyclodextrin as defined in the present application are used in the treatment and / or prevention of diseases that can be treated and / or prevented by an increase. HDL-cholesterol and / or reduction or prevention of atheromatous plaque, particularly atherosclerosis or complications related to atheroma, Alzheimer's disease, or Niemann-Pick type disease vs.
    [0039] In the context of the present invention, the increase in HDL cholesterol is measured in any type of biological fluid. It is preferentially the level of plasma HDL-cholesterol. This HDL-cholesterol level can be measured by any method known to those skilled in the art, for example by precipitation, or by direct methods in homogeneous phase using immunological techniques. An assay of the protein part (Apo A1 protein) making up HDL is also possible. HDL cholesterol is usually expressed as the number of moles of cholesterol transported by high density lipoprotein (HDL) per liter of blood. HDL-cholesterol is related to "good cholesterol" as opposed to cholesterol transported by LDL. According to the invention, the diseases that can be treated and / or prevented by an increase in the HDL-cholesterol level are all the diseases whose symptoms and / or causes disappear or are attenuated in a patient when the cholesterol- HDL is superior to HDL-cholesterol before treatment. Preferably, the diseases are those that can be treated and / or prevented by an increase in the HDL-cholesterol level. By "increase" can be meant an increase in HDL cholesterol level of at least 5, 7.5, 10, 15 or 20%.
    [0040] Diseases that can be treated and / or prevented by an increase in the HDL-cholesterol level are preferably diseases related to overloading, and / or storage, and / or cholesterol accumulation in the tissues, as well as as their consequences. Examples of diseases that may be related to overloading, and / or storage, and / or accumulation of cholesterol in the tissues include cardiovascular diseases, vascular diseases, occlusive peripheral arterial diseases such as than atherosclerosis or complications related to atheroma. Another example is Niemann-Pick type C disease characterized by an accumulation of unesterified cholesterol in the Central Nervous System (CNS).
    [0041] The accumulation of cholesterol in the brain can also be the cause of Alzheimer's disease and an increase in HDL-cholesterol levels promotes its transport to the liver where it is degraded. There is strong evidence that malfunctioning cholesterol metabolism in the brain and the vascular system is likely to be closely involved in Alzheimer's disease. In this context, a treatment whose effect is an increase in the level of HDL cholesterol that contributes to the transport of excess cholesterol to the liver where it is degraded makes perfect sense for this application. Indeed, a cluster of observations, statistical data and experiments at the molecular level lead to a more and more significant role for cholesterol metabolism in the genesis of Alzheimer's disease. In particular a convergence between atherosclerosis and Alzheimer's disease (AD) as well as between Alzheimer's disease and Niemann-Pick type C disease is firmly established. This last rare disease is remembered by the excessive accumulation of cholesterol in nerve cells. Furthermore, the present invention also relates to diseases that can be treated and / or prevented by a reduction or prevention of atheroma plaques. By atheroma plaque reduction is preferably meant that the plaques have a smaller surface area in the presence of the treatment than in the absence thereof. In particular, the reduction of the surface area of the plates by 10, 20, 30, 40 or 50%. Preferably, this reduction is at least 30 or 40%. The surface of the atheroma plaques can be determined by any method known to those skilled in the art and in particular medical imaging methods such as MRI (Magnetic Resonance Imaging) prevention of atheromatous plaques, is understood to mean slowing down the development or formation of these plaques. The diseases that can be treated and / or prevented by a reduction or prevention of atheromatous plaques, are in particular cardiovascular diseases, vascular diseases, and preferentially occlusive peripheral arterial diseases such as atherosclerosis or complications related to an atheroma. According to the invention, the diseases that can be treated and / or prevented are preferably atherosclerosis or complications related to atheroma, Alzheimer's disease or Niemann-Pick type C disease and, advantageously, atherosclerosis. or complications related to atheroma. The atheroma-related complications which are treated and / or prevented by the use of a pharmaceutical composition comprising at least one methyl-cyclodextrin of the invention are, in a nonlimiting manner, ischemia, for example myocardial ischemia, coronary heart disease, angina pectoris, acute coronary syndrome, myocardial infarction, mesenteric infarction, cerebrovascular accident, aneurysm or arterial disease of the lower limbs.
    [0042] In another particular embodiment, the compositions of the invention used further comprise at least one additional active agent. The additional active agent is preferably selected from the group of active agents known to those skilled in the art to treat and / or prevent atherosclerosis or complications related to atheroma. The subjects to be treated are preferably humans or animals, preferably humans. They may have a proven illness (diagnosed or established) or be at risk of developing this disease. In particular, the present invention "treatment" means a decrease in the causes or symptoms of a disease, the delay in the onset of the disease, a slowing of the development of the latter but also a cure. Examples of active agents used in the treatment of atherosclerosis or complications related to atheroma include: statins; antihypertensive agents, in particular: angiotensin converting enzyme inhibitors, for example perindopril, captopril, enalapril, lisinopril, or ramipril; o angiotensin II receptor antagonists, also known as "sartans", such as losartan, valsartan, candesartan; o beta-blockers, such as acebutolol, labetalol, nadolol, oxprenolol, penbutolol, pindolol, propranolol; platelet antiaggregants or anticoagulants, in particular: o asipirine; o clopidogrel (PLAVIX®); o new oral anticoagulants such as dabigatran / Pradaxa®, apixaban / Eliquis®, rivaroxaban / Xarelto®, indicated for the prevention of phlebitis, embolism or stroke in the indication of atrial fibrillation; o anti-vitamin K, very effective but little used today because require a very close monitoring of coagulation. Preferably, the additional active agent will preferably be selected from angiotensin II receptor antagonists.
    [0043] The compositions according to the present invention are capable of being administered orally, parenterally, mucosally or cutaneously. The parenteral route preferably comprises subcutaneous, intravenous, intramuscular or intraperitoneal administration, although the latter is rather reserved for the animal. The mucosal route preferably comprises administration via the nasal route, via the pulmonary route, via the rectal mucosa. The dermal route advantageously comprises the dermal route, in particular via a transdermal device, typically a patch. Other routes of administration relating more particularly to diseases affecting the Central Nervous System (CNS), in particular Niemann-Pick type C disease or Alzheimer's disease, are the intrathecal or spinal route. The compositions according to the present invention also comprise a pharmaceutically acceptable excipient. Any excipient suitable for the galenical forms known to those skilled in the art can be used in particular for systemic administration, preferably for oral administration of parenteral administration, cutaneous or mucosal administration, in particular subcutaneous, intravenous, intramuscular, intraperitoneal, nasal, pulmonary, rectal, dermal, intrathecal or spinal. For example, saline, physiological, isotonic, buffered, etc., solutions compatible with a pharmaceutical use and known to those skilled in the art may be mentioned. The compositions may contain one or more agents or vehicles selected from dispersants, solubilizers, stabilizers, preservatives, etc. Agents or vehicles that can be used in formulations (liquid and / or injectable) include methylcellulose, hydroxymethylcellulose, carboxymethylcellulose, polysorbate 80, mannitol, gelatin, lactose, vegetable oils, acacia, liposomes etc. The compositions may be formulated as injectable suspensions, gels, oils, tablets, suppositories, powders, capsules, aerosols, etc., optionally using dosage forms or devices providing sustained and / or delayed release. For this type of formulation, an agent such as cellulose, carbonates or starches is advantageously used. It is advantageous to imagine a dosage form in which the cyclodextrin according to the invention is administered in a form complexed with a lipid substance, so as to allow it to pass into the bloodstream after administration by non-invasive routes, and / or in the case where the passage of the blood-brain barrier is desired, to allow the passage of this barrier. Among these lipid substances, mention may be made of tocopherol.
    [0044] The compositions that may be administered to an individual in the context of the invention comprise between 1 and 100 mg / kg, preferably between 20 and 70 mg / kg, more preferably between 30 and 50 mg / kg, and even more preferably 40 mg / kg of methyl-cyclodextrin as defined in the present invention, relative to the total weight of the individual. Of course, those skilled in the art are able to adapt the dose of methyl-cyclodextrin defined in the present application according to the weight of the individual to be treated. Advantageously, the compositions are therefore capable of being administered in a therapeutically effective amount in an individual suffering from a disease that can be treated and / or prevented by an increase in the level of HDL-cholesterol, or in an individual predisposed to developing such a disease. By effective therapeutic amount is meant a sufficient amount of composition capable of being administered in an individual to prevent and / or treat a disease as defined in the present invention.
    [0045] The compositions used in the invention can be administered in varying ways. In particular, they can be injected one to five times per week for 1, 2, 3, 4 weeks, or even 1, 2, 3 or more months. The methods of administration also include treatments at intervals spaced several weeks or months apart. For the treatment and / or prevention of atherosclerosis in particular, it is advantageous to envisage administration at intervals of 3 to 6 months, up to 12 months, of a duration of one week. Another object of the invention relates to the use of the pharmaceutical compositions as defined in the present application to further promote a decrease in the level of triglycerides and circulating fatty acids. A further object of the invention is the use of the pharmaceutical compositions as defined herein to reduce atheroma plaques. The use of the compositions of the invention make it possible both to increase the level of HDL-cholesterol, to reduce the levels of triglycerides and fatty acids circulating in the blood and to reduce the atheroma plaques. The composition of the invention also makes it possible to induce a decrease in the MMP-9 responsible for the weakening of the atheroma plaques, and therefore the complications related to atheroma. All these effects are obtained without modification of the LDL cholesterol level, and without any toxicity being detected. The decrease in MMP-9 also suggests the advantage of the composition according to the invention for use in the treatment and / or prevention of cancer. The following examples serve to illustrate and show other aspects and advantages of the invention and should be considered as non-limiting. EXAMPLES Male Apo E - / - mice 11 weeks old were used. The methyl-cyclodextrin composition used is the commercial product KLEPTOSE® CRYSMEB (ROQUETTE). The mice were divided into 6 groups: 2 groups of mice subjected to a normal diet for 16 weeks. This atheroma model is characterized by early disease. the first group was treated with a placebo solution (control mice, n = 9), the second group was treated with 40 mg / kg KLEPTOSE® CRYSMEB (treated mice, n = 12). 2 groups of mice fed a high cholesterol diet for 11 weeks. This model of atheroma is characterized by an advanced disease. the first group was treated with a placebo solution (control mice, n = 9), the second group was treated with 40 mg / kg KLEPTOSE® CRYSMEB (treated mice, n = 11). The treatments were performed by intraperitoneal injection of a volume of 200 μL of placebo (PBS solution) or solution of KLEPTOSE® CRYSMEB, three times a week. The blood samples were taken at the sacrifice of the animals, after the 16 or 11 weeks of treatment, by cardiac puncture, to determine the impact of the treatment on the lipidemia. Other values such as blood glucose, hematocrit values (hemoglobin level, erythrocyte count, leukocytes, lymphocytes and platelets) were measured without any differences between the different groups of mice. Therefore, these results are not presented here. After sacrifice, a quantification of the atheromatous surface was also performed on each group of mice by "computed-assisted morphometry", on 4 a 10.1 dm aortic sections labeled with haematoxiline and Oil-ref-O, taken at 200. , 400, 600 and 800! Dm after the departure of the cusp valve, according to the method described in the article "Caligiuri G, Groyer E, Khallou-Laschet J, Al Haj Zen A, Sainz J, Urbain D et al. Reduced immunoregulatory CD31 + T in the blood of atherosclerotic mice with plaque thrombosis. Arterioscler Thromb Vasc Biol 2005; 25: 1659-1664. ". Immunohistochemical markings of the MMP-9 atherosclerotic plaques were also performed and quantified to determine their fragility (R & D Systems kit). The results obtained are presented in Tables 1 and 2.25 Table 1: Mice under a normal diet and treated with a composition of methyl-cyclodextrins according to the invention Control mice (n = 9) Mice treated (n = 12) p Weight of body (g) Lipidemia 31.84 ± 2.70 30.71 ± 3.09 0.4137 Total cholesterol (mmol / L) 14.49 ± 1.65 14.19 ± 3.02 0.8070 LDL cholesterol ( mmol / L) 9.29 ± 1.22 9.76 ± 2.34 0.8621 HDL cholesterol (mmol / L) 2.77 ± 0.15 3.03 ± 0.38 0.1451 Triglycerides (mmol / ml) L) 2.20 ± 0.66 1.65 ± 0.55 0.0491 Free fatty acids (mmol / L) 1.33 ± 0.36 1.03 ± 0.40 0.0955 Sinus of the aortic valve Oil -red-O, x 103 lum 2 295.06 ± 36.25 246.14 ± 46.38 0.0278 MMP-9,% 6.35 ± 4.78 3.26 ± 4.84 0.0481 Aortic area plate (%) 5.56 ± 2.65 3.39 ± 1.26 0.0278 Values are expressed as mean ± standard deviation.
    [0046] The values of p are calculated according to the Mann-Whitney U-test.
    [0047] Table 2: Mice on a high cholesterol diet and treated with a methyl-cyclodextrin composition according to the invention Control mice (n = 9) Mice treated (n = 11) p Body weight (g) 30.44 ± 2 , 34 28.34 ± 2.80 0.1194 Lipidemia Total cholesterol (mmol / L) 21.48 ± 1.37 20.17 ± 1.37 0.4119 LDL cholesterol (mmol / L) 17.05 ± 3 , 81 17.51 ± 4.00 0.9999 HDL cholesterol (mmol / L) 3.44 ± 0.49 4.16 ± 0.82 0.0334 Triglycerides (mmol / L) 1.47 ± 0.65 0.90 ± 0.36 0.0136 Free fatty acids (mmol / L) 0.99 ± 0.25 0.75 ± 0.20 0.0310 Sinus of the aortic valve Oil-red-O, x 10'1 = 2,465.56 ± 66.99 439.45 ± 86.58 0.4119 MMP-9,% 22.80 ± 15.88 12.45 ± 9.80 0.1119 Aorta Plate area (%) 24 , 73 ± 6.75 15.00 ± 7.56 0.0200 Values are expressed as mean ± standard deviation. The values of p are calculated according to the Mann-Whitney U-test. It should be noted in these results that the displacement of the values resulting from the treatment is obtained not only after a rich diet, but also and in a surprising and favorable manner following a normal diet, not enriched in cholesterol.
    [0048] In both cases, an increase in the HDL-cholesterol level has been observed, showing the interest of the methyl-cyclodextrins according to the invention for use in the treatment and / or the prevention of diseases that can be treated and / or prevented by an increase in HDL cholesterol.
    [0049] In both cases, the surface of the atheroma plaques is significantly diminished. A significant decrease of nearly 40% in the atheromatous area was observed. These results demonstrate the interest of methyl-cyclodextrins according to the invention, for use in the treatment and / or prevention of atherosclerosis or complications related to atheroma, a decrease in triglycerides, free fatty acids and MMP-9 levels have been observed, and reinforce the interest of the methyl-cyclodextrins according to the invention for use in the treatment and / or prevention of atherosclerosis or complications related to atheroma.
    权利要求:
    Claims (18)
    [0001]
    REVENDICATIONS1. Pharmaceutical composition comprising at least one methyl-cyclodextrin having a degree of molar substitution of between 0.05 and 1.5, for its use in the treatment and / or prevention of diseases that can be treated and / or prevented by an increase HDL cholesterol level.
    [0002]
    2. A pharmaceutical composition comprising at least one methyl-cyclodextrin having a degree of molar substitution of between 0.05 and 1.5, for its use in the treatment and / or prevention of atherosclerosis or complications related to atheroma, Alzheimer's disease, or Niemann-Pick type C.
    [0003]
    3. A pharmaceutical composition for use according to claim 1 or 2 in the treatment and / or prevention of atherosclerosis or atheroma-related complications.
    [0004]
    A pharmaceutical composition for use as claimed in any one of claims 1 to 3 in the treatment and / or prevention of atheroma-related complications which include ischemia, preferably myocardial ischemia, coronary heart disease, angina pectoris, acute coronary syndrome, myocardial infarction, mesenteric infarction, cerebrovascular accident, aneurysm or arterial disease of the lower limbs and their consequences.
    [0005]
    5. Pharmaceutical composition for its use according to any one of claims 1 to 4, characterized in that the methyl-cyclodextrin has a degree of molar substitution of between 0.2 and 1.2, preferably between 0.4 and 0, 9.
    [0006]
    6. Pharmaceutical composition for its use according to any one of claims 1 to 5, characterized in that the methyl-cyclodextrin has a degree of molar substitution of between 0.6 and 0.8.
    [0007]
    7. Pharmaceutical composition for its use according to any one of claims 1 to 6, characterized in that the methyl-cyclodextrin is a methyl-Pcyclodextrin.
    [0008]
    8. Pharmaceutical composition for its use according to any one of claims 1 to 7, characterized in that the methyl-cyclodextrin is substituted on the hydroxyl borne by the carbon C2 of the glucopyranose units, or by the C3 and / or C6 carbons glucopyranose units, or by a combination of the C2, C3 and / or C6 carbons, preferably C2 and C6 glucopyranose units.
    [0009]
    A pharmaceutical composition for use as claimed in any one of claims 1 to 8, wherein the methyl cyclodextrin composition comprises one or more methyl-β-cyclodextrins selected from the group consisting of substituted methyl-β-cyclodextrins. on the hydroxyl carried by the C2 carbon of the glucopyranose units, hydroxyl-substituted methyl-β-cyclodextrins carried by the C3 and / or C6 carbons of the glucopyranose units, hydroxyl-substituted methyl-β-cyclodextrins carried on the carbons C2, C3 and / or C6, preferably C2 and C6 glucopyranose units and said methyl-β-cyclodextrins having a molar degree of substitution of between 0.6 and 0.8.
    [0010]
    Pharmaceutical composition for its use according to any one of claims 1 to 9, characterized in that the methyl-cyclodextrin composition comprises at least 50, 60 or 75% of methyl substituted on the hydroxyl carried by the carbon. C2 glucopyranose units.
    [0011]
    Pharmaceutical composition for its use according to any one of claims 1 to 10, characterized in that the composition comprising at least one methyl-cyclodextrin also comprises a cyclodextrin, in particular an unsubstituted cyclodextrin and / or a cyclodextrin, in particular p-cyclodextrin, substituted with sulfobutyl ether (SBE-) or hydroxypropyl (HP-) groups, preferably with a molar degree of substitution of between 0.05 and 1.5. 30
    [0012]
    12. The pharmaceutical composition for use according to any one of claims 1 to 11 further comprising at least one additional active agent.
    [0013]
    13. Pharmaceutical composition for its use according to claim 12, characterized in that the additional active agent is an active agent used in the treatment of atherosclerosis or complications related to an atheroma, preferably, - a statin, - an agent platelet antiaggregant or anticoagulant, preferably selected from aspirin, clopidogrel, new oral anticoagulants such as dabigatran, apixaban, rivaroxaban, and anti-vitamin K - an antihypertensive agent, preferably selected from the group of inhibitors angiotensin converting enzyme such as perindopril, captopril, enalapril, lisinopril or ramipril, angiotensin II receptor antagonists such as losartan, valsartan, or candesartan, and / or beta-blockers such as acebutolol, labetalol, nadolol, oxprenolol, penbutolol, pindolol, or propranolol, or a combination thereof. 15
    [0014]
    14. A pharmaceutical composition for use according to claim 13, characterized in that the additional active agent is an angiotensin II receptor antagonist, such as losartan, valsartan, or candesartan. 20
    [0015]
    15. Pharmaceutical composition for use according to any one of claims 1 to 14, characterized in that the composition is capable of being administered by administration orally, parenterally, or cutaneous or mucosal.
    [0016]
    16. A pharmaceutical composition for use as claimed in any one of claims 1 to 15 further promoting a decrease in the level of triglycerides and circulating fatty acids.
    [0017]
    17. A pharmaceutical composition for use as claimed in any one of claims 1 to 15 for reducing and / or preventing atheroma plaques. 30
    [0018]
    18. Composition for use according to any one of claims 1 to 17, characterized in that said composition is free of phospholipid vesicles.
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    同族专利:
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    EP3082831A1|2016-10-26|
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    PL3082831T3|2021-06-28|
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    JP2018123153A|2018-08-09|
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    CN110123831A|2019-08-16|
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    AU2020200500A1|2020-02-13|
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    WO2015087016A1|2015-06-18|
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    FR3083234B1|2018-06-29|2020-11-27|Roquette Freres|NEW HYDROXYPROPYL-BETA-CYCLODEXTRINS AND THEIR PREPARATION METHODS|
    EP3814386A1|2018-06-29|2021-05-05|Roquette Freres|NOVEL HYDROXYPROPYL-ß-CYCLODEXTRIN AND PROCESS FOR THE PRODUCTION THEREOF|
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    优先权:
    申请号 | 申请日 | 专利标题
    FR1362633A|FR3014694B1|2013-12-13|2013-12-13|METHYL-CYCLODEXTRIN-BASED COMPOSITIONS FOR THE TREATMENT AND / OR PREVENTION OF DISEASES BY INCREASING THE CHOLESTEROL-HDL RATE|FR1362633A| FR3014694B1|2013-12-13|2013-12-13|METHYL-CYCLODEXTRIN-BASED COMPOSITIONS FOR THE TREATMENT AND / OR PREVENTION OF DISEASES BY INCREASING THE CHOLESTEROL-HDL RATE|
    KR1020217017348A| KR20210072129A|2013-12-13|2014-12-12|Compositions based on methyl cyclodextrins for the treatment and/or prevention of diseases by increasing the hdl cholesterol level|
    KR1020217042008A| KR20210158867A|2013-12-13|2014-12-12|Compositions based on methyl cyclodextrins for the treatment and/or prevention of diseases by increasing the hdl cholesterol level|
    AU2014363270A| AU2014363270B2|2013-12-13|2014-12-12|Compositions based on methyl cyclodextrins for the treatment and/or prevention of diseases by increasing the HDL cholesterol level|
    DK14827505.0T| DK3082831T3|2013-12-13|2014-12-12|COMPOSITION BASED ON METHYL-CYCLODEXTRINS FOR THE TREATMENT AND / OR PREVENTION OF DISEASES BY INCREASING THE CONCENTRATION OF HDL CHOLESTEROL|
    CN201910316561.5A| CN110123831A|2013-12-13|2014-12-12|For the composition based on methyl flamprop by increasing the treatment of HDL cholesterol levels and/or prevention disease|
    EP14827505.0A| EP3082831B1|2013-12-13|2014-12-12|Compositions comprising methyl-cyclodextrines to treat or prevent diseases by enhancement of the hdl-cholesterol level|
    JP2016538683A| JP6322289B2|2013-12-13|2014-12-12|Composition based on methylcyclodextrin for treating and / or preventing diseases by increasing HDL cholesterol levels|
    PCT/FR2014/053309| WO2015087016A1|2013-12-13|2014-12-12|Compositions based on methyl cyclodextrins for the treatment and/or prevention of diseases by increasing the hdl cholesterol level|
    KR1020167013320A| KR20160088874A|2013-12-13|2014-12-12|Compositions based on methyl cyclodextrins for the treatment and/or prevention of diseases by increasing the hdl cholesterol level|
    PCT/FR2014/053310| WO2015087017A1|2013-12-13|2014-12-12|Compositions based on methyl cyclodextrins for the treatment and/or prevention of diseases by increasing the hdl cholesterol level|
    EP19184268.1A| EP3581188A1|2013-12-13|2014-12-12|Compositions based on methyl cyclodextrins for the treatment and/or prevention of cns diseases by increasing the hdl cholesterol level|
    CA2930489A| CA2930489A1|2013-12-13|2014-12-12|Compositions based on methyl cyclodextrins for the treatment and/or prevention of diseases by increasing the hdl cholesterol level|
    CN201480065300.6A| CN105792833B|2013-12-13|2014-12-12|Compositions based on methylcyclodextrin for the treatment and/or prevention of diseases by increasing HDL cholesterol levels|
    US15/039,864| US10022392B2|2013-12-13|2014-12-12|Compositions based on methyl cyclodextrins for the treatment and/or prevention of diseases by increasing the HDL cholesterol level|
    PL14827505T| PL3082831T3|2013-12-13|2014-12-12|Compositions comprising methyl-cyclodextrines to treat or prevent diseases by enhancement of the hdl-cholesterol level|
    BR112016013481-8A| BR112016013481A2|2013-12-13|2014-12-12|pharmaceutical composition, pharmaceutical composition for use, and non-therapeutic use of a composition|
    RU2016128411A| RU2677889C1|2013-12-13|2014-12-12|Compositions based on methyl cyclodextrins for treatment and/or prevention of diseases by increasing hdl cholesterol level|
    MX2016007658A| MX2016007658A|2013-12-13|2014-12-12|Compositions based on methyl cyclodextrins for the treatment and/or prevention of diseases by increasing the hdl cholesterol level.|
    ES14827505T| ES2859609T3|2013-12-13|2014-12-12|Compositions based on methyl-cyclodextrins for the treatment and / or prevention of diseases by increasing the level of HDL-cholesterol|
    US15/903,738| US11266680B2|2013-12-13|2018-02-23|Compositions based on methyl cyclodextrins for the treatment and/or prevention of diseases by increasing the HDL cholesterol level|
    JP2018073664A| JP2018123153A|2013-12-13|2018-04-06|Compositions based on methyl cyclodextrins for treating and/or preventing diseases by increasing hdl cholesterol level|
    AU2020200500A| AU2020200500B2|2013-12-13|2020-01-23|Compositions based on methyl cyclodextrins for the treatment and/or prevention of diseases by increasing the hdl cholesterol level|
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