CN1558766A - A method of reducing the 'in vivo' cholesterol ester transfer protein mediated transfer of cholesteryl esters between high density lipoproteins (HDL) and low density lipoproteins (LDL) - Google Patents
A method of reducing the 'in vivo' cholesterol ester transfer protein mediated transfer of cholesteryl esters between high density lipoproteins (HDL) and low density lipoproteins (LDL) Download PDFInfo
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Abstract
A method of reducing the in vivo cholesterol ester transfer protein mediated transfer of cholesteryl esters between high density lipoproteins (HDL) and low density lipoproteins (LDL) comprises administering a therapeutically effective amount of one or more compounds: wherein R is a sterol or stanol moiety R2 is derived from ascorbic acid and R3 is hydrogen or any metal, alkali earth metal, or alkali metal; and all salts thereof, whereby plasma HDL and LDL are controlled as a result of such administration.
Description
Invention field
The present invention relates to treatment or prevention animal, especially people's the cardiovascular disease and the method for basis sick (underlying condition) thereof, described cardiovascular disease and basic disease thereof comprise atherosclerosis, dyslipidaemia disease or imbalance.
Background of invention
Though progress of science and technology has promoted raising and people's life-time dilatation of people's life quality in recent years, atherosclerotic prevention does not still fully solve, and described atherosclerosis is the basic reason of cardiovascular disease (" CVD ").Atherosclerosis is a kind of degenerative process, comes from heredity (gene) factor and influencing each other such as the environmental factors of diet and life style.Studies show that up to the present, by form atherosclerotic plaque in blood vessel, according to the position of speckle in arterial tree, final blocking-up is to the blood supply of cardiac muscle or to the blood supply of brain or extremity, cholesterol may in atherosclerosis, work (1,2).Relevant summary shows that individual total serum cholesterol reduces by 1% and makes the danger of coronary artery events reduce by 2% (3).On the statistics, in the U.S., the average serum cholesterol reduces the death (4) that 10% (for example, from 6.0mmol/L to 5.3mmol/L) can prevent 100,000 people every year.Therefore, relevant with the high concentration of T-CHOL and low density lipoprotein, LDL (LDL) cholesterol hyperlipemia is an important risk.
Research shows that also the low plasma concentration of high density lipoprotein (HDL) cholesterol is the important risk factor (5) of progression of atherosclerosis, and high level has protectiveness.
Lipoprotein is lipid and proteic complex, is kept being bonded to each other by non-covalent bond.Every type lipoprotein has distinctive quality, chemical composition, density and physiological action.No matter how many density or granular sizes be, circulation lipid is made up of the core of cholesteryl ester and triglyceride and the peplos of phospholipid, free cholesterol and apolipoprotein.Apolipoprotein participates in the assembling and the secretion of lipoprotein, and structural intergrity is provided, and activates the enzyme that lipoprotein is modified, and is the part of a large amount of receptors and memebrane protein.The lipoprotein type of finding in blood plasma comprises HDL, LDL, intermediate density lipoprotein (IDL) (IDL) and very low density lipoprotein (VLDL) (VLDL).
Every type lipoprotein has the composition or the ratio of distinctive apolipoprotein.Topmost apolipoprotein is apolipoprotein-AI (apo-AI) among the HDL, and it accounts for the about 70% of albumen quality, and apo-AII accounts for other 20%.The ratio of apo-AI and apo-AII can be determined the function of HDL and the feature of anti-gruel type.Circulation HDL granule is made up of the plate-like with 200 to 400 kilodalton molecular weight and 7 to 10nm diameters and the non-uniform composition of spheroidal particle.
HDL is a kind of lipoprotein of main type, described lipoprotein is used for transporting the lipid of blood plasma, and HDL has multiple function in body, comprises reverse cholesterol transport, the synthetic cholesterol molecule substrate of bile acid is provided, transhipment agglutinin (clusterin), transhipment paraoxonase (paraoxonase), prevents lipoprotein oxidation and by adrenal cells selectivity picked-up cholesterol.The main lipid relevant with HDL comprises cholesterol, cholesteryl ester, triglyceride, phospholipid and fatty acid.
In order to understand HDL better is anti-gruel type how, and the atherosclerotic once process of brief explanation is necessary.Atherosclerotic process starts from LDL and is trapped in the blood vessel wall.The oxidation of this LDL causes the combination of the endotheliocyte of mononuclear cell and lining blood vessel wall.These mononuclear cells are activated and move to the endothelium gap, thereby change into the further oxidation that macrophage causes LDL at endothelium gap mononuclear cell.The LDL of oxidation is absorbed by the scavenger receptor on macrophage, causes the formation of foam cell.Propagation and migration by arterial smooth muscle cell produce fibrous cap (fibrou cap), therefore produce atheromatous plaque.
HDL is very important for the cholesterol of tissue beyond the transhipment liver to liver, and cholesterol is secreted in the bile with the form of free cholesterol or with the form of bile acid in liver, and described bile acid is formed by cholesterol.This process need several steps.The first step is to form newborn or preceding-β HDL granule in liver and intestinal.Unnecessary cholesterol passes cell membrane via the effect migration of ABCAI transport protein and enters among the newborn HDL.Lecithin cholesterol acyl transferase (LCAT) is converted into cholesteryl ester with cholesterol, and the HDL with new life is converted into sophisticated HDL subsequently.Then, the cholesterol of esterification is transferred to the lipoprotein that contains apo-B by cholesterol ester transfer protein (CETP) from HDL, and described lipoprotein is subjected to bulk absorption in the liver in a large number.1 new life's HDL is regenerated by liver triglyceride lipase and phospholipid transfer protein, and continues this circulation.Except the cholesterol of removing from peripheral cell, HDL also accepts the cholesterol from LDL and erythrocyte membrane.The mechanism of other reverse cholesterol transport can be included in passive diffusion cholesterol between the film that lacks cholesterol and HDL or other acceptor molecule.
HDL not only also may be by stoping the atherosis development of mode prevention of arterial of LDL oxidation by the effect of its reverse cholesterol transport.The enzyme that several HDL-are relevant participates in this process.Paraoxonase (PON1), the phospholipid hydroperoxide that LCAT and platelet activating factor PAF-AH (PAFAH) all generate in the LDL oxidizing process by hydrolysis participates in this process, and synergism is with the pre-anti-oxidation gathering of lipid in LDL.These enzymes make HDL have antioxidation and anti-inflammatory property.
CETP is by liver and the excretory a kind of plasma adiponectin transfer protein of fatty tissue, the transfer and the exchange (6) of its mediation neutral lipid and phospholipid.The cholesteryl ester of the triglyceride exchange HDL of CETP and VLDL, IDL and LDL.Because the catabolism of these lipoproteins is faster than HDL, so CETP has promoted the removing of HDL cholesteryl ester.This process causes the reduction of HDL size and protein content.Therefore, handle by cholesterol is moved back to liver from periphery, CETP has important function undoubtedly in reverse cholesterol transport.
Prove that the inhibition of CETP can be adjusted the ratio (7) of blood plasma HDL/LDL effectively, because the mobile effect with reduction HDL of cholesteryl ester from HDL to LDL.The evidence of these effects is described (8,9,10) by a lot of technical staff of this area.Other CETP inhibitor is described (11-19) in detail by researcheres.
In addition, there is the application of a lot of patents and announcement to disclose the multiple chemical compound that allegedly can be used for suppressing the CETP effect.These documents comprise: United States Patent (USP) 5,519,001, and it has described a kind of 36 amino acid whose peptides from baboon Apo C-1; WO publication 98/35937; European patent application 796,846, it has described the pyridine that the 2-aryl replaces; European patent application 818,448, it has described the tetrahydrochysene quinoline derivant; European patent application 818,197, it has described the pyridine with condensed hetero ring; PCT/US99/27946 (publication WO 00/38725) has described a kind of therapeutic alliance that comprises known CETP inhibitor and ileal bile acid transfer inhibitor; United States Patent (USP) 5,932,587, it has described heterocyclic fused pyridine; United States Patent (USP) 5,948,435 have described big liposome.
Above-mentioned list of references has shown that purpose is to develop continue and the ongoing work of the chemical compound of lipid adjusting safely and effectively.One object of the present invention is exactly to eliminate or alleviate the shortcoming and defect of safety known in the art and effectiveness aspect.
Summary of the invention
The invention provides a kind of being used to reduces the method that the protein mediated cholesteryl ester of body inner cholesterol transesterify shifts between high density lipoprotein (HDL) and low density lipoprotein, LDL (LDL), described method comprises one or more following chemical compounds of administering therapeutic effective dose:
Wherein R is sterol or stanol (stanol) part, and R2 comes from ascorbic acid, and R3 is hydrogen or metal arbitrarily, alkaline-earth metal, perhaps alkali metal; And all salt, so blood plasma HDL and LDL control by this administering mode.
The present invention comprises further and is used to reduce the protein mediated cholesteryl ester of body inner cholesterol transesterify transfer compositions between high density lipoprotein and low density lipoprotein, LDL that described compositions comprises that one or more have the chemical compound of following formula:
Wherein R is sterol or stanol (stanol) part, and R2 comes from ascorbic acid, and R3 is hydrogen or metal arbitrarily, alkaline-earth metal, perhaps alkali metal; And all salt of these structures; And carrier medicinal or food stage.
The present invention further provides and a kind ofly be used for the treatment of or prevent animal cardiovascular disease and basis thereof sick, comprise atherosclerosis, high fat of blood, the method of tangier's disease and hypercholesterolemia, described method comprises and reduces the protein mediated transfer of cholesteryl ester between high density lipoprotein (HDL) and low density lipoprotein, LDL (LDL) of body inner cholesterol transesterify, and described reduction is by using one or more sterols with above-mentioned formula and/or stanol (stanol) derivant is achieved to animal.
It has been found that the chemical compound of the present invention effectively protein mediated transfer of cholesteryl ester between HDL and LDL of cholesterol reducing transesterify astoundingly.Especially, cause like this rising of serum hdl level.Up to this point, also nobody recognizes the regulating effect of these chemical compounds for the cholesterol transfer of CETP-mediation.Purpose of the present invention just provides a kind of good method to control and to regulate surrounding tissue in vivo, cell, the lipid content and the composition in film and zone, extracellular.Another object of the present invention provides the chemical compound that is used for this method.
These effects and other major advantage will be described below in more detail.
Description of drawings
The present invention describes by following non-limitative drawings, wherein:
Fig. 1 is the chemical constitution of a kind of preferred compound of the present invention: phytostanol (phytostanol)-phosphoryl-ascorbic acid (also referring to FM-VP4) and sodium salt thereof;
Fig. 2 has shown that at dexycholate under TP2 or FM-VP4 (a kind of chemical compound of the present invention) existence or the non-existent condition, [3H] CE of CETP mediation is from the transfer of LDL to HDL, and wherein CETP is a purification.Data show is mean+/-standard deviation (n=4); Compare with control value,
*P＞0.05; But ND=is lower than the detection range of analysis;
Fig. 3 has shown that at dexycholate under TP2 or FM-VP4 (a kind of chemical compound of the present invention) existence or the non-existent condition, [3H] CE of CETP mediation is from the transfer of LDL to HDL, and wherein CETP originates from human plasma.Data show is mean+/-standard deviation (n=4); Compare with control value,
*P＞0.05; But ND=is lower than the detection range of analysis; With
Fig. 4 shown under the condition that the chemical compound of the present invention (FM-VP4) of high concentration exists, and [3H] CE of CETP mediation is from the transfer of LDL to HDL, and compared purification and the CETP human plasma source.Data show is mean+/-standard deviation (n=4); Compare with FM-VP4,
*P＞0.05.
The preferred embodiments of the invention
Providing of following detailed description is in order to help those skilled in the art to implement the present invention.Yet this detailed description should not be construed over-drastic limiting the scope of the invention.Those of ordinary skill in the art can carry out the modification and the change of these embodiments described herein, only otherwise deviate from the spirit and scope of the present invention.
According to the present invention, provide a kind of method to be used to reduce the transfer of the protein mediated cholesteryl ester of body inner cholesterol transesterify between high density lipoprotein (HDL) and low density lipoprotein, LDL (LDL), described method comprises one or more following chemical compounds of administering therapeutic effective dose:
Wherein R is sterol or stanol (stanol) part, and R2 comes from ascorbic acid, and R3 is hydrogen or metal arbitrarily, alkaline-earth metal, perhaps alkali metal; And all salt, so blood plasma HDL and LDL control by this administering mode.
Purpose is the dosage of authenticating compound to term " treatment is effectively ", thus the purpose of being achieved as follows:
A) suppress the transfer of CE between HDL and LDL that CETP-mediates; And therefore
B) level of raising HDL; And
C) prevention reduces, and eliminates or improves dyslipidemia disease or imbalance; Perhaps
D) prevention reduces, and eliminates or improves hypercholesterolemia, tangier's disease, the development of toxic shock syndrome or atherosclerotic lesions; Perhaps
E) prevention reduces, any situation, disease or imbalance that elimination or improvement have following feature: they are to lack HDL or to have excessive LDL in the blood plasma, VLDL, Lp (a), β-VLDL, therefore IDL or residue lipoprotein perhaps worsen as its basis.
In a kind of preferred mode, described method further comprises periodicity analysis plasma LDL levels (technology by employing known in the art and extensive is carried out) and adjusts to be treated to the amount and/or the concentration of drug compound or adjusts the step of medication if desired.
Utilize method described herein, the level of serum hdl is improved, and is selected from LDL, and the level of the atherogenic lipoprotein of VLDL and IDL is effectively controlled.The conciliation of plasma lipoprotein and control can be used for prevention, reduce, eliminate or improve a large amount of diseases and imbalance, described disease and imbalance include but not limited to: cardiovascular disease and basis thereof are sick, comprise atherosclerosis, the sick or imbalance of dyslipidemia, hypercholesterolemia, and tangier's disease, the development of atherosclerotic lesions and toxic shock syndrome.A lot of other diseases also can be improved by method of the present invention, and described other disease is to lack HDL or to have excessive LDL in the blood plasma, and therefore VLDL or IDL perhaps worsen as its basis.
Be described in more detail below the composition of chemical compound.Should be noted that, in whole disclosing, term " chemical compound ", " derivant ", " structure " and " analog " can be exchanged application each other to describe said structure, described structure and sterol or stanol (stanol) and ascorbic acid link to each other, and have been found that the transfer of CE between HDL and LDL that can effectively suppress the CETP-mediation.
Sterol (stanol)
Term used herein " sterol " comprises all hard-core sterols, for example: sitosterol, campesterol, stigmasterol, brassicasterol (comprising Neospongosterol,dihydro-), 24-dehydrocholesterol, spongosterol (chalinosterol), poriferasterol (poriferasterol), chionasterol, ergosterol, coprosterol, codisterol, isofucosterol, 24-ethylidenecholest-5-en-3.beta.-ol., the paulownia sterol, neural sterol (nervisterol), lathosterol, asteriasterol (stellasterol), chondrillasterol, cartilage sterol (chondrillasterol), peposterol, avenasterol, different avenasterol, coprostenol (fecosterol), pollinastasterol, cholesterol and all natural or synthetic form and derivants thereof comprise isomer.Term " stanol (stanol) " is meant saturated or hydrogenant sterol, comprises all natural or synthetic form and derivant thereof, and isomer.Should be appreciated that for the modification of sterol and stanol (stanol), promptly comprise the modification of side chain, be also included within the scope of the present invention.For example, scope of the present invention comprises 24 β-ethyl Dihydrocholesterol (ethylchlostanol) undoubtedly, 24-α-ethyl-22-dehydrogenation Dihydrocholesterol (dehydrochol).Should be appreciated that also when query occurring in whole description, except as otherwise noted, term " sterol " comprises sterol and stanol (stanol).
According to the present invention, the sterol and the stanol (stanol) that are used to form derivant can be from multiple natural origins.For example, they can derive from the course of processing of plant (comprising water plant) oil, such as Semen Maydis oil and other vegetable oil, and wheat germ oil, soybean extract, Oryza sativa L. extract, Testa oryzae, Oleum Brassicae campestris, Oleum helianthi, Oleum sesami and fish (and other marine products source) oil.They also can be from fungus, for example ergosterol, perhaps animal, for example cholesterol.Therefore, the invention is not restricted to any sterol source.United States Patent (USP) 4,420,427 have told about utilization prepares sterol such as methanol solvent from vegetable oil dregs.Perhaps, plant sterol and phytostanol (phytostanol) can derive from and be described in United States Patent (USP) 5,770, the by-product of 749 tall oil pitch or tall oil soap, forest exploitation, and described document is incorporated herein by reference.
In a kind of preferred form, derivant of the present invention is with natural origin or synthetic cupreol, campestanol (campestanol), the form of sitostamol (sitostanol) and campesterol forms, and the every kind of derivant that forms like this can be mixed into compositions before transporting in varing proportions.In the preferred form of another kind, derivant of the present invention forms with the form of sitostamol natural origin or synthetic (sitostanol) or with the form of sitostamol natural origin or synthetic (sitostanol) or with the form of campestanol natural origin or synthetic (campestanol) or its mixture.
In a kind of most preferred form, sterol is its saturated form and is sitostamol (sitostanol).
R2
R2 comprises ascorbic acid or its derivant arbitrarily.What realize within the scope of the invention is a kind of new structure of preparation or chemical compound, and wherein sterol or stanol (stanol) part chemistry is connected on the ascorbic acid.This two parts that benefit and strengthened this new structure that are combined with.Originally the relatively poor plant sterol of dissolubility part is as the part of new derivative, and becoming is very easy to water-soluble and non-aqueous media, in oil ﹠ fat.Therefore, the administration of sterol need not any further improvement and just transports and can carry out to adjust it.
R3
R3 can be hydrogen atom or parent compound can be converted into salt.Most important consideration is in selecting suitable salt, and they are pharmaceutically useful, health cares, perhaps can be used for food, in the beverage.Such salt must have acceptable anion or cation.Within the scope of the invention, suitable acid-addition salts comprises those materials, and it is from mineral acid, such as hydrochloric acid, and hydrobromic acid, phosphoric acid, Metaphosphoric acid, nitric acid, sulfonic acid and sulphuric acid; And organic acid, such as acetic acid, benzenesulfonic acid, benzoic acid, citric acid, ethyl sulfonic acid, fumaric acid, gluconic acid, glycuronic acid (glyconic), hydroxyacetic acid, different thionic acid, lactic acid, lactobionic acid, maleic acid, malic acid, methanesulfonic acid, succinic acid, toluenesulfonic acid and tartaric acid.
Suitable alkali salt comprises ammonium salt, perhaps slaine, alkali salt or alkali metal salt arbitrarily.Preferably, R3 is selected from: calcium, magnesium, manganese, copper, zinc, sodium, potassium and lithium.Most preferably, R3 is a sodium.
In a kind of most preferred form of the present invention, chemical compound is above-mentioned structure 1, and stanol (stanol) is that sitostamol (sitostanol) and R3 are sodium.
The formation of derivant
The formation of ester of the present invention and salt thereof is described among the PCT/CA00/00730, and it is incorporated herein by reference in full.
Combination with the cholesterol transport regulator
In another embodiment, administration or administration respectively in an interval can be mixed, be total to derivant of the present invention with the medicament or the chemical compound of one or more cholesterol regulating transhipments before administration.The fact that the principle basis of this combination is following: along with the level of CETP raising HDL, the amount of transferring to the cholesterol the liver from surrounding tissue can improve.This may cause that the following mediation of ldl receptor in the liver contains the raising of the particulate output of apo B.CETP-inhibitor of the present invention and suppress combination of compounds that intestinal absorbs cholesterol again by be kept away from liver the chemical constituent gradient solved this problem, thereby stop the synthetic increase of liver lipoprotein.The suitable compound that cholesterol regulating absorbs includes but not limited to: the bile acid chelate, the bile acid transport protein inhibitor, plant sterol, phytostanol (phytostanol), the proteic regulator of abc transport, the regulator of PPAR (α and γ) and ezetimibe (ezetimibe).
The combination of these cholesterol absorption inhibitors and sterol derivative of the present invention is a co-action, has produced and kept the beneficial effect of regulating lipid.
Mechanism of action
Though chemical compound of the present invention is also uncertain for the accurate mechanism of action of CETP, there are two kinds of possible explanations.Thereby the combination of blocking-up CETP and lipoprotein prevents the transfer of CE on these chemical compounds possibility physiology.Perhaps, chemical compound of the present invention can be competed 26 amino acid whose hydrophobic binding sites of approaching-COOH end with CE, and described competitive way is similar to the competitiveness combination of TP2 monoclonal antibody.For any mode, effect all is identical.
Using method
Can different ways realize suppressing the effect that needs that the CE of CETP mediation shifts between HDL and LDL.These chemical compounds can utilize any medicine that is applicable to, health food, and food, the usual manner of beverage etc. carries out administration.
Do not limit above-mentioned generality, derivant of the present invention can be mixed with variety carrier or adjuvant, helps direct administration or help compositions of the present invention is mixed food, and beverage is in health food or the medicine.In order to understand the various possible carrier of sending derivant, provide following exemplifying.Suppressing the amount or the dosage of the necessary chemical compound of effect will determine according to multiple factor certainly for the CETP that need to obtain, such as, the particular compound of selecting, administering mode and prevention reduce, and eliminate or improve the mode of dyslipidemia disease or imbalance.
1) pharmaceutical dosage form
It is contemplated that within the scope of the invention chemical compound of the present invention can be included in multiple conventional medicine preparation and the dosage form, such as the tablet that is used for oral cavity buccal (bucally) or sublingual administration (common with coating), capsule is (hard with soft, gelatin has or does not have other coating), powder, granule (comprising effervescent granule), pill, microparticle, solution is (such as micelle, syrup, elixir and drop), lozenge, pastille, injection, Emulsion, microemulsion, ointment, emulsifiable paste, suppository, gel, the release dosage form of percutaneous patch and improvement is together with conventional excipients and/or diluent and stabilizing agent.
The derivant of the present invention that is suitable for above-mentioned dosage forms can administration be given and is comprised human animal, and administering mode can be for oral, by injection (intravenous, subcutaneous, intraperitoneal, Intradermal, perhaps intramuscular), part or alternate manner.
Preferably, chemical compound of the present invention comprises transhipment with other hydration lipid form mutually by physiology such as liposome with the phospholipid system.Be meant and form covalent bond and catch molecule this comprising, be widely used in the dissolubility that improves active component and decomposition subsequently.
The hydration lipid system that comprises liposome can utilize multiple lipid and lipid mixtures to be prepared, and described lipid and lipid mixtures comprise phospholipid, such as phosphatidylcholine (lecithin), phosphoglycerol diester and sphingolipid, glycolipid or the like.Lipid can be preferably and charged species unite use, described charged species is, such as charged phospholipid, fatty acid, and potassium salt and sodium salt, purpose is the stable lipid system that produces.The typical process process that forms liposome is as described below:
1) lipid of the present invention and chemical compound are dispersed in the organic solvent (such as, chloroform, dichloromethane, ether, ethanol or other alcohol are perhaps in its mixture).Can add charged kind to reduce the gathering in the liposome forming process subsequently.Also can add antioxidant (such as, ascorbic palmitate, alpha-tocopherol, Yoshinox BHT and Yoshinox BHT ether) to protect any unsaturated lipid that may exist;
2) filtering mixt is removed a spot of insoluble component;
3) remove solvent guaranteeing not occur under the condition of component phase-splitting (pressure, temperature);
4) by being exposed to the aqueous media that contains dissolved solute " exsiccant " lipid mixtures is carried out hydration, described dissolved solute comprises buffer salt, intercalating agent, cryoprotective agent or the like; With
5) by suitable technique, such as homogenization, extruding etc. reduce the granularity of liposome and the state that improvement forms lamella.
Any method with active component generation and load hydration lipid that well known to a person skilled in the art may be used in the scope of the present invention.For example, the appropriate method of preparation liposome is described in list of references 20 and 21, and these two lists of references all are incorporated herein by reference.The variant of these methods is described in United States Patent (USP) 5,096, and in 629, the document also is incorporated herein by reference.
United States Patent (USP) 4,508,703 (also being incorporated herein by reference) have been described a kind of method for preparing liposome, by amphoteric lipidic component and hydrophobic components dissolved are formed solution, and subsequently in air-flow atomized soln produce powder mixture, make liposome thus.
In other preferred form, the form administration that chemical compound of the present invention can cyclodextrin complexes.Cyclodextrin is a class ring-type oligosaccharide molecular, comprises the glucopyranose subunit and has the circular cylinder spatial configuration.This commonly used quasi-molecule comprises and contains six (alpha-cyclodextrins), the molecule of seven (beta-schardinger dextrin-) and eight (gamma-cyclodextrin) glucopyranose molecules, the hydroxyl of its Semi-polarity (hydrophilic) is towards the outside of structure, and the oxygen atom of nonpolar (lipophilic) skeleton carbon atom and ether is arranged in annular interior intracavity.This cavity can by the combination in non-covalent mode hold (loading) active component (guest molecule refers to derivant of the present invention here) thus lipophilic portion form and to comprise complex.
Had for the improvement dissolubility of aqueous medium and the derivant of other improved characteristics that needs thereby the outside hydroxyl substituent of cyclodextrin molecular can modify to form, the described improved characteristics that other needs be such as the toxicity that reduces etc.The example of this derivant is: alkyl derivative, such as, 2, the 6-DM-; Hydroxyalkylation derivant is such as hydroxypropyl-beta-schardinger dextrin-; Ramose derivant is such as the didextrose group-beta-cyclodextrin; The sulfoalkyl derivant is such as sulfo group butyl ether-beta-schardinger dextrin-; And carboxyl methylation derivant, such as carboxymethyl-beta-cyclodextrin.The chemical modification that well known to a person skilled in the art other type is also included within the scope of the present invention.
Cyclodextrin complexes is given guest molecule (referring to derivant of the present invention here) improved dissolution usually, dispersibility, stability (chemistry, physics with microorganism), the toxic characteristic of bioavailability and reduction.
There is multiple known mode to produce cyclodextrin complexes in this area.For example can produce complex: under the condition that heats or do not heat, one or more derivants are stirred in cyclodextrin aqueous solution or the blended water-organic solution by using following basic skills; With cyclodextrin and the present composition in suitable device at the water, organic liquid or the mixing water-organic liquid that add appropriate amount, mediate under heating or the condition that do not heat, size mixing or mix; Perhaps utilize suitable mixing arrangement that cyclodextrin and compositions of the present invention are carried out physical mixed.The separation that comprises complex of Xing Chenging can realize by following process like this: co-precipitation, filter and drying; Extrude/nodularization and drying; The segmentation and the drying of wet material; Spray drying; Lyophilization or undertaken by other suitable technique according to the method that is used to form cyclodextrin complexes.Can adopt the optional step of the isolating solid composite of further mechanical lapping.
These cyclodextrin complexes have further improved dissolubility and rate of dissolution, and have improved the stability of derivant.
Most preferably, chemical compound of the present invention can carry out administration by mode oral and the intravenous therapy associating.But the accurate mode of movement under every kind of situation will depend on the purpose of dosage regimen, and whether promptly described mode of movement can prevent, and reduce, and eliminate or improve the sick or imbalance of dyslipidemia.Under the situation that disease and imbalance occur, mode of movement will depend on the seriousness of imbalance, and the age of aforesaid individuality, size and sex.
2) food/beverage/health food:
In another form of the present invention, derivant of the present invention can be mixed food, and in beverage and the health food, it includes but not limited to following material:
1) milk product-such as, cheese, butter, milk and other milk beverage, tablespread and breast system mixture, ice-cream and yoghourt;
2) fat-based product-such as, margarine, tablespread, mayonnaise, shortening, culinary art and fried oil and flavoring agent;
3) no matter whether these foods are cooked, toast or carried out other processing based on the product of corn-comprise grain (for example, bread and Italian noodle);
4) sweet food-such as chocolate, confection, chewing gum, dessert, non-dairy (for example, the Cool Whip that gravys with meat or vegetables poured over rice or noodles (toppings)
TM), sherbet, sugar-coat and other additive;
5) beverage-no matter be ethanol or Nonalcoholic, comprising can happy other soft drink, fruit drink, food additive and meal replacement beverage, such as those with trade name Boost
TMAnd Ensure
TMCommercially available beverage; With
6) other products-comprise egg and egg product, the food of processing, such as soup, the pasta sauce of pre-preparation, ready-formed food or the like.
Derivant of the present invention can be inculcated by such as mixing, injection, and fusion disperses, emulsifying, dipping, sprinkling and the technology of mediating directly need not be mixed food with further modifying, in health food or the beverage.Perhaps, consumer can be applied directly to derivant on the food or in the beverage before suction.These are the modes of sending of simple economy.
Embodiment
The present invention is described by following non-limiting examples:
Embodiment 1
Purpose: determine whether a kind of chemical compound of the present invention can improve the transfer of cholesteryl ester (CE) between HDL and LDL of CETP-mediation; described chemical compound is water miscible phytostanol acid ascorbyl ester (phytostanol (phytostanol)-phosphoryl-ascorbic acid), is also referred to as FM-VP4.
The separation of lipoprotein:
Utilize the density gradient ultracentrifugation method that separating plasma is become HDL and LDL, adjust blood plasma density with sodium bromide.
Plasma lipid and proteic quantitative:
From Sigma
TMThe enzyme assay kit be used to determine total lipoprotein triglyceride, cholesterol and proteic concentration.
EXPERIMENTAL DESIGN:
Comprise that test strategy additional and inhibition CETP is used to show the transfer of CE between lipoprotein that suppresses the CETP-mediation by a kind of chemical compound of the present invention.In order to determine whether phytostanol (phytostanol)-phosphoryl-ascorbic acid has improved the transfer of CE, be rich in [
3H] cholesterol acid ester ([
3H] CE) LDL and phytostanol (phytostanol)-phosphoryl-ascorbic acid (10-100 μ M) (50 μ MTris-HCl in the T150 of pH7.4 buffer of high concentration; 150mM NaCl; 0.02% Hydrazoic acid,sodium salt; 0.01% 2 sodium edta) cultivates altogether; described buffer contain unlabelled HDL+/-(be purification or human plasma source) CETP (1-2 μ g albumen/ml), cultivated 90 minutes of purification at 37 ℃.After the cultivation, LDL precipitates, and determines the percentage ratio of the CE that shifts in 90 minutes time.Direct a kind of monoclonal antibody-TP2 at CETP (4 μ g albumen/ml), and a kind of known surfactant-dexycholate (50 μ m) is the additional treatments group of cultivating altogether with radiolabeled LDL.TP2 is used to guarantee mensuration that CE shifts by the CETP-mediation, and the effect that dexycholate is used to illustrate above-mentioned observed phytostanol (phytostanol)-phosphoryl-ascorbic acid is not nonspecific surface activity phenomenon.
Statistical analysis:
Under the condition that has the different disposal group, the difference of the CE transfer activity of CETP-mediation is by one-way analysis of variances (PCANOAV; Human Systems Dynamics) determines.Critical difference is estimated by Neuman-Keuls posthoc test.If p＜0.05 difference is considered to significant.All data are expressed as+/-standard deviation.
The result:
The effectiveness that phytostanol (phytostanol)-phosphoryl-ascorbic acid that Fig. 2 clearly illustrates two kinds of experimental concentration shifts between LDL and HDL for the CE of the CETP-mediation that suppresses purification.At 100 μ M, chemical compound is reduced to the transfer of CE and is lower than certain level, and it is can be detected that described level is utilized described analytical method.Fig. 3 confirms to utilize these results of human plasma opposite with the CETP of purification.Similarly, Fig. 4 has confirmed that the effect of FM-VP4 is by the CETP regulatory mechanism, rather than is produced by some other mode.
Conclusion:
Clearly, chemical compound suppressed the CETP-mediation CE at LDL to the transfer between the HDL.Cholesteryl ester only could take place in by the CETP mediation in the transfer between LDL and the HDL.The transfer that CE is opposite, promptly from HDL to the transfer of LDL can be the CETP mediation or produce by the transfer of diffusion.For this reason, this research has only been assessed from LDL and has been suppressed the CETP activity to the unidirectional transfer of HDL and to it, to guarantee that the result has reflected the effect of chemical compound to CETP really, promptly spreads variable and has been removed.But the CE of CETP mediation can be by using chemical compound of the present invention by suitable inhibition to the transfer of LDL (lipoprotein of tremulous pulse medicated porridge shape sample) from HDL (lipoprotein of anti--tremulous pulse medicated porridge shape sample).Known TP2 can be attached to the position identical with the CE binding site of CETP specifically, and these results have confirmed blocking-up and inhibition that the CE of CETP-mediation shifts.
List of references
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7.Morton?Current?Opinions?in?Lipidology?1999；10：321-322
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14.Coval Deng the people, Bioorg Med Chem Lett 1995; 5:605-610
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21.Pharmaceutical Technology:Liposomes as Drug DeliverySystems Parts I, II and III are published in October 1992 respectively, November 1992 and January 1993
Claims (27)
1. one kind is used to reduce the method that the protein mediated cholesteryl ester of body inner cholesterol transesterify shifts between high density lipoprotein (HDL) and low density lipoprotein, LDL (LDL), and described method comprises one or more following chemical compounds of administering therapeutic effective dose:
Wherein R is sterol or stanol part, and R2 comes from ascorbic acid, and R3 is hydrogen or metal, alkaline-earth metal or alkali metal arbitrarily; And all salt, so blood plasma HDL and LDL since this administering mode controlled.
2. the process of claim 1 wherein that sterol is selected from sitosterol, campesterol, stigmasterol, brassicasterol, 24-dehydrocholesterol, spongosterol, poriferasterol, chionasterol, ergosterol, coprosterol, codisterol, isofucosterol, 24-ethylidenecholest-5-en-3.beta.-ol., paulownia sterol, neural sterol, lathosterol, asteriasterol, chondrillasterol, cartilage sterol, peposterol, avenasterol, different avenasterol, coprostenol, pollinastasterol, cholesterol and all natural or synthetic form and derivants thereof comprise isomer.
3. the process of claim 1 wherein that stanol is selected from all saturated or hydrogenant sterols, and all natural or synthetic form and derivant thereof, comprise isomer.
4. the process of claim 1 wherein that stanol is a sitostamol.
5. the process of claim 1 wherein that R3 is selected from calcium, magnesium, manganese, copper, zinc, sodium, potassium and lithium.
6. the process of claim 1 wherein that the level of serum hdl is owing to this administering mode is improved.
7. the process of claim 1 wherein to be selected from LDL that the atherogenic lipoprotein of VLDL and IDL is controlled.
8. the method for claim 1, if desired, described method comprises the periodicity analysis plasma LDL levels in addition and adjusts the step of the amount of the chemical compound for the treatment of administration.
9. the process of claim 1 wherein that chemical compound passes through oral administration.
10. the process of claim 1 wherein that chemical compound passes through intravenous administration.
11. the process of claim 1 wherein that chemical compound can mix with the medicament of one or more cholesterol regulating transhipments, administration or administration respectively in an interval altogether before administration.
12. the method for claim 11, wherein medicament is selected from bile acid sequestration thing, bile acid transport protein inhibitor, plant sterol, phytostanol, the proteic regulator of abc transport, the regulator of PPAR (α and γ) and ezetimibe.
13. one kind is used to reduce the protein mediated cholesteryl ester of body inner cholesterol transesterify transfer compositions between high density lipoprotein and low density lipoprotein, LDL, described compositions comprises that one or more have the chemical compound of following formula structure:
Wherein R is sterol or stanol part, and R2 comes from ascorbic acid, and R3 is hydrogen or metal, alkaline-earth metal or alkali metal arbitrarily; And the salt of all these structures; And a kind of pharmaceutical carrier.
14. the compositions of claim 13, wherein sterol is selected from sitosterol, campesterol, stigmasterol, brassicasterol, 24-dehydrocholesterol, spongosterol, poriferasterol, chionasterol, ergosterol, coprosterol, codisterol, isofucosterol, 24-ethylidenecholest-5-en-3.beta.-ol., paulownia sterol, neural sterol, lathosterol, asteriasterol, chondrillasterol, cartilage sterol, peposterol, avenasterol, different avenasterol, coprostenol, pollinastasterol, cholesterol and all natural or synthetic form and derivants thereof comprise isomer.
15. the compositions of claim 13, wherein stanol is selected from all saturated or hydrogenant sterols, and all natural or synthetic form and derivant thereof, comprises isomer.
16. the compositions of claim 13, wherein stanol is a sitostamol.
17. the compositions of claim 13, wherein R3 is selected from calcium, magnesium, manganese, copper, zinc, sodium, potassium and lithium.
18. the compositions of claim 13, wherein chemical compound is a structure 1, and stanol is a sitostamol.
19. the compositions of claim 13, described compositions comprise the medicament or the chemical compound of one or more cholesterol regulating transhipments in addition.
20. the compositions of claim 13, wherein medicament is selected from bile acid sequestration thing, bile acid transport protein inhibitor, plant sterol, phytostanol, the proteic regulator of abc transport, the regulator of PPAR (α and γ) and ezetimibe.
21. one kind is used for the treatment of or prevents animal cardiovascular disease and basis disease thereof, comprise atherosclerosis, unusual lipidemia or imbalance, hypercholesterolemia, method with tangier's disease, described method comprises the protein mediated transfer of cholesteryl ester between high density lipoprotein (HDL) and low density lipoprotein, LDL (LDL) of reduction body inner cholesterol transesterify, and described reduction is achieved by use one or more sterols with following formula and/or steroid alkanol derivative to animal:
Wherein R is sterol and/or stanol part, and R2 comes from ascorbic acid, and R3 is hydrogen or metal, alkaline-earth metal or alkali metal arbitrarily; And all salt.
22. the method for claim 21, wherein animal is behaved.
23. the method for claim 21, wherein sterol is selected from sitosterol, campesterol, stigmasterol, brassicasterol, 24-dehydrocholesterol, spongosterol, poriferasterol, chionasterol, ergosterol, coprosterol, codisterol, isofucosterol, 24-ethylidenecholest-5-en-3.beta.-ol., paulownia sterol, neural sterol, lathosterol, asteriasterol, chondrillasterol, cartilage sterol, peposterol, avenasterol, different avenasterol, coprostenol, pollinastasterol, the group of cholesterol and all natural or synthetic form and derivant thereof comprise isomer.
24. the method for claim 21, wherein stanol is selected from all saturated or hydrogenant sterols, and all natural or synthetic form and derivant thereof, comprises isomer.
25. the method for claim 21, wherein stanol is a sitostamol.
26. the method for claim 21, wherein R3 is selected from calcium, magnesium, manganese, copper, zinc, sodium, potassium and lithium.
27. the method for claim 21, wherein chemical compound is a structure 1, and stanol is a sitostamol.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US96568701A | 2001-09-26 | 2001-09-26 | |
| US09/965,687 | 2001-09-26 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN1558766A true CN1558766A (en) | 2004-12-29 |
Family
ID=25510339
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNA028189434A Pending CN1558766A (en) | 2001-09-26 | 2002-09-26 | A method of reducing the 'in vivo' cholesterol ester transfer protein mediated transfer of cholesteryl esters between high density lipoproteins (HDL) and low density lipoproteins (LDL) |
Country Status (8)
| Country | Link |
|---|---|
| EP (1) | EP1432425A1 (en) |
| JP (1) | JP2005507890A (en) |
| CN (1) | CN1558766A (en) |
| BR (1) | BR0212826A (en) |
| CA (1) | CA2461136A1 (en) |
| NZ (1) | NZ531938A (en) |
| RU (1) | RU2004112556A (en) |
| WO (1) | WO2003026672A1 (en) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20030232797A1 (en) * | 2002-06-06 | 2003-12-18 | Forbes Medi-Tech Inc. | Novel derivatives of androstane and androstene with ascorbic acid and use thereof in treating or preventing various conditions, diseases, and disorders |
| WO2005030185A2 (en) | 2003-09-26 | 2005-04-07 | Japan Tobacco Inc. | Method of inhibiting remnant lipoprotein production |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5866147A (en) * | 1995-05-15 | 1999-02-02 | Avon Products, Inc. | Ascorbyl-phosphoryl-cholesterol |
| FI974648A (en) * | 1997-09-09 | 1999-05-06 | Raisio Benecol Oy | Hydroxy acid, lactic acid and hydroxyalkanoate esters and their uses |
| RU2002101483A (en) * | 1999-06-23 | 2003-09-20 | Форбз Меди-Тек Инк. (Ca) | Conjugates of phytosterol or phytostanol with ascorbic acid and their use for the treatment or prevention of cardiovascular diseases |
-
2002
- 2002-09-26 RU RU2004112556/14A patent/RU2004112556A/en not_active Application Discontinuation
- 2002-09-26 CA CA002461136A patent/CA2461136A1/en not_active Abandoned
- 2002-09-26 WO PCT/CA2002/001457 patent/WO2003026672A1/en not_active Application Discontinuation
- 2002-09-26 NZ NZ531938A patent/NZ531938A/en unknown
- 2002-09-26 BR BR0212826-8A patent/BR0212826A/en not_active IP Right Cessation
- 2002-09-26 JP JP2003530307A patent/JP2005507890A/en not_active Withdrawn
- 2002-09-26 CN CNA028189434A patent/CN1558766A/en active Pending
- 2002-09-26 EP EP02764428A patent/EP1432425A1/en not_active Withdrawn
Also Published As
| Publication number | Publication date |
|---|---|
| WO2003026672A1 (en) | 2003-04-03 |
| CA2461136A1 (en) | 2003-04-03 |
| NZ531938A (en) | 2006-04-28 |
| RU2004112556A (en) | 2005-03-10 |
| JP2005507890A (en) | 2005-03-24 |
| EP1432425A1 (en) | 2004-06-30 |
| BR0212826A (en) | 2004-08-24 |
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