EP1556406A1 - Derivatives comprising sterols and/or stanols and specific classes of anti-inflammatory agents and use thereof in treating or preventing cardiovascular disease - Google Patents
Derivatives comprising sterols and/or stanols and specific classes of anti-inflammatory agents and use thereof in treating or preventing cardiovascular diseaseInfo
- Publication number
- EP1556406A1 EP1556406A1 EP03747766A EP03747766A EP1556406A1 EP 1556406 A1 EP1556406 A1 EP 1556406A1 EP 03747766 A EP03747766 A EP 03747766A EP 03747766 A EP03747766 A EP 03747766A EP 1556406 A1 EP1556406 A1 EP 1556406A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- compound
- group
- acid
- acids
- inflammation
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Withdrawn
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J9/00—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of more than two carbon atoms, e.g. cholane, cholestane, coprostane
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/575—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of three or more carbon atoms, e.g. cholane, cholestane, ergosterol, sitosterol
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/06—Antihyperlipidemics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/12—Antihypertensives
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J1/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, not substituted in position 17 beta by a carbon atom, e.g. estrane, androstane
Definitions
- This present invention relates to the field of sterols and stands and novel derivatives thereof and their use in treating and preventing cardiovascular disease and other disorders.
- Atherosclerosis is a degenerative process resulting from an interplay of inherited (genetic) factors and environmental factors such as diet and lifestyle.
- CVD cardiovascular disease
- Studies to date suggest that cholesterol may play a role in atherosclerosis by forming atherosclerotic plaques in blood vessels, ultimately cutting off blood supply to the heart muscle or alternatively to the brain or limbs, depending on the location of the plaque in the arterial tree (1,2).
- Overviews have indicated that a 1% reduction in a person's total serum cholesterol yields a 2% reduction in risk of a coronary artery event (3).
- a 10% decrease in average serum cholesterol (e.g. from 6.0 mmol/L to 5.3 mmol/L) may result in the prevention of 100,000 deaths in the United States annually (4).
- Sterols are naturally occurring compounds that perform many critical cellular functions. Phytosterols such as campesterol, stigmasterol and beta-sitosterol in plants, ergosterol in fungi and cholesterol in animals are each primary components of cellular and sub- cellular membranes in their respective cell types.
- the dietary source of phytosterols in humans comes from plant materials i.e. vegetables and plant oils.
- the estimated daily phytosterol content in the conventional western-type diet is approximately 60-80 milligrams in contrast to a vegetarian diet which would provide about 500 milligrams per day.
- Phytosterols have received a great deal of attention due to their ability to decrease serum cholesterol levels when fed to a number of mammalian species, including humans. While the precise mechanism of action remains largely unknown, the relationship between cholesterol and phytosterols is apparently due in part to the similarities between the respective chemical structures (the differences occurring in the side chains of the molecules). It is assumed that phytosterols displace cholesterol from the micellar phase and thereby reduce its absorption or possibly compete with receptor and/or carrier sites in the cholesterol absorption process.
- Prostaglandins play a major role in the inflammation process and the inhibition of prostaglandin production, especially production of PGG 2 , PGH 2 and PGE 2 , and have been a common target of anti-inflammatory drug discovery.
- NSAID's common non- steroidal anti-inflammatory drugs
- use of high doses of most common NSAID's can produce severe side effects, including life-threatening ulcers, that limit their therapeutic potential.
- corticosteroids An alternative to NSAID's is the use of corticosteroids, which also produce severe adverse effects, especially when long-term therapy is involved.
- COX-1 is a constitutive isoform found in blood vessels, stomach, and kidney while COX-2 is induced in settings of inflammation by cytokines and inflammatory mediators.
- PGG 2 /PHG 2 cyclooxygenase products differ from tissue to tissue depending on the particular PGG 2 /PHG 2 metabolizing enzymatic activities present.
- Arachidonic acid also can be converted via 12-lipoxygenase to 12-HPETE and 12-HETE or via the 5-lipoxygenase pathway to a variety of leukotrienes.
- Aspirin and other NSAIDS inhibit the cyclooxygenase enzyme and prostaglandin production; they do not inhibit lipoxygenase pathways and hence, do not suppress leukotriene production.
- the present invention provides, in one aspect, novel derivatives comprising sterols and/or stanols and an NSAID selected from salicylic acids and arylalkanoic acids, including salts of these derivatives, and having one or more of the following formulae:
- R is a sterol or stanol moiety
- the present invention provides, in another aspect, a composition
- a composition comprising at least one sterol and/or stanol and at least one an NSAID selected from salicylic acids and arylalkanoic acids.
- the present invention also comprises processes of preparing the novel derivatives having the above noted formulae.
- the present invention further comprises a pharmaceutical composition for treating or preventing CVD and its underlying conditions including, without limitation, atherosclerosis, hypercholesterolemia, hyperlipidemia, hypertension, thrombosis, coronary artery disease, inflammation including coronary plaque inflammation, bacterial-induced inflammation, viral induced inflammation and inflammation associated with acute pain and surgical procedures which comprises one or more derivatives of sterols and/or stanols and an NSAID selected from salicylic acids and arylalkanoic acids, having one or more of the above noted formulae, and a pharmaceutically acceptable carrier therefor.
- a pharmaceutical composition for treating or preventing CVD and its underlying conditions including, without limitation, atherosclerosis, hypercholesterolemia, hyperlipidemia, hypertension, thrombosis, coronary artery disease, inflammation including coronary plaque inflammation, bacterial-induced inflammation, viral induced inflammation and inflammation associated with acute pain and surgical procedures which comprises one or more derivatives of sterols and/or stanols and an NSAID selected from salicylic acids
- the present invention further comprises a pharmaceutical composition for treating or preventing CVD and its underlying conditions including, without limitation, atherosclerosis, hypercholesterolemia, hyperlipidemia, hypertension, thrombosis, coronary artery disease, and for treating and reducing inflammation including coronary plaque inflammation, bacterial-induced inflammation, viral induced inflammation and inflammation associated with acute pain and with surgical procedures which comprises one or more sterols and/or stanols and one or more NSAIDs selected from salicylic acids and arylalkanoic acids, and a pharmaceutically acceptable carrier therefor.
- the present invention further provides foods, beverages and nutraceuticals supplemented with derivatives of sterols and/or stanols and an NSAID selected from salicylic acids and arylalkanoic acids, or compositions thereof having one or more of the above noted formulae.
- the present invention further provides foods, beverages and nutraceuticals supplemented with a composition comprising one or more sterols and/or stanols and one or more NSAIDs selected from salicylic acids and arylalkanoic acids.
- the present invention further provides a method for treating or preventing CVD and its underlying conditions including, without limitation, atherosclerosis, hypercholesterolemia, hyperlipidemia, hypertension, thrombosis, coronary artery disease, and for treating and reducing inflammation including coronary plaque inflammation, bacterial-induced inflammation, viral induced inflammation and inflammation associated with acute pain and surgical procedures which comprises administering to an animal, a non-toxic and therapeutically effective amount of one or more derivatives of sterols and/or stanols and an NSAID selected from salicylic acids and arylalkanoic acids, having one or more of the above noted formulae.
- the present invention further provides a method for treating or preventing CVD and its underlying conditions including, without limitation, atherosclerosis, hypercholesterolemia, hyperlipidemia, hypertension, thrombosis, coronary artery disease, inflammation including coronary plaque inflammation, bacterial-induced inflammation, viral induced inflammation and inflammation associated with acute pain and surgical procedures which comprises administering to an animal, a non-toxic and therapeutically effective amount of a composition comprising one or more sterols and/or stanols and one or more NSAIDs selected from salicylic acids and arylalkanoic acids.
- the derivatives and compositions of the present invention exhibit superior activity in both for treating or preventing CVD and its underlying conditions, particularly hyperlipidemia, and treating conditions having inflammation as a part of their aetiology or presentation. There may be an additive or svnerqistic therapeutic effect, in both of these respects. Equally importantly, it is believed that when the salicylic acids and/or arylalkanoic acids are either derivatized with the sterol/stanol component as described herein, or merely co-adminstered with sterols/stanols in composition, a lower dosage of the selected NSAID may be required to achieve the desired therapeutic effects. This is important due to the documented long-term adverse effects of the administration of many anti-inflammatory agents such as NSAIDs of which the salicylic acids and arylalkanoic acids form part. These effects and other significant advantages will become apparent herein below.
- Figure 1 is a schematic showing the formation of one derivative of the present invention, a phytostanyl-acetylsalicylate by reaction of an acid chloride with the hydroxyl group of the phytostanol component;
- Figure 2 is a schematic showing the formation of another derivative of the present invention, acetoxyphytostanyl salicylates by reaction of activated phytostanyl chloride with the carboxylate group of the salicylic acid component;
- Figure 3 is a bar graph showing the inhibition of cholesterol absorption by one of the derivatives of the present invention.
- Figure 4 is a bar graph showing percent inhibition of COX-1 in the presence of one of the derivatives of the present invention "FDC-2-4".
- SC-560 is an inhibitor of COX-1 with an IC50 of 10 nM.
- FDC-2-4 is treated with PL/C (PL+) and untreated with PL/C (PL-).
- PL only groups are only treated with PL/C alone (no drug).
- Data presented as percentage inhibition of mean absorbance compared to 100% activity ⁇ standard error, n 3. * indicates p ⁇ 0.05 vs. 0.45 mM ASA;
- Figure 5 is a bar graph showing percent inhibition of COX-2 in the presence of one of the derivatives of the present invention "FDC-2-4".
- DuP-697 is an inhibitor of COX-2 with an IC50 of 50 nM.
- FDC-2-4 is treated with PL/C (PL+) and untreated with PL/C (PL-).
- PL only groups are only treated with PL/C alone (no drug).
- Data presented as percentage inhibition of mean absorbance compared to 100% activity ⁇ standard error, n 3. * indicates p ⁇ 0.05 vs. 0.45 mM ASA;
- Figure 6 is a digital image of a 1mL aqueous solution containing 4mg of one compound of the present invention called FDC 2-4 and 120mg of polysorbate 80, against a black background;
- Figure 7 is transmission electron microscope image of an aqueous solution containing FDC-2-4 (4mg/ml) and polysorbate 80 (120mg/ml), possibly showing micelles;
- Figure 8 is a graph showing the particle size distribution of a 4mg/ml FDC 2-4 aqueous solution with 120mg/ml polysorbate 80;
- Figure 9 is a graph showing the particle size distribution of a 120mg/ml polysorbate 80 solution (control).
- Figure 10 is the structure of one of the preferred compounds of the present invention, "FDC 2-4". PREFERRED EMBODIMENTS OF THE INVENTION
- novel derivatives of sterol and/or stanol and an NSAID selected from salicylic acids and arylalkanoic acids which are suitable for use per se in treating or preventing CVD and its underlying conditions including, without limitation, atherosclerosis, hypercholesterolemia, hyperlipidemia, hypertension, thrombosis, coronary artery disease, inflammation including coronary plaque inflammation, bacterial-induced inflammation, viral induced inflammation and inflammation associated with acute pain and surgical procedures.
- the derivatives of the present invention are represented by one or more of the following formulae:
- R is a sterol or stanol moiety
- novel compositions comprising sterols and/or stanols and an NSAID selected from salicylic acids and arylalkanoic acids which are suitable for use per se in treating or preventing CVD and its underlying conditions including, without limitation, atherosclerosis, hypercholesterolemia, hyperlipidemia, hypertension, thrombosis, coronary artery disease, inflammation including coronary plaque inflammation, bacterial-induced inflammation, viral induced inflammation and inflammation associated with acute pain and surgical procedures.
- an NSAID selected from salicylic acids and arylalkanoic acids
- sterol includes all sterols without limitation, for example: sitosterol, campesterol, stigmasterol, brassicasterol (including dihydrobrassicasterol), desmosterol, chalinosterol, poriferasterol, clionasterol, ergosterol, coprosterol, codisterol, isofucosterol, fucosterol, clerosterol, nervisterol, lathosterol, stellasterol, spinasterol, chondrillasterol, peposterol, avenasterol, isoavenasterol, fecosterol, pollinastasterol, cholesterol and all natural or synthesized forms and derivatives thereof, including isomers.
- stanol refers to saturated or hydrogenated sterols including all natural or synthesized forms and derivatives thereof, and isomers. It is to be understood that modifications to the sterols and stanols i.e. to include side chains also falls within the purview of this invention. For example, the purview of this invention clearly includes 24 beta-ethylchlostanol, 24-alpha-ethyl-22-dehydrocholstanol. It is also to be understood that, when in doubt throughout the specification, and unless otherwise specified, the term “sterol” encompasses both sterol and stanol.
- the sterols and stanols for use in forming derivatives in accordance with this invention may be procured from a variety of natural sources.
- they may be obtained from the processing of plant oils (including aquatic plants) such as corn oil and other vegetable oils, wheat germ oil, soy extract, rice extract, rice bran, rapeseed oil, sunflower oil, sesame oil and fish (and other marine-source) oils.
- plant oils including aquatic plants
- They may also be / derived from fungi, for example ergosterol, or animals, for example cholesterol.
- the present invention is not to be limited to any one source of sterols.
- US Patent Serial No. 4,420,427 teaches the preparation of sterols from vegetable oil sludge using solvents such as methanol.
- phytosterols and phytostanols may be obtained from tall oil pitch or soap, by-products of forestry practises as described in US Patent Serial No.5,770,749, incorporated herein by reference.
- the derivative of the present invention is formed of naturally- derived or synthesized beta-sitosterol, campestanol, sitostanol, cholesterol or campesterol and each of these derivatives so formed may then be admixed in a composition prior to delivery in various ratios.
- the derivative of the present invention is formed with naturally-derived or synthesized sitostanol or with naturally derived or synthesized campestanol or mixtures thereof.
- the most preferred form of derivative of the present invention comprises either a sitostanyl ester and campestanyl ester or a cholestanyl ester as described further herein.
- Suitable anti-inflammatory agents for use within the scope of the present invention are selected from the below-listed specific classes of NSAIDs i.e. those agents which exhibit anti-inflammatory activity in animals, particularly humans, but which do not possess any steroidal structural element. More specifically, the term "arylalkanoic acid' is intended to encompass herein:
- arylethanoic (arylacetic) acid compounds such as acemetacin, amfenac sodium, bendazac, glucametacin, oxametacin;
- arylpropanoic (arylpropionic) acid compounds such as alminoprofen, ibuprofen, ketoprofen, flurbiprofen, fenoprofen, oxaprozin;
- arylbutanoic (arylbutyric) acid compounds such as bumadizon, butibufen, fenbufen, and xenbucin;
- salicylic acid as used herein is intended to encompass: • salicylic acid compounds such as acetylsalicylic acid (ASA), aluminium ASA, sodium ASA, ASA glycolates, salicylic acid, salicylic acid glycolates, salicins, salicortin, tremulacin, acetaminosalol; balsalazide, benorylate, gentisic acid, imidazole salicylate, lysine acetylsalicylate, mesalamine, morpholine salicylate, naphthyl salicylate,olsalazine, parsalimide, phenyl salicylate, salicylsulfuric acid, choline magnesium trisalicylate, and other salts, diflunisal, etersalate, fosfosal, salol, salsalate, salacetamide, salicylsalicylic acid, sulfasalazine, o
- Naturally derived salicylates may be extracted, for example, from the bark of Salix alba, S. prupurea L, S. fragilis L. (also known as willow, a deciduous shrub) by techniques which are known and available in the art.
- the NSAID is a salicylic acid derivative, more preferably, ASA or one of its' derivatives.
- the derivatives are formed between salicylic acid compounds and the sterol/stanol moiety and have one of the following structures:
- R H or CH 3 and R1, R2, R3, R4, R5 are selected, independently, from the group consisting of OH, acetyl, halogen (CI, Br, I, or F) and an alkyl moiety having from 1-5 carbon atoms;
- R H or CH 3 and R1 , R2, R3, R4, R5 are independently selected from the group consisting of OH, acetyl, halogen (CI, Br, l,or F) and an alkyl moiety having from 1 -5 carbon atoms;
- R1, R2, R3, R4, R5 are independently selected from the group consisting of OH, acetyl, halogen (CI, Br, I, or F) and an alkyl moiety having from 1-5 carbon atoms; and
- R1, R2, R3, R4, R5 are independently selected from the group consisting of OH, acetyl, halogen (CI, Br, l,or F) and an alkyl moiety having from 1-5 carbon atoms.
- the derivative of the present invention is selected from the group consisting of phytostanyl acetylsalicylates, phytostanyl salicylates , acetoxyphytostanyl acetylsalicylates, acetoxyphytostanyl salicylates, acetoxyphytostanyl acetate, cholestanyl salicylates, acetoxycholestanyl salicylates, and acetoxyphytostanyl aminosalicylates as represented by the following formulae:
- novel structures comprising sterols and/or stanols and the selected anti-inflammatory agent can be formed.
- the selected sterol or stanol (or halophosphate, halocarbonate or halo-oxalate derivatives thereof) and the anti-inflammatory agent are mixed together under reaction conditions to permit condensation of the "acid" moiety with the "alcohol” (phytosterol).
- reaction conditions are the same as those used in other common esterification reactions in which the acid chloride formed from the acid component and the alcohol component are allowed to react directly or in the presence of a suitable acid catalyst such as mineral acid, sulfuric acid, phosphoric acid, p- toluenesulfonic acid.
- organic solvents generally employed in such esterification reactions are ethers such as diethyl ether, tetrahydrofuran, or benzene, toluene or similar aromatic solvents and the temperatures can vary from room to elevated temperatures depending on the reactivity of the reactants undergoing the reaction.
- the process to form the ester derivative comprises "protecting" the hydroxyl groups of the anti-inflammatory or derivatives thereof as esters (for example, as acetate esters) or ethers (for example, methyl ethers) and then condensing the protected anti-inflammatory agent with the reactive sterol/stanol (or its halophosphate, halocarbonate or halo-oxalate) under suitable reaction conditions.
- ester/stanol or its halophosphate, halocarbonate or halo-oxalate
- condensation reactions are conducted in an organic solvent such as diethyl ether, tetrahydrofuran, or benzene, toluene or similar aromatic solvents.
- the reaction temperatures may vary from low (-15°C) to elevated temperatures.
- Figure 1 is a schematic showing the formation of the "protected" anti-inflammatory agent (acetylsalicylic acid chloride) and the phytostanol in a condensation reaction yielding one of novel derivatives of the present invention.
- the overall formation of the desired ester may be achieved by the creation of an activated chloride in the stanyl or steryl component which is subsequently reacted with the carboxylic acid or carboxylate unit of the anti-inflammatory agent.
- a carboxy "linker" between the anti-inflammatory agent and the steryl/stanyl component may comprise preferably from 1-5 carbon atoms.
- monochloroacetic acid was reacted with a stanol mixture to achieve the stanyl monochloroacetic ester.
- the present invention encompasses the biologically acceptable metal, alkali earth metal, or alkali metal salts of the disclosed derivatives. These salts are generally more water soluble than the corresponding parent compounds and therefore their efficacy and evaluation both in vitro and in vivo is improved.
- Salt formation of the derivatives of the present invention can be readily performed by treatment of any parent compound containing a phenolic OH group with a series of bases (for example, sodium methoxide or other metal alkoxides) to produce the corresponding alkali metal salts.
- bases for example, sodium methoxide or other metal alkoxides
- Other metal salts of calcium, magnesium, manganese, copper, zinc, and the like can be generated by reacting the parent with suitable metal alkoxides.
- FDC 2-4 is the structure as shown in Figure 10 and is a stanol derivative (mixture of sitostanol and campestanol attached to ASA. It is a preferred compound in accordance with the present invention.
- the present invention provides a method for:
- CVD cardiovascular disease
- cardiovascular disease cardiovascular disease
- cardiovascular disease cardiovascular disease
- cardiovascular disease cardiovascular disease
- cardiovascular disease cardiovascular disease
- cardiovascular disease cardiovascular disease
- composition comprising one or more sterols or stanols and at least one NSAID selected from salicylic acids and arylalkanoic acids or one or more derivatives of sterols and/or stanols and an NSAID selected from salicylic acids and arylalkanoic acids, having one or more of the following formulae:
- R is a sterol or stanol moiety
- This invention further comprises the use of any of the disclosed compounds for these indications.
- terapéuticaally effective is intended to qualify the amount of the compound(s) or composition administered in order to achieve one or more of the following goals: a) treating conditions associated with CVD generally; b) treating atherosclerosis; c) treating hypercholesterolemia; d) treating a hyperlipidic condition; e) treating hypertension; f) treating thrombosis; g) treating coronary artery disease; h) treating coronary plaque inflammation; i) treating any inflammatory condition including bacterial or viral-induced inflammation, or inflammation associated with acute pain and surgical procedures; and/or j) inhibiting COX-1 and/or COX-2 activity
- the compounds of the present invention have been found to be especially useful in addressing at least two significant factors contributing to the multi-factorial presentation of cardiovascular disease: elevated cholesterol levels and inflammation. It is now documented that endothelial inflammatory response, together with plasma cholesterol levels, both play important roles in the development of atherosclerosis (11 ). Accordingly, it is highly advantageous to administer one compound which simultaneously lowers cholesterol absorption, thereby lowering serum cholesterol and at the same time reduces the inflammation associated with and recognized as part of the disease progression. No other compound to date achieves this beneficial dual effect.
- the desired effects described herein may be achieved in a number of different ways.
- the compounds and compositions of the present invention may be administered by any conventional means available for use in conjunction with pharmaceuticals, nutraceuticals, foods, beverages, and the like.
- the amount of the compound or composition which is required to achieve the desired effects will, of course, depend on a number of factors such as the particular compound or composition chosen, the mode of administration and the condition of the patient.
- compositions of the present invention can be administered to a patient either by themselves, or in pharmaceutical compositions where they are mixed with suitable carriers or excipients.
- compositions of the present invention may be administered parenterally, such as by intravenous injection.
- pharmaceutically acceptable carriers well known in the art into dosages suitable for oral administration.
- Such carriers enable the compounds and compositions of the invention to be formulated as tablets, pills, capsules, liquids, gels, syrups, slurries, suspensions and the like, for oral ingestion by a patient to be treated.
- compositions comprising one or more of the compounds of the present invention, include compositions wherein the active ingredients are contained in an effective amount to achieve their intended purpose. Determination of the effective amounts is well within the capability of those skilled in the art, especially in light of the detailed disclosure provided herein.
- compositions may contain suitable pharmaceutically acceptable carriers comprising excipients and auxiliaries which facilitate processing of the active compounds into preparations which can be used pharmaceutically.
- suitable pharmaceutically acceptable carriers comprising excipients and auxiliaries which facilitate processing of the active compounds into preparations which can be used pharmaceutically.
- the preparations formulated for oral administration may be in the form of tablets, dragees, capsules, or solutions.
- compositions of the present invention may be manufactured in a manner that is itself known, e.g., by means of conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping or lyophilizing processes.
- compositions for parenteral administration include aqueous solutions of the active compounds in water-soluble form. Additionally, suspensions of the active compounds may be prepared as appropriate oily injection suspensions. Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, or synthetic fatty acid esters, such as ethyl oleate or triglycerides, or liposomes. Aqueous injection suspensions may contain substances which increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran. Optionally, the suspension may also contain suitable stabilizers or agents which increase the solubility of the compounds to allow for the preparation of highly concentrated solutions.
- compositions for oral use can be obtained by combining the active compounds with solid excipient, optionally grinding a resulting mixture, and processing the mixture of granules, after adding suitable auxiliaries, if desired, to obtain tablets or dragee cores.
- suitable excipients include lactose, sucrose, mannitol, sorbitol, maize starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methyl cellulose, hydroxypropylmethyl-cellulose, sodium carboxymethylcellulose, and polyvinylpyrrolidone (PVP).
- disintegrating agents may be added, such as the cross-linked polyvinyl pyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate.
- Dragee cores are provided with suitable coatings.
- suitable coatings For this purpose, concentrated sugar solutions may be used, which may optionally contain gum arabic, talc, polyvinyl pyrrolidone, carbopol gel, polyethylene glycol, and/or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures.
- Dyestuffs or pigments may be added to the tablets or dragee coatings for identification or to characterize different combinations of active compound doses.
- compositions which can be used orally include push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol.
- the push-fit capsules can contain the active ingredients in admixture with filler such as lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate and, optionally, stabilizers.
- the active compounds may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols.
- stabilizers may be added.
- Oral liquid preparations may be in the form of, for example, emulsions, syrups, or elixirs, or may be presented as a dry product for reconstitution with water or other suitable vehicle before use.
- Such liquid preparations may contain conventional additives such as suspending agents, for example sorbitol, syrup, methyl cellulose, gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminium stearate gel, hydrogenated edible fats; emulsifying agents, for example lecithin, sorbitan monooleate, or acacia; non-aqueous vehicles (which may include edible oils), for example almond oil, fractionated coconut oil, oily esters such as esters of glycerine, propylene glycol, or ethyl alcohol; preservatives, for example methyl or propyl p-hydroxybenzoate or sorbic acid; and if desired conventional flavouring or colouring agents. Due to the poor aqueous solubility of the sterol/stanol
- the compounds of the present invention are added to a selected solubility enhancing agent, mixed with a non-toxic organic solvent and subjected to one or more steps of heating, sonication, and evaporation in order to dissolve the compounds and remove the solvent.
- the selected solubility enhancing agent have a hydrophilic/lipophilic balance ("HLB") of 12 or greater.
- HLB hydrophilic/lipophilic balance
- the selected solubility enhancing agent have an HLB of 8 or less.
- the HLB scale represents the relative solubilizing power of a molecule vis-a-vis its lipophilic tendencies i.e. a relative ratio of polar and non-polar groups in the molecule.
- Preferred solubility enhancing agents for enhancing aqueous and lipid solubility include, but are not limited to surfactants such as polysorbate-80 and polysorbate- 60 (sold under the trade marks Tween-80TM and Tween-60TM respectively), poly(ethylene oxide)-poly(propylene oxide) tri-block copolymers surfactants (PluronicTM for example: Pluronic P-85, Pluronic F-127, and Pluronic F-108, a a poly(ethylene oxide) (PEO)-containing non-ionic surfactant) and macrogolglycerols (C8-C18 Glycerides; Fatty Acids C8-C18 Ethoxylated) such as GelcireTM generally and Gelcire 44/14 specifically.
- surfactants such as polysorbate-80 and polysorbate- 60 (sold under the trade marks Tween-80TM and Tween-60TM respectively), poly(ethylene oxide)-poly(propylene oxide) tri-block copolymers sur
- the organic solvent may be selected from any commonly used, non-toxic agents including, but not limited to, all halogenated aliphatic hydrocarbons and all branched and straight chain C3-C5 aliphatic alcohols. Most preferably, the organic solvent is selected from the group consisting of propanol, isopropanol, butanol, isobutanol, pentanol, isopentanol, chloroform, dichloromethane (methylene chloride) and dimethylsulphoxide (“DMSO").
- DMSO dimethylsulphoxide
- solubility enhancing agent and organic solvent chosen it may be required to heat the solution in order to dissolve the compounds of the present invention therein. Under such circumstances, the solution may be heated to a temperature of from about 25-75°, more preferably from about 50-70°C and most preferably to around 65°C.
- sonication may be used to put the compounds of the present invention into the selected organic solvent.
- the organic solvent may be removed by any suitable type of evaporation, including but not limited to nitrogen evaporation and rotary or roto-evaporation.
- Preferred mode A the two preferred modes of solubilizing the compounds of the present invention into an aqueous or lipid based vehicle are as follows: Preferred mode A:
- one or more of the compounds of the present invention are mixed with a selected solubility enhancing agent, preferably polysorbate-80;
- the compounds and solubility enhancing agent are dissolved into the solvent, by heating (preferably up to about 65°C), sonication or other dissolution methods;
- one or more of the compounds of the present invention are mixed with a selected solubility enhancing agent, preferably polysorbate-80;
- an organic solvent preferably chloroform, is added at or about room temperature and mixed;
- the compounds and compositions of the present invention may be administered through foods, beverages and nutraceuticals, including, without limitation, the following:
- Dairy Products such as cheeses, butter, milk and other dairy beverages, spreads and dairy mixes, ice cream and yoghurt;
- Fat-Based Products such as margarines, spreads, mayonnaise, shortenings, cooking and frying oils and dressings;
- Confectioneries such as chocolate, candies, chewing gum, desserts, non-dairy toppings (for example Cool WhipTM), sorbets, icings and other fillings;
- the compounds and compositions of the present invention may be incorporated directly and without further modification into the food, nutraceutical or beverage by techniques such as mixing, infusion, injection, blending, dispersing, emulsifying, immersion, spraying and kneading.
- the compounds and compositions may be applied directly onto a food or into a beverage by the consumer prior to ingestion. These are simple and economical modes of delivery.
- Acetylsalicylic acid (1g) was suspended in oxalyl chloride (5ml) and the mixture was refluxed for 1hr. Excess oxalyl chloride was removed by distillation, and the residue was dried under vacuum overnight to afford a yellowish wax (1.1g).
- the stanol mixture (2g, campestanol: 36.4%w/w; sitostanol: 62.3%w/w) and pyridine (10ml) was added, and the mixture was then stirred overnight at room temperature.
- the red solution was poured into water (100ml), filtered, the solid was collected, (2.1g).
- the crude product was loaded on a silica gel column (100ml), eluted with petroleum (30-50°C):EtOAc (100:3) to yield a white powder, (1.5g, yield 55%).
- the stanol mixture (4g, campestanol: 36.4%w/w; sitostanol: 62.3%w/w) in monochloroacetic acid (10ml) was heated to 120°C under stirring for 3 hours. After cooling down to room temperature, water (50ml) was added to the reaction mixture, the precipitate was collected and washed with water (10mlx2), an dried under vacuum to yield phytostanyl monochloroacetate as a white solid (4.5g, yield 95%).
- Intralipid is a sterile non-pyrogenic fat emulsion prepared for administration as a source of calories and essential fatty acids. It is made up of 10% Soybean Oil (refined natural product consisting of a mixture of neutral triglycerides and unsaturated fatty acids), 1.2% egg yolk phospholipids, 2.25% glycerin and water. In addition sodium hydroxide was added to adjust the pH so that the final product pH is 8.0; pH range is 6.0 to 8.9. The major components fatty acids are linoleic (50%), oleic (26%), palmitic (10%), linolenic (9%) and stearic (3.5%). Each animal received 20mg/kg body weight test substance dissolved in water or other appropriate solvent. The same final volume of the vehicle was administered to rats in the control group.
- Soybean Oil refined natural product consisting of a mixture of neutral triglycerides and unsaturated fatty acids
- egg yolk phospholipids 2.25% glycerin and water
- Plasma samples were collected 10 hours after oral gavage by cardiac puncture and plasma prepared by centrifugation at 40C and 4,000 rpm for 15 minutes. Plasma samples were analyzed for [3H] cholesterol by radioactivity and the effectiveness of novel sterol/stanol compounds reported as a percentage of inhibition of cholesterol absorption compared to controls.
- FIG. 3 shows a comparison between the FDC-2-4 and control groups as compared to another effective cholesterol absorption inhibitor (an ascorbate ester) called VP4.
- VP4 another effective cholesterol absorption inhibitor
- pancreatic lipase/colipase- treated acetoxyphytostanyl salicylate derivative of the present invention (which is designated as "FDC-2-4"), can inhibit cyclooxygenase (COX) activity.
- FDC-2-4 was treated with a 1 :1 ratio of porcine pancreatic lipase and colipase (PL/C).
- Inhibition of cyclooxygenase was determined using a colorimetric (ovine) COX inhibitor screening assay. The conversion of arachidonic acid to prostaglandin H 2 was monitored by a colorimetric reaction.
- PL/C-treated FDC-2-4 was constituted in 0, 0.45, 4.5- ⁇ M concentrations in a 1 ⁇ M hematin/0.1 M Tris-HCI, pH 8.0, buffer. Reaction was initiated by adding 100- ⁇ M arachidonic acid and 100- ⁇ M tetramethyl-p-phenylenediamine (TMPD — the colourimetric substrate). The optical density of the colored product was determined at 620 nm. Acetylsalicylate was used as a positive control in all experiments.
- Pancreatic lipase/Colipase treatment The enzymatic reaction was carried out in a final volume of 50 mL assay buffer (30 mM Tris-HCI, pH 8.0, ⁇ .0 mM CaCI2, 4 mM taurodeoxycholate), 0.312 mM triolein, in the absence or presence of FDC-2-4. The solution was vortexed for 2 min. and sonicated for 5 min. before adding 2.5 mg porcine pancreatic lipase and 2.5 mg porcine colipase. The reaction was incubated at room temperature for 2 hours.
- Inhibition of Cyclooxygenase was determined using a colorimetric (ovine) COX inhibitor screening assay (Cayman Chemicals). The conversion of arachidonic acid to prostaglandin H2 was monitored by a colorimetric reaction. COX was exposed to the inhibitors for 5 minutes. Reaction was initiated by adding 100- ⁇ M arachidonic acid and 100- ⁇ M tetramethyl-p-phenylenediamine (TMPD— the colourimetric substrate). The optical density of the colored product was determined at 620 nm 5 minutes after initiation.
- TMPD tetramethyl-p-phenylenediamine
- PL/C-treated FDC-2-4 was constituted in 0, 0.45, 4.5- ⁇ M concentrations in a 1 ⁇ M hematin/0.1 M Tris-HCI, pH 8.0, buffer.
- PL/C- treated FDC-2-4 was compared with non-PL/C-treated FDC-2-4 and control (no FDC-2-4 added) in determining COX inhibition.
- Acetylsalicylate (ASA) was used as a positive control in all experiments.
- ASA Statistical Analysis on all treatment groups were done using ANOVA and Tukey Posthoc tests .
- FIGS. 4 and 5 show that FDC-2-4 was found to be effective in inhibiting both isoforms of cyclooxygenase (COX-1 and COX-2).
- PL/C-treated FDC-2-4 exhibits a stronger inhibition of cyclooxygenase than non-PL/C treated FDC-2-4.
- EXAMPLE 9 Forming the water insoluble FDC-2-4 (phytostanyl analogue having a chemical designation of phytostanyl-O-acetylsalicyloxyacetates and a molecular weight of 631.66g/mol) into a 4mg/ml to 8mg/ml aqueous solution using a solubility enhancing agent.
- FDC-2-4 and the solubility enhancing agent being tested were dissolved using a suitable organic solvent; heat was applied if necessary. The organic solvent was removed by nitrogen evaporation and water was added to the test tubes. The mixtures were visually inspected for cloudiness or particles. The formulation developed was characterized using light microscopy, particle size measurement, zeta potential measurement, and transmission electron microscopy.
- the nitrogen evaporator was turned on and the temperature was set for 65°C (without nitrogen air - the nitrogen evaporator was initially used as a hot water bath). 2.
- Four mg of FDC 2-4 was measured into 16 x 100mm test tubes. In the same test tubes, 120mg of Tween 80 was measured out using a glass pipette.
- the parafilm was removed from the test tubes, the temperature of the nitrogen evaporator was reduced to 60°C, and the nitrogen air was turned on. The pressure of the nitrogen air was initially about 7 psi for about 30 minutes to ensure that none of the solution splattered out. After about 30 minutes, the psi was increased to 15-20. The samples were left in the nitrogen evaporator for a total of about 2.5 hours.
- 1 mL formulations were prepared containing either 4mg of FDC 2-4 and 120mg of polysorbate 80 or 8mg of FDC 2-4 and 240mg of polysorbate 80. Therefore, the formulations had a 1 :30 mass ratio of FDC 2-4 to polysorbate 80.
- Figure 6 shows a digital image of a 1mL aqueous solution containing 4mg of FDC 2- 4 and 120mg of polysorbate 80, against a black background showing a clear solution.
- the particle size in the formulation was measured in the Zetasizer 3000 HS.
- the mean peak analysis by volume (the mean particle size) in the 4mg/mL formulation was 4.3nm. This may indicate that the compound of the present invention and the selected solubility enhancing agent, polysorbate 80 form micelles, as illustrated in Figure 7.
- the mean particle size of the 120mg/ml polysorbate 80 control was 5.7nm. Note in Figure 8 and Figure 9 the similarity of the particle size distribution between the FDC-2-4 formulation and the control.
- the compounds of the present invention can be more than adequately solubilized into an aqueous solutions.
- EXAMPLE 10- Characterizing the formulation of Example 9 and performing in vivo cholesterol uptake studies using rats.
- the formulation was administered to rats to measure cholesterol uptake in the presence of FDC-2-4.
- Table 3 Plasma concentration of [ 3 H] cholesterol 10 hours after a single oral gavage of [ 3 H] cholesterol, unlabelled cholesterol, and FDC 2-4 co-administered in Tween 80 to Sprague-Dawley Male Fasted Rats.
- Tween 80 Control is a mixture of 1 0 and 240mg amounts). Rats weighed between 360-400g.
- the concentration value of 4mg/mL - 8mg/mL was selected because a similar water- soluble phytostanol known by the present inventors (" FM-VP4"), shows optimal cholesterol inhibition at 10mg/kg - 20mg/kg dose. For a rat that weighs approximately 400g, this relates to a dose of 4mg - 8mg.
- FM-VP4 water- soluble phytostanol known by the present inventors
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Animal Behavior & Ethology (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Heart & Thoracic Surgery (AREA)
- Cardiology (AREA)
- Epidemiology (AREA)
- Communicable Diseases (AREA)
- Oncology (AREA)
- Diabetes (AREA)
- Hematology (AREA)
- Obesity (AREA)
- Vascular Medicine (AREA)
- Virology (AREA)
- Pain & Pain Management (AREA)
- Rheumatology (AREA)
- Urology & Nephrology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Steroid Compounds (AREA)
- Medicinal Preparation (AREA)
Applications Claiming Priority (5)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US255558 | 1988-10-11 | ||
US10/255,558 US20040236125A1 (en) | 2002-09-25 | 2002-09-25 | Novel structures and compositions comprising sterols and/or stanols and specific classes of anti-inflammatory agents and use thereof in treating or preventing cardiovascular disease, its underlying conditions including hyperlipidemia and other disorders having inflammation as part of their aetiology or presentation |
US66484303A | 2003-09-16 | 2003-09-16 | |
US664843 | 2003-09-16 | ||
PCT/CA2003/001412 WO2004029068A1 (en) | 2002-09-25 | 2003-09-25 | Derivatives comprising sterols and/or stanols and specific classes of anti-inflammatory agents and use thereof in treating or preventing cardiovascular disease |
Publications (1)
Publication Number | Publication Date |
---|---|
EP1556406A1 true EP1556406A1 (en) | 2005-07-27 |
Family
ID=32044971
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP03747766A Withdrawn EP1556406A1 (en) | 2002-09-25 | 2003-09-25 | Derivatives comprising sterols and/or stanols and specific classes of anti-inflammatory agents and use thereof in treating or preventing cardiovascular disease |
Country Status (10)
Country | Link |
---|---|
EP (1) | EP1556406A1 (ja) |
JP (1) | JP2006503840A (ja) |
KR (1) | KR20050084572A (ja) |
CN (1) | CN1684971A (ja) |
AU (1) | AU2003266885A1 (ja) |
BR (1) | BR0314700A (ja) |
CA (1) | CA2499817A1 (ja) |
NO (1) | NO20051932L (ja) |
RU (1) | RU2005112247A (ja) |
WO (1) | WO2004029068A1 (ja) |
Families Citing this family (11)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20080182801A1 (en) | 2003-12-22 | 2008-07-31 | Btg International Limited | Core 2 glcnac-t inhibitors |
GB0329667D0 (en) | 2003-12-22 | 2004-01-28 | King S College London | Core 2 GlcNAc-T inhibitor |
GB0513881D0 (en) | 2005-07-06 | 2005-08-10 | Btg Int Ltd | Core 2 GLCNAC-T Inhibitors III |
DE102004008035A1 (de) * | 2004-02-19 | 2005-09-08 | Symrise Gmbh & Co. Kg | Verwendung von (2-Hydroxyphenyl)-alkoholen sowie diese Verbindungen enthaltende kosmetische oder therapeutische Formulierungen |
GB0513888D0 (en) | 2005-07-06 | 2005-08-10 | Btg Int Ltd | Core 2 GLCNAC-T Inhibitors II |
GB0513883D0 (en) | 2005-07-06 | 2005-08-10 | Btg Int Ltd | Diagnosis of Atherosclerosis |
DK2662382T3 (en) * | 2012-05-10 | 2016-06-27 | Beta Innov | Sterol, MANUFACTURING METHOD THEREOF, PHARMACEUTICAL COMPOSITIONS CONTAINING THEM, AND USE THEREOF FOR THE TREATMENT OF MULTIPLE glioblastoma |
CN104530167B (zh) * | 2014-12-16 | 2016-02-24 | 吉林农业大学 | 水杨酸环戊烷并多氢菲酯a及其提取方法和药物用途 |
CN104434927A (zh) * | 2014-12-16 | 2015-03-25 | 吉林农业大学 | 丙二酸双环戊烷并多氢菲酯b在制备降血压药物中的应用 |
CN111053741B (zh) * | 2019-12-31 | 2021-09-28 | 江苏省中医院 | 一种用于治疗炎症性肠病的基于β-谷甾醇与5-ASA的口服多敏感胶束前药 |
CN114014905B (zh) * | 2021-12-03 | 2023-07-21 | 浙江科技学院 | 靶向PPARγ的甘草次酸类衍生物及其制备方法和用途 |
Family Cites Families (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE19518221A1 (de) * | 1995-05-10 | 1996-11-14 | Schering Ag | Verwendung nichtsteroidaler Entzündungshemmer zur Verbesserung der physiologischen Verträglichkeit partikulärer pharmazeutischer Zubereitungen |
CA2346881A1 (en) * | 1998-07-20 | 2000-02-03 | Egon Novak | Compositions comprising phytosterol, phytostanol or mixtures of both and omega-3 fatty acids or derivatives thereof and use of the composition in treating or preventing cardiovascular disease and other disorders |
DE60017128T2 (de) * | 1999-06-21 | 2006-01-26 | Forbes Medi-Tech Inc., Vancouver | Aromatische und heterocyclische Denvate von Phytosterolen und/oder Phytostano- len zur Behandlung von Gefässkrankheiten |
KR100711861B1 (ko) * | 1999-06-23 | 2007-04-25 | 포비스 메디-테크 인코포레이티드 | 심혈관질환을 치료하거나 예방하기 위한 피토스테롤 또는 피토스타놀과 아스코르브산의 결합체 및 그 용도 |
AU2001242130A1 (en) * | 2000-03-07 | 2001-09-17 | Forbes Medi-Tech Inc. | Novel derivatives comprising phytosterols and/or phytostanols and alpha-lipoic and use thereof in treating or preventing cardiovascular disease, its underlying conditions and other disorders |
JP2004511573A (ja) * | 2000-10-25 | 2004-04-15 | フォーブス メディ−テック インコーポレーテッド | フィトステロール及び/又はフィトスタノール及びアスコルビン酸を含む新規構造体並びに体重調節剤としてのその使用 |
PL371436A1 (en) * | 2002-01-30 | 2005-06-13 | Pharmacia Corporation | Aldosterone antagonist and non-steroidal anti-inflammatory agent combination therapy to prevent or treat cardiovascular disorders |
-
2003
- 2003-09-25 JP JP2004538597A patent/JP2006503840A/ja not_active Withdrawn
- 2003-09-25 KR KR1020057004898A patent/KR20050084572A/ko not_active Application Discontinuation
- 2003-09-25 EP EP03747766A patent/EP1556406A1/en not_active Withdrawn
- 2003-09-25 BR BR0314700-2A patent/BR0314700A/pt not_active IP Right Cessation
- 2003-09-25 CN CNA038230283A patent/CN1684971A/zh active Pending
- 2003-09-25 AU AU2003266885A patent/AU2003266885A1/en not_active Abandoned
- 2003-09-25 RU RU2005112247/04A patent/RU2005112247A/ru not_active Application Discontinuation
- 2003-09-25 WO PCT/CA2003/001412 patent/WO2004029068A1/en not_active Application Discontinuation
- 2003-09-25 CA CA002499817A patent/CA2499817A1/en not_active Abandoned
-
2005
- 2005-04-20 NO NO20051932A patent/NO20051932L/no not_active Application Discontinuation
Non-Patent Citations (1)
Title |
---|
See references of WO2004029068A1 * |
Also Published As
Publication number | Publication date |
---|---|
RU2005112247A (ru) | 2006-01-20 |
AU2003266885A1 (en) | 2004-04-19 |
BR0314700A (pt) | 2005-07-26 |
NO20051932L (no) | 2005-04-20 |
WO2004029068A1 (en) | 2004-04-08 |
KR20050084572A (ko) | 2005-08-26 |
CN1684971A (zh) | 2005-10-19 |
JP2006503840A (ja) | 2006-02-02 |
CA2499817A1 (en) | 2004-04-08 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CA2290331C (en) | Phytosterol and/or phytostanol derivatives | |
ES2220986T5 (es) | Composicion que comprende esteres de estanol vegetal y el uso del mismo para reducir el colesterol en el suero. | |
AU771960B2 (en) | Compositions comprising phytosterol and/or phytostanol having enhanced solubility and dispersability | |
EP1189924B1 (en) | Conjugates of phytosterol or phytostanol with ascorbic acid and use thereof in treating or preventing cardiovascular disease | |
EP1227734A2 (en) | Compositions comprising edible oils or fats and phytosterols and/or phytostanols substantially dissolved therein | |
CA2531836A1 (en) | Novel compounds and compositions comprising sterols and/or stanols and cholesterol biosynthesis inhibitors and use thereof in treating or preventing a variety of diseases and conditions. | |
WO2000015201A2 (en) | Compositions comprising one or more phytosterols, phytostanols or mixtures of both and one or more alpha, beta, delta, or gamma tocotrienols or derivatives thereof and use of the compositions in treating or preventing cardiovascular disease, its underlying conditions and other disorders | |
WO2004029068A1 (en) | Derivatives comprising sterols and/or stanols and specific classes of anti-inflammatory agents and use thereof in treating or preventing cardiovascular disease | |
US7645749B2 (en) | Sterol/stanol nitroderivatives and use thereof | |
US20070254026A1 (en) | Softgel capsules | |
EP1189923B1 (en) | Aromatic and heterocyclic derivatives of phytosterols and/or phytostanols for use in treating or preventing cardiovascular disease | |
WO2001066560A2 (en) | Novel derivatives comprising phytosterols and/or phytostanols and alpha-lipoic and use thereof in treating or preventing cardiovascular disease, its underlying conditions and other disorders | |
NZ189297A (en) | Pgs inhibitor containing sterol glycosides | |
US20040236125A1 (en) | Novel structures and compositions comprising sterols and/or stanols and specific classes of anti-inflammatory agents and use thereof in treating or preventing cardiovascular disease, its underlying conditions including hyperlipidemia and other disorders having inflammation as part of their aetiology or presentation | |
AU2006201562A1 (en) | Novel crystalline composites comprising phytosterols and phytostanols or derivatives thereof | |
JP2005535611A (ja) | アスコルビン酸を伴った新規アンドロスタン及びアンドロステン誘導体並びに種々の病気、疾患及び障害の治療または予防におけるそれらの使用 | |
RU2172629C2 (ru) | Станоловая композиция и ее применение | |
AU2005211536B2 (en) | Conjugates of phytosterol or phytostanol with ascorbic acid and use thereof in treating or preventing cardiovascular disease | |
CA2461136A1 (en) | 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) | |
AU2005209658A1 (en) | Aromatic and heterocyclic derivatives of phytosterols and/or phytostanols for use in treating or preventing cardiovascular disease | |
AU2005202497A1 (en) | Aromatic and heterocyclic derivatives of phytosterols and/or phytostanols for use in treating or preventing cardiovascular disease | |
AU2005202571A1 (en) | Conjugates of phytosterol or phytostanol with ascorbic acid and use thereof in treating or preventing cardiovascular disease |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
PUAI | Public reference made under article 153(3) epc to a published international application that has entered the european phase |
Free format text: ORIGINAL CODE: 0009012 |
|
17P | Request for examination filed |
Effective date: 20050422 |
|
AK | Designated contracting states |
Kind code of ref document: A1 Designated state(s): AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HU IE IT LI LU MC NL PT RO SE SI SK TR |
|
AX | Request for extension of the european patent |
Extension state: AL LT LV MK |
|
17Q | First examination report despatched |
Effective date: 20061117 |
|
STAA | Information on the status of an ep patent application or granted ep patent |
Free format text: STATUS: THE APPLICATION IS DEEMED TO BE WITHDRAWN |
|
18D | Application deemed to be withdrawn |
Effective date: 20070328 |