EP0000704A1 - Polyethers; process for their preparation and their use as lipid absorption inhibitors - Google Patents
Polyethers; process for their preparation and their use as lipid absorption inhibitors Download PDFInfo
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- EP0000704A1 EP0000704A1 EP78100357A EP78100357A EP0000704A1 EP 0000704 A1 EP0000704 A1 EP 0000704A1 EP 78100357 A EP78100357 A EP 78100357A EP 78100357 A EP78100357 A EP 78100357A EP 0000704 A1 EP0000704 A1 EP 0000704A1
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- Prior art keywords
- ethylene oxide
- oxide content
- polymeric
- molecular weight
- polyethers
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- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
- C08G65/00—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule
- C08G65/02—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule from cyclic ethers by opening of the heterocyclic ring
- C08G65/26—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule from cyclic ethers by opening of the heterocyclic ring from cyclic ethers and other compounds
- C08G65/2603—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule from cyclic ethers by opening of the heterocyclic ring from cyclic ethers and other compounds the other compounds containing oxygen
- C08G65/2606—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule from cyclic ethers by opening of the heterocyclic ring from cyclic ethers and other compounds the other compounds containing oxygen containing hydroxyl groups
- C08G65/2609—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule from cyclic ethers by opening of the heterocyclic ring from cyclic ethers and other compounds the other compounds containing oxygen containing hydroxyl groups containing aliphatic hydroxyl groups
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- 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
- A61K31/74—Synthetic polymeric materials
- A61K31/765—Polymers containing oxygen
- A61K31/77—Polymers containing oxygen of oxiranes
Definitions
- the present invention relates to new polyethers, several processes for their preparation and their use as medicaments which influence the metabolism, in particular as lipid absorption inhibitors.
- polyethers consisting of ethylene oxide and propylene oxide groups (see US Pat. No. 2,674,619). It is also known that polyoxyalkylenes with molecular weights of approx. 1000 to approx. 11,000 have surface-active properties and can also be used in pharmaceutical preparations. US Pat. No. 3,641,240 claims and describes the use of polyoxyalkylenes with a molecular weight of approximately 2000 to 10,000 and an ethylene oxide content of 50 to 90% as antithrombotics. In this patent it is expressly pointed out that the applicable Polyoxyalkylene should contain at least 50% ethylene oxide.
- U.S. Patent 3,202,578 describes polyoxyalkylenes which can be used as laxatives. In addition to the laxative effect, this patent also mentions an effect on lowering cholesterol in the blood. According to the statements in this patent specification, such polyoxyalkylenes are particularly suitable as cholesterol-lowering compounds which have a molecular weight of 7,500 and contain 80% ethylene oxide.
- polyethers of general structure (I) with an average molecular weight of 4000, a propylene oxide content of 70% and an ethylene oxide content of 30%.
- the polyethers of the general structure (I) according to the invention are prepared by Propylene glycol in the presence of alkali hydroxide by polyaddition first with propylene oxide and then with a corresponding amount of ethylene oxide, the alkali metal hydroxide is then neutralized with aqueous mineral acid and, after dehydration of the polyether, removed by salt filtration.
- the polyethers according to the invention have a narrow molecular weight distribution.
- the characterization and composition of the polymeric oxyalkylene compounds is carried out analytically by determining the molecular weight from the hydroxyl number.
- the ethylene oxide content is determined from the H-NMR spectrum.
- the polyethers according to the invention surprisingly show very strong effects in the treatment of fat and carbohydrate metabolism disorders. In particular, they lower the elevated cholesterol in serum and tissue and at the same time reduce hypertriglyceridaemia.
- the compounds according to the invention are suitable for the treatment of hyperlipoproteinaemia, atherosclerosis, obesity and for the treatment of metabolic disorders triggered thereby.
- polyethers according to the invention of the present application have such a pronounced hypolipidemic effect in this molecular weight range from 3 to 5000, in particular 4000, and the special propylene oxide / ethylene oxide ratio. Since the compounds according to the invention are at the same time very well tolerated in addition to this strong action, they represent an enrichment of the pharmaceutical industry.
- the present invention includes pharmaceutical preparations which, in addition to non-toxic, inert pharmaceutically suitable excipients, contain one or more compounds of the above formula or which consist of one or more compounds of the above formula, and processes for the preparation of these preparations.
- the invention also includes pharmaceutical preparations in dosage units.
- the dosage units can e.g. 1, 2, 3 or 4 single doses or 1/2, 1/3 or 1/4 of a single dose.
- a single dose preferably contains the amount of active ingredient which is administered in one application and which usually corresponds to a whole, a half or a third or a quarter of a daily dose.
- Non-toxic, inert pharmaceutically suitable excipients are to be understood as solid, semisolid or liquid diluents, fillers and formulation auxiliaries of all kinds.
- Tablets, dragees, capsules, pills, granules, suppositories, solutions, suspensions and emulsions, pastes may be mentioned as preferred pharmaceutical preparations.
- Tablets, coated tablets, capsules, pills and granules can contain the active ingredient (s) in addition to the usual carriers, such as (a) fillers and extenders, for example starches, Milk sugar, cane sugar, glucose, mannitol and silica, (b) binders, e.g. carboxymethyl cellulose, alginates, gelatin, polyvinylpyrrolidone, (c) humectants, e.g. glycerin, (d) disintegrants, e.g. agar-agar, calcium carbonate and sodium bicarbonate, (e) dissolving agents , e.g. paraffin and (f) absorption accelerators, e.g.
- fillers and extenders for example starches, Milk sugar, cane sugar, glucose, mannitol and silica
- binders e.g. carboxymethyl cellulose, alginates, gelatin, polyvinylpyrrolidone
- humectants e.g
- quaternary ammonium compounds (g) wetting agents, e.g. cetycohol, glycerol monostearate, (h) adsorbents, e.g. kaolin and bentonite and (i) lubricants, e.g. talc, calcium and magnesium stearate and solid polyethylene glycols or mixtures of the substances listed under (a) - (i).
- wetting agents e.g. cetycohol, glycerol monostearate
- adsorbents e.g. kaolin and bentonite
- lubricants e.g. talc, calcium and magnesium stearate and solid polyethylene glycols or mixtures of the substances listed under (a) - (i).
- the tablets, dragees, capsules, pills and granules can be provided with the usual coatings and casings, optionally containing opacifying agents, and can also be composed such that they release the active ingredient (s) only or preferably in a certain part of the intestinal tract, if necessary with a delay , where as embedding compounds, for example Polymer substances and waxes can be used.
- the active ingredient (s) can optionally also be in microencapsulated form with one or more of the above-mentioned excipients.
- suppositories can contain the usual water-soluble or water-insoluble carriers, for example polyethylene glycols, fats, for example cocoa fat, and higher esters (for example C 14 alcohol with C 16 fatty acid) or mixtures of these substances.
- water-soluble or water-insoluble carriers for example polyethylene glycols, fats, for example cocoa fat, and higher esters (for example C 14 alcohol with C 16 fatty acid) or mixtures of these substances.
- solutions and emulsions can contain the usual carriers, such as solvents, solubilizers and emulsifiers, e.g. Water, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils, in particular cottonseed oil, peanut oil, corn oil, olive oil, castor oil and sesame oil, glycerin, glycerol formate, fatty alcohol ester fatty acid, tetrahydrofuran desorbate or mixtures of these substances.
- solvents e.g. Water, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils, in particular cottonseed
- solutions and emulsions can also be in sterile and blood isotonic form.
- suspensions can contain the usual carriers, such as liquid diluents, e.g. Water, ethyl alcohol, propylene glycol, suspending agents e.g. contain ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide, bentonite, agar and tragacanth or mixtures of these substances.
- liquid diluents e.g. Water, ethyl alcohol, propylene glycol
- suspending agents e.g. contain ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide, bentonite, agar and tragacanth or mixtures of these substances.
- the formulation forms mentioned can also contain colorants, preservatives and additives which improve the smell and taste, for example peppermint oil and eucalyptus oil, and sweeteners, for example saccharin.
- the therapeutically active compounds should be present in the pharmaceutical preparations listed above in a concentration of about 0.1 to 99.5, preferably about 0.5 to 95 percent by weight of the total mixture.
- the pharmaceutical preparations listed above can also contain other active pharmaceutical ingredients.
- the pharmaceutical preparations listed above are prepared in a conventional manner by known methods, e.g. by mixing the active substance or substances with the carrier substance or substances.
- the present invention also includes the use of the compounds of the above formula and the use of pharmaceutical preparations which contain one or more compounds of the above formula in human and veterinary medicine for preventing, ameliorating and / or curing the above-mentioned diseases.
- the active substances or the pharmaceutical preparations can be administered orally, parenterally, intraperitoneally and / or rectally, preferably orally.
- the active ingredient (s) in amounts of about 0.05 to about 500, preferably 0.5 to 200 mg / kg body weight per 24 hours. , to be applied over 1 to 6 administrations, namely before or / and during or / and after the meal.
- a single dose ent holds the active ingredient (s) preferably in amounts of about 0.1 to about 100 mg / kg body weight.
- ea may be sufficient to make do with less than the above-mentioned amount of active ingredient, while in other cases the amount of active ingredient mentioned above must be exceeded.
- the optimum dosage and type of application of the active ingredients required in each case can easily be determined by any person skilled in the art on the basis of his specialist knowledge.
Abstract
Description
Vorliegende Erfindung betrifft neue Polyäther, mehrere Verfahren zu ihrer Herstellung sowie ihre Verwendung als stoffwechselbeeinflussende Arzneimittel, insbesondere als Lipidabsorptionshemmer.The present invention relates to new polyethers, several processes for their preparation and their use as medicaments which influence the metabolism, in particular as lipid absorption inhibitors.
Es ist bereits bekannt geworden, Polyäther, die aus Äthylenoxid- und Propylenoxidgruppierungen bestehen, herzustellen (vgl. US-Patent 2 674 619). Es ist ebenfalls bekannt, daß Polyoxialkylene mit Molgewichten von ca. 1000 bis ca. 11 000 oberflächenaktive Eigenschaften besitzen und darüberhinaus auch in pharmazeutischen Zubereitungen Verwendung finden können. In der US-Patentschrift 3 641 240 wird die Verwendung von Polyoxialkylenen mit einem Molekulargewicht von ca. 2000 bis 10 000 und einem Äthylenoxidgehalt von 50 bis 90 % als Antithrombotika beansprucht und beschrieben. In dieser Patentschrift wird ausdrücklich darauf hingewiesen, daß das anzuwendende Polyoxialkylen mindestens 50 % Äthylenoxid enthalten soll.It has already become known to produce polyethers consisting of ethylene oxide and propylene oxide groups (see US Pat. No. 2,674,619). It is also known that polyoxyalkylenes with molecular weights of approx. 1000 to approx. 11,000 have surface-active properties and can also be used in pharmaceutical preparations. US Pat. No. 3,641,240 claims and describes the use of polyoxyalkylenes with a molecular weight of approximately 2000 to 10,000 and an ethylene oxide content of 50 to 90% as antithrombotics. In this patent it is expressly pointed out that the applicable Polyoxyalkylene should contain at least 50% ethylene oxide.
In dem US-Patent 3 202 578 werden Polyoxialkylene beschrieben, die als Laxantia Verwendung finden können. In dieser Patentschrift wird neben der laxierenden Wirkung auch eine Wirkung auf die Cholesterinsenkung im Blut erwähnt. Nach den Ausführungen dieser Patentschrift sind solche Polyoxialkylene besor.ders als cholesterinsenkende Verbindungen geeignet, die ein Molekulargewicht von 7500 besitzen und 80 % Äthylenoxid enthalten.U.S. Patent 3,202,578 describes polyoxyalkylenes which can be used as laxatives. In addition to the laxative effect, this patent also mentions an effect on lowering cholesterol in the blood. According to the statements in this patent specification, such polyoxyalkylenes are particularly suitable as cholesterol-lowering compounds which have a molecular weight of 7,500 and contain 80% ethylene oxide.
Die vorliegende Erfindung betrifft neue Polyäther der allgemeinen Struktur
- X, Y und Z so gewählt werden, daß ein Molekulargewicht von 3000 bis 5000 resultiert und daß der Propylenoxidanteil 60 bis 80 % und der Äthylenoxidanteil 20 bis 40 % beträgt.
- X, Y and Z are chosen so that a molecular weight of 3000 to 5000 results and that the propylene oxide content is 60 to 80% and the ethylene oxide content is 20 to 40%.
Von besonderem Interesse sind Polyäther der allgemeinen Struktur (I) mit einem mittleren Molekulargewicht von 4000, einem Propylenoxidanteil von 70 % und einem Äthylenoxidanteil von 30 %.Of particular interest are polyethers of general structure (I) with an average molecular weight of 4000, a propylene oxide content of 70% and an ethylene oxide content of 30%.
Die Herstellung der erfindungsgemäßen Polyäther der allgemeinen Struktur (I) erfolgt, indem man
Propylenglykol in Gegenwart von Alkalihydroxid durch Polyaddition zunächst mit Propylenoxid und danach mit einer entsprechenden Menge Äthylenoxid umsetzt, das Alkalihydroxid dann mit wäßriger Mineralsäure neutralisiert und nach Entwässerung des Polyäthers durch Salzfiltration entfernt.The polyethers of the general structure (I) according to the invention are prepared by
Propylene glycol in the presence of alkali hydroxide by polyaddition first with propylene oxide and then with a corresponding amount of ethylene oxide, the alkali metal hydroxide is then neutralized with aqueous mineral acid and, after dehydration of the polyether, removed by salt filtration.
Die erfindungsgemäßen Polyäther haben eine enge Molekulargewichtsverteilung.The polyethers according to the invention have a narrow molecular weight distribution.
Die Charakterisierung und Zusammensetzung der polymeren Oxialkylenverbindungen erfolgt analytisch durch Ermittlung des Molekulargewichts aus der Hydroxylzahl. Der Äthylenoxidgehalt wird aus dem H-NMR-Spektrum bestimmt.The characterization and composition of the polymeric oxyalkylene compounds is carried out analytically by determining the molecular weight from the hydroxyl number. The ethylene oxide content is determined from the H-NMR spectrum.
Die erfindungsgemäßen Polyäther zeigen überraschenderweise sehr starke Wirkungen bei der Behandlung von Fett- und Kohlenhydratstoffwechselstörungen. Sie bewirken insbesondere eine Senkung des erhöhten Cholesterins im Serum und im Gewebe und vermindern gleichzeitig eine Hypertriglyceridämie. Die erfindungsgemäßen Verbindungen eignen sich zur Behandlung von Hyperlipoproteinämien, Atherosklerose, Adipositas und zur Behandlung hierdurch ausgelöster Stoffwechselstörungen.The polyethers according to the invention surprisingly show very strong effects in the treatment of fat and carbohydrate metabolism disorders. In particular, they lower the elevated cholesterol in serum and tissue and at the same time reduce hypertriglyceridaemia. The compounds according to the invention are suitable for the treatment of hyperlipoproteinaemia, atherosclerosis, obesity and for the treatment of metabolic disorders triggered thereby.
Es ist als ausgesprochen überraschend zu bezeichnen, daß die erfindungsgemäßen Polyäther der vorliegenden Anmeldung ausgerechnet in diesem Molekulargewichtsbereich von 3 bis 5000, insbesondere 4000, und dem speziellen Propylenoxid/Äthylenoxid-Verhältnis eine so ausgeprägte hypolipidämische Wirkung besitzen. Da die erfindungsgemäßen Verbindungen neben dieser starken Wirkung gleichzeitig sehr gut verträglich sind, stellen sie eine Bereicherung der Pharmazie dar.It is to be described as extremely surprising that the polyethers according to the invention of the present application have such a pronounced hypolipidemic effect in this molecular weight range from 3 to 5000, in particular 4000, and the special propylene oxide / ethylene oxide ratio. Since the compounds according to the invention are at the same time very well tolerated in addition to this strong action, they represent an enrichment of the pharmaceutical industry.
Zur vorliegenden Erfindung gehören pharmazeutische Zubereitungen, die neben nichttoxischen, inerten pharmazeutisch geeigneten Trägerstoffen eine oder mehrere Verbindungen der obigen Formel enthalten oder die aus einer oder mehreren Verbindungen der obigen Formel bestehen sowie Verfahren zur Herstellung dieser Zubereitungen.The present invention includes pharmaceutical preparations which, in addition to non-toxic, inert pharmaceutically suitable excipients, contain one or more compounds of the above formula or which consist of one or more compounds of the above formula, and processes for the preparation of these preparations.
Zur vorliegenden. Erfindung gehören auch pharmazeutische Zubereitungen in Dosierungseinheiten. Dies bedeutet, daß die Zubereitungen in Form einzelner Teile, z.B. Tabletten, Dragees, Kapseln, Pillen, Suppositorien und Ampullen, vorliegen, deren Wirkstoffgehalt einem Bruchteil oder einem Vielfachen einer Einzeldosis entsprechen. Die Dosierungseinheiten können z.B. 1, 2, 3 oder 4 Einzeldosen oder 1/2, 1/3 oder 1/4 einer Einzeldosis enthalten. Eine Einzeldosis enthält vorzugsweise die Menge Wirkstoff, die bei einer Applikation verabreicht wird und die gewöhnlich einer ganzen, einer halben oder einem Drittel oder einem Viertel einer Tagesdosis entspricht.To the present. The invention also includes pharmaceutical preparations in dosage units. This means that the preparations in the form of individual parts, e.g. Tablets, coated tablets, capsules, pills, suppositories and ampoules are present, the active ingredient content of which corresponds to a fraction or a multiple of a single dose. The dosage units can e.g. 1, 2, 3 or 4 single doses or 1/2, 1/3 or 1/4 of a single dose. A single dose preferably contains the amount of active ingredient which is administered in one application and which usually corresponds to a whole, a half or a third or a quarter of a daily dose.
Unter nichttoxischen, inerten pharmazeutisch geeigneten Trägerstoffen sind feste, halbfeste oder flüssige Verdünnungsmittel, Füllstoffe und Formulierungshilfsmittel jeder Art zu verstehen.Non-toxic, inert pharmaceutically suitable excipients are to be understood as solid, semisolid or liquid diluents, fillers and formulation auxiliaries of all kinds.
Als bevorzugte pharmazeutische Zubereitungen seien Tabletten, Dragees, Kapseln, Pillen, Granulate, Suppositorien, Lösungen, Suspensionen und Emulsionen, Pasten genannt.Tablets, dragees, capsules, pills, granules, suppositories, solutions, suspensions and emulsions, pastes may be mentioned as preferred pharmaceutical preparations.
Tabletten, Dragees, Kapseln, Pillen und Granulate können den oder die Wirkstoffe neben den üblichen Trägerstoffen enthalten, wie (a) Füll- und Streckmittel, z.B. Stärken, Milchzucker, Rohrzucker, Glukose, Mannit und Kieselsäure, (b) Bindemittel, z.B. Carboxymethylcellulose, Alginate, Gelatine, Polyvinylpyrrolidon, (c) Feuchthaltemittel, z.B. Glycerin, (d) Sprengmittel, z.B. Agar-Agar, Calciumcarbonat und Natriumbicarbonat, (e) Lösungsverzögerer, z.B. Paraffin und (f)-Resorptionsbeschleuniger, z.B. quarternäre Ammoniumverbindungen, (g) Netzmittel, z.B. Cetylakohol, Glycerinmonostearat, (h) Adsorptionsmittel, z.B. Kaolin und Bentonit und (i) Gleitmittel, z.B. Talkum-, Calcium- und Magnesiumstearat und feste Polyäthylenglykole oder Gemische der unter (a) - (i) aufgeführten Stoffe.Tablets, coated tablets, capsules, pills and granules can contain the active ingredient (s) in addition to the usual carriers, such as (a) fillers and extenders, for example starches, Milk sugar, cane sugar, glucose, mannitol and silica, (b) binders, e.g. carboxymethyl cellulose, alginates, gelatin, polyvinylpyrrolidone, (c) humectants, e.g. glycerin, (d) disintegrants, e.g. agar-agar, calcium carbonate and sodium bicarbonate, (e) dissolving agents , e.g. paraffin and (f) absorption accelerators, e.g. quaternary ammonium compounds, (g) wetting agents, e.g. cetycohol, glycerol monostearate, (h) adsorbents, e.g. kaolin and bentonite and (i) lubricants, e.g. talc, calcium and magnesium stearate and solid polyethylene glycols or mixtures of the substances listed under (a) - (i).
Die Tabletten, Dragees, Kapseln, Pillen und Granulate können mit den üblichen gegebenenfalls Opakisierungsmittel enthaltenden Ueberzügen und Hüllen versehen sein und auch so zusammengesetzt sein, daß sie den oder die Wirkstoffe nur oder bevorzugt in einem bestimmten Teil des Intestinal- traktes,.gegebenenfalls verzögert abgeben, wobei als Einbettungsmassen z.B. Polymersubstanzen und Wachse verwendet werden können.The tablets, dragees, capsules, pills and granules can be provided with the usual coatings and casings, optionally containing opacifying agents, and can also be composed such that they release the active ingredient (s) only or preferably in a certain part of the intestinal tract, if necessary with a delay , where as embedding compounds, for example Polymer substances and waxes can be used.
Der oder die Wirkstoffe können gegebenenfalls mit einem oder mehreren der oben angegebenen Trägerstoffe auch in mikroverkapselter Form vorliegen.The active ingredient (s) can optionally also be in microencapsulated form with one or more of the above-mentioned excipients.
Suppositorien können neben dem oder den Wirkstoffen die üblichen wasserlöslichen oder wasserunlöslichen Trägerstoffe enthalten, z.B. Polyäthylenglykole, Fette z.B. Kakaofett und höhere Ester (z.B. C14-Alkohol mit C16-Fettsäure) oder Gemische dieser Stoffe.In addition to the active substance or substances, suppositories can contain the usual water-soluble or water-insoluble carriers, for example polyethylene glycols, fats, for example cocoa fat, and higher esters (for example C 14 alcohol with C 16 fatty acid) or mixtures of these substances.
Lösungen und Emulsionen können neben dem oder den Wirkstoffen die üblichen Trägerstoffe, wie Lösungsmittel, Lösungsvermittler und Emulgatoren, z.B. Wasser, Aethylalkohol, Isopropylalkohol, Aethylcarbonat, Aethylacetat, Benzylalkohol, Benzylbenzoat, Propylenglykol, 1,3-Butylenglykol, Dimethylformamid, Oele, insbesondere Baumwollsaatöl, Erdnußöl, Maiskeimöl, Olivenöl, Ricinusöl und Sesamöl, Glycerin, Glycerinformal, Tetrahydrofurfurylalkohol, Polyäthylenglykole und Fettsäureester des Sorbitans oder Gemische dieser Stoffe enthalten.In addition to the active ingredient (s), solutions and emulsions can contain the usual carriers, such as solvents, solubilizers and emulsifiers, e.g. Water, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils, in particular cottonseed oil, peanut oil, corn oil, olive oil, castor oil and sesame oil, glycerin, glycerol formate, fatty alcohol ester fatty acid, tetrahydrofuran desorbate or mixtures of these substances.
Zur parenteralen Applikation können die Lösungen und Emulsionen auch in steriler und blutisotonischer Form vorliegen.For parenteral administration, the solutions and emulsions can also be in sterile and blood isotonic form.
Suspensionen können neben dem oder den Wirkstoffen die üblichen Trägerstoffe, wie flüssige Verdünnungsmittel, z.B. Wasser, Aethylalkohol, Propylenglykol, Suspendiermittel z.B. äthoxylierte Isostearylalkohole, Polyoxyäthylensorbit- und -sorbitanester, mikrokristalline Cellulose, Aluminiummethanhydroxid, Bentonit, Agar-Agar und Traganth oder Gemische dieser Stoffe enthalten.In addition to the active ingredient (s), suspensions can contain the usual carriers, such as liquid diluents, e.g. Water, ethyl alcohol, propylene glycol, suspending agents e.g. contain ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide, bentonite, agar and tragacanth or mixtures of these substances.
Die genannten Formulierungsformen können auch Färbemittel, Konservierungsstoffe sowie geruchs- und geschmachsverbessernde Zusätze, z.B. Pfefferminzöl und Eukalyptusöl, und Süßmittel, z.B. Saccharin, enthalten.The formulation forms mentioned can also contain colorants, preservatives and additives which improve the smell and taste, for example peppermint oil and eucalyptus oil, and sweeteners, for example saccharin.
Die therapeutisch wirksamen Verbindungen sollen in den oben aufgeführten pharmazeutischen Zubereitungen in einer Konzentration von etwa 0,1 bis 99,5 , vorzugsweise von etwa 0,5 bis 95 Gewichtsprozent der Gesamtmischung, vorhanden sein.The therapeutically active compounds should be present in the pharmaceutical preparations listed above in a concentration of about 0.1 to 99.5, preferably about 0.5 to 95 percent by weight of the total mixture.
Die oben aufgeführten pharmazeutischen Zubereitungen können außer Verbindungen der obigen Formel auch andere pharmazeutische Wirkstoffe enthalten.In addition to compounds of the above formula, the pharmaceutical preparations listed above can also contain other active pharmaceutical ingredients.
Die Herstellung der oben aufgeführten pharmazeutischen Zubereitungen erfolgt in üblicher Weise nach bekannten Methoden, z.B. durch Mischen des oder der Wirkstoffe mit dem oder den Trägerstoffen.The pharmaceutical preparations listed above are prepared in a conventional manner by known methods, e.g. by mixing the active substance or substances with the carrier substance or substances.
Zur vorliegenden Erfindung gehört auch die Verwendung der Verbindungen der obigen Formel sowie die Verwendung von pharmazeutischen Zubereitungen, die eine oder mehrere Verbindungen der oben angegebenen Formel enthalten, in der Human- und Veterinärmedizin zur Verhütung, Besserung und/oder Heilung der oben angeführten Erkrankungen.The present invention also includes the use of the compounds of the above formula and the use of pharmaceutical preparations which contain one or more compounds of the above formula in human and veterinary medicine for preventing, ameliorating and / or curing the above-mentioned diseases.
Die Wirkstoffe oder die pharmazeutischen Zubereitungen können oral, parenteral, intraperitoneal und/oder rectal, vorzugsweise oral, appliziert werden.The active substances or the pharmaceutical preparations can be administered orally, parenterally, intraperitoneally and / or rectally, preferably orally.
Im allgemeinen hat es sich sowohl in der Human- als auch in der Veterinär-Medizin als vorteilhaft erwiesen, den oder die Wirkstoffe in Mengen von etwa 0,05 bis etwa 500,vorzugsweise 0,5 bis 200 mg/kg Körpergewicht je 24 Stdn., verteilt auf 1 bis 6 Verabreichungen, und zwar vor oder/und während oder/und nach der Mahlzeit zu applizieren. Eine Einzelgabe enthält den oder die Wirkstoffe vorzugsweise in Mengen von etwa 0,1 bis etwa 100 mg/kg Körpergewicht. Es kann jedoch erforderlich sein, von den genannten Dosierungen abzuweichen, und zwar in Abhängigkeit von der Art und dem Körpergewicht des zu behandelnden Objekts, der Art und der Schwere der Erkrankung, der Art der Zubereitung und der Applikation des Arzneimittels sowie dem Zeitraum bzw. Intervall, innerhalb welchem die Verabreichung erfolgt. So kann ea in einigen Fällen ausreichend sein, mit weniger als der o.g. Menge Wirkstoff auszukommen, während in anderen Fällen die oben angeführte Wirkstoffmenge überschritten werden muß. Die Festlegung der jeweils erforderlichen optimalen Dosierung und Applikationsart der Wirkstoffe kann durch jeden Fachmann aufgrund seines Fachwissens leicht erfolgen.In general, it has proven to be advantageous in both human and veterinary medicine to use the active ingredient (s) in amounts of about 0.05 to about 500, preferably 0.5 to 200 mg / kg body weight per 24 hours. , to be applied over 1 to 6 administrations, namely before or / and during or / and after the meal. A single dose ent holds the active ingredient (s) preferably in amounts of about 0.1 to about 100 mg / kg body weight. However, it may be necessary to deviate from the doses mentioned, depending on the type and body weight of the object to be treated, the type and severity of the disease, the type of preparation and administration of the drug, and the period or interval within which the administration takes place. In some cases, ea may be sufficient to make do with less than the above-mentioned amount of active ingredient, while in other cases the amount of active ingredient mentioned above must be exceeded. The optimum dosage and type of application of the active ingredients required in each case can easily be determined by any person skilled in the art on the basis of his specialist knowledge.
In einem 10 L-Glaskolben mit Heizbad, Rührer, Rückflußkühler, Epoxiddosiereinrichtung unter Stickstoff werden 93,5 g Propylenglykol und 62 g 50%ige Kalilauge vorgelegt. Durch azeotrope oder Vakuumdestillation wird entwässert. Danach werden bei 100-120° zunächst 4707 g Propylenoxid und danach 1200 g Aethylenoxid polyaddiert. Das Kalium hydroxid wird durch Zugabe von verdünnter Schwefelsäure neutralisiert. Nach der Entwässerung des Polyäthers und destillativer Entfernung von leichtflüchtigen Anteile wird das entstandene Kaliumsulfat durch Filtration entfernt. Das Molekulargewicht des Polyäthers, berechnet aus der OH-Zahl, beträgt 4000, und das Produkt enthält 20,0 Gew. % Aethylenoxid.93.5 g of propylene glycol and 62 g of 50% strength potassium hydroxide solution are placed in a 10 L glass flask with a heating bath, stirrer, reflux condenser, epoxy metering device under nitrogen. Dewatering is carried out by azeotropic or vacuum distillation. Then 4707 g of propylene oxide and then 1200 g of ethylene oxide are polyaddled at 100-120 °. The potassium hydroxide is neutralized by adding dilute sulfuric acid. After dehydration of the polyether and removal of volatile components by distillation, the potassium sulfate formed is removed by filtration. The molecular weight of the polyether, calculated from the OH number, is 4000, and the product contains 20.0% by weight of ethylene oxide.
Durch Polyaddition von 4134,5 g (bzw. 3506,5 g) Propylenoxid und 1800,0 g (bzw. 2400,0 g) Äthylenoxid an 93,5 g Propylenglykol in Gegenwart von 62,0 g 50%iger Kalilauge wird nach dem in Beispiel 1 beschriebenen Verfahren ein Polyäther mit 30 (bzw. 40) Gew.-% Äthylenoxid und einem Molgewicht von 4000 erhalten.By polyaddition of 4134.5 g (or 3506.5 g) propylene oxide and 1800.0 g (or 2400.0 g) ethylene oxide to 93.5 g propylene glycol in the presence of 62.0 g 50% potassium hydroxide solution process described in Example 1 obtained a polyether with 30 (or 40) wt .-% ethylene oxide and a molecular weight of 4000.
Claims (7)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19772732929 DE2732929A1 (en) | 1977-07-21 | 1977-07-21 | POLYAETHER, METHOD FOR THE PRODUCTION THEREOF AND THEIR USE AS A LIPID ABSORPTION INHIBITOR |
| DE2732929 | 1977-07-21 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| EP0000704A1 true EP0000704A1 (en) | 1979-02-21 |
Family
ID=6014492
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| EP78100357A Withdrawn EP0000704A1 (en) | 1977-07-21 | 1978-07-11 | Polyethers; process for their preparation and their use as lipid absorption inhibitors |
Country Status (13)
| Country | Link |
|---|---|
| EP (1) | EP0000704A1 (en) |
| JP (1) | JPS5422497A (en) |
| AU (1) | AU3806878A (en) |
| CA (1) | CA1111453A (en) |
| DE (1) | DE2732929A1 (en) |
| DK (1) | DK324678A (en) |
| ES (1) | ES471900A1 (en) |
| FI (1) | FI782284A (en) |
| IL (1) | IL55160A0 (en) |
| IT (1) | IT1097831B (en) |
| NO (1) | NO782332L (en) |
| PT (1) | PT68307A (en) |
| ZA (1) | ZA784129B (en) |
Cited By (11)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0011237A1 (en) * | 1978-11-18 | 1980-05-28 | Bayer Ag | Polyether derivatives, a method for their preparation and their use as pharmaceuticals |
| EP0018591A1 (en) * | 1979-04-25 | 1980-11-12 | BASF Aktiengesellschaft | Moulding materials containing styrene-acrylonitrile copolymers and three-block copolymers of ethylene oxide/propylene oxide, their use and mouldings thereof |
| EP0103290A2 (en) * | 1982-09-14 | 1984-03-21 | Intermedicat Gmbh | Pharmaceutical compositions for treating undesirable coalescence and their use |
| EP0166958A1 (en) * | 1984-06-02 | 1986-01-08 | Hoechst Aktiengesellschaft | Polyethylene glycols |
| WO1988006038A1 (en) * | 1987-02-20 | 1988-08-25 | Emory University | Antiinfective compounds and method of use |
| EP0576612A1 (en) * | 1991-03-19 | 1994-01-05 | Cytrx Corporation | Polyoxypropylene/polyoxyethylene copolymers with improved biological activity |
| US5674911A (en) * | 1987-02-20 | 1997-10-07 | Cytrx Corporation | Antiinfective polyoxypropylene/polyoxyethylene copolymers and methods of use |
| US5811088A (en) * | 1987-02-20 | 1998-09-22 | Emory University | Antiinfective compounds and methods of use |
| USRE38558E1 (en) | 1991-03-19 | 2004-07-20 | Cytrx Corporation | Polyoxypropylene/polyoxyethylene copolymers with improved biological activity |
| US6933286B2 (en) | 1991-03-19 | 2005-08-23 | R. Martin Emanuele | Therapeutic delivery compositions and methods of use thereof |
| US7202225B1 (en) | 1993-10-15 | 2007-04-10 | Emanuele R Martin | Therapeutic delivery compositions and methods of use thereof |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS6030650B2 (en) * | 1979-10-26 | 1985-07-17 | 日本油脂株式会社 | Suppository base composition |
| JP2001508762A (en) | 1996-06-27 | 2001-07-03 | ジー．ディー．サール アンド カンパニー | Particles consisting of an amphiphilic copolymer having a cross-linked outer shell region and inner core region, useful for pharmaceutical and other applications |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB610505A (en) * | 1944-02-08 | 1948-10-18 | Carbide & Carbon Chem Corp | A method for making polyoxyalkylene glycols |
| FR1116M (en) * | 1961-02-02 | 1962-02-12 | Bernard Andre Francois Mirande | Use of surface-active substances originating from the condensation of ethylene oxide on propylene glycols in the absorption of local or systematized tissue edema. |
| NL6618108A (en) * | 1965-12-23 | 1967-06-26 |
-
1977
- 1977-07-21 DE DE19772732929 patent/DE2732929A1/en active Pending
-
1978
- 1978-07-04 NO NO782332A patent/NO782332L/en unknown
- 1978-07-11 EP EP78100357A patent/EP0000704A1/en not_active Withdrawn
- 1978-07-17 AU AU38068/78A patent/AU3806878A/en active Pending
- 1978-07-17 PT PT68307A patent/PT68307A/en unknown
- 1978-07-18 IL IL55160A patent/IL55160A0/en unknown
- 1978-07-19 IT IT25897/78A patent/IT1097831B/en active
- 1978-07-19 JP JP8721378A patent/JPS5422497A/en active Pending
- 1978-07-19 FI FI782284A patent/FI782284A/en not_active Application Discontinuation
- 1978-07-20 ES ES471900A patent/ES471900A1/en not_active Expired
- 1978-07-20 CA CA307,799A patent/CA1111453A/en not_active Expired
- 1978-07-20 DK DK324678A patent/DK324678A/en unknown
- 1978-07-20 ZA ZA00784129A patent/ZA784129B/en unknown
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB610505A (en) * | 1944-02-08 | 1948-10-18 | Carbide & Carbon Chem Corp | A method for making polyoxyalkylene glycols |
| FR1116M (en) * | 1961-02-02 | 1962-02-12 | Bernard Andre Francois Mirande | Use of surface-active substances originating from the condensation of ethylene oxide on propylene glycols in the absorption of local or systematized tissue edema. |
| NL6618108A (en) * | 1965-12-23 | 1967-06-26 |
Cited By (18)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0011237A1 (en) * | 1978-11-18 | 1980-05-28 | Bayer Ag | Polyether derivatives, a method for their preparation and their use as pharmaceuticals |
| EP0018591A1 (en) * | 1979-04-25 | 1980-11-12 | BASF Aktiengesellschaft | Moulding materials containing styrene-acrylonitrile copolymers and three-block copolymers of ethylene oxide/propylene oxide, their use and mouldings thereof |
| EP0103290A2 (en) * | 1982-09-14 | 1984-03-21 | Intermedicat Gmbh | Pharmaceutical compositions for treating undesirable coalescence and their use |
| EP0103290A3 (en) * | 1982-09-14 | 1984-09-05 | Intermedicat Gmbh | Pharmaceutical compositions for treating undesirable coalescence and their use |
| EP0166958A1 (en) * | 1984-06-02 | 1986-01-08 | Hoechst Aktiengesellschaft | Polyethylene glycols |
| US5674911A (en) * | 1987-02-20 | 1997-10-07 | Cytrx Corporation | Antiinfective polyoxypropylene/polyoxyethylene copolymers and methods of use |
| WO1988006038A1 (en) * | 1987-02-20 | 1988-08-25 | Emory University | Antiinfective compounds and method of use |
| US5811088A (en) * | 1987-02-20 | 1998-09-22 | Emory University | Antiinfective compounds and methods of use |
| EP0576612A1 (en) * | 1991-03-19 | 1994-01-05 | Cytrx Corporation | Polyoxypropylene/polyoxyethylene copolymers with improved biological activity |
| EP0576612A4 (en) * | 1991-03-19 | 1994-11-09 | Cytrx Corp | Polyoxypropylene/polyoxyethylene copolymers with improved biological activity. |
| US5990241A (en) * | 1991-03-19 | 1999-11-23 | Cytrx, Corporation | Polyoxypropylene/polyoxyethylene copolymers with improved biological activity |
| USRE36665E (en) * | 1991-03-19 | 2000-04-18 | Cytrx Corporation | Polyoxypropylene/polyoxyethylene copolymers with improved biological activity |
| USRE37285E1 (en) | 1991-03-19 | 2001-07-17 | Cytrx Corporation | Polyoxypropylene/polyoxyethylene copolmers with improved biological activity |
| US6359014B1 (en) | 1991-03-19 | 2002-03-19 | Cytrx Corporation | Polyoxypropylene/polyoxyethylene copolymers with improved biological activity |
| US6747064B2 (en) | 1991-03-19 | 2004-06-08 | Cytrx Corporation | Polyoxypropylene/polyoxyethylene copolymers with improved biological activity |
| USRE38558E1 (en) | 1991-03-19 | 2004-07-20 | Cytrx Corporation | Polyoxypropylene/polyoxyethylene copolymers with improved biological activity |
| US6933286B2 (en) | 1991-03-19 | 2005-08-23 | R. Martin Emanuele | Therapeutic delivery compositions and methods of use thereof |
| US7202225B1 (en) | 1993-10-15 | 2007-04-10 | Emanuele R Martin | Therapeutic delivery compositions and methods of use thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| DE2732929A1 (en) | 1979-02-01 |
| CA1111453A (en) | 1981-10-27 |
| ES471900A1 (en) | 1979-02-01 |
| IT1097831B (en) | 1985-08-31 |
| AU3806878A (en) | 1980-01-17 |
| IT7825897A0 (en) | 1978-07-19 |
| NO782332L (en) | 1979-01-23 |
| JPS5422497A (en) | 1979-02-20 |
| ZA784129B (en) | 1979-07-25 |
| PT68307A (en) | 1978-08-01 |
| IL55160A0 (en) | 1978-09-29 |
| DK324678A (en) | 1979-01-22 |
| FI782284A (en) | 1979-01-22 |
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