ITTO940893A1 - CATIONIC CELLULOSE DERIVATIVE, ITS USE FOR THE REDUCTION OF CHOLESTEROL LEVELS AND ITS PHARMACEUTICAL COMPOSITION. - Google Patents
CATIONIC CELLULOSE DERIVATIVE, ITS USE FOR THE REDUCTION OF CHOLESTEROL LEVELS AND ITS PHARMACEUTICAL COMPOSITION. Download PDFInfo
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- ITTO940893A1 ITTO940893A1 IT94TO000893A ITTO940893A ITTO940893A1 IT TO940893 A1 ITTO940893 A1 IT TO940893A1 IT 94TO000893 A IT94TO000893 A IT 94TO000893A IT TO940893 A ITTO940893 A IT TO940893A IT TO940893 A1 ITTO940893 A1 IT TO940893A1
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- cationic cellulosic
- cellulosic derivative
- pharmaceutical composition
- quaternary ammonium
- cationic
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- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 title claims abstract description 24
- 239000001913 cellulose Substances 0.000 title claims description 18
- 229920002678 cellulose Polymers 0.000 title claims description 18
- 239000008194 pharmaceutical composition Substances 0.000 title claims description 14
- 125000002091 cationic group Chemical group 0.000 claims abstract description 39
- 125000001453 quaternary ammonium group Chemical group 0.000 claims abstract description 13
- 239000003814 drug Substances 0.000 claims abstract description 5
- 229940079593 drug Drugs 0.000 claims abstract description 4
- 150000003856 quaternary ammonium compounds Chemical class 0.000 claims description 7
- 238000002360 preparation method Methods 0.000 claims description 6
- 229910052739 hydrogen Inorganic materials 0.000 claims description 5
- 239000001257 hydrogen Substances 0.000 claims description 5
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 5
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 4
- 150000001450 anions Chemical class 0.000 claims description 4
- 235000012000 cholesterol Nutrition 0.000 claims description 4
- 229910052736 halogen Inorganic materials 0.000 claims description 4
- 238000006243 chemical reaction Methods 0.000 claims description 3
- 150000001875 compounds Chemical class 0.000 claims description 3
- 239000003085 diluting agent Substances 0.000 claims description 3
- 239000003937 drug carrier Substances 0.000 claims description 3
- AFEQENGXSMURHA-UHFFFAOYSA-N oxiran-2-ylmethanamine Chemical compound NCC1CO1 AFEQENGXSMURHA-UHFFFAOYSA-N 0.000 claims description 3
- 238000002560 therapeutic procedure Methods 0.000 claims description 3
- 239000004480 active ingredient Substances 0.000 claims description 2
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- 125000005843 halogen group Chemical group 0.000 claims 2
- 210000002966 serum Anatomy 0.000 claims 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 claims 1
- BHQCQFFYRZLCQQ-UHFFFAOYSA-N (3alpha,5alpha,7alpha,12alpha)-3,7,12-trihydroxy-cholan-24-oic acid Natural products OC1CC2CC(O)CCC2(C)C2C1C1CCC(C(CCC(O)=O)C)C1(C)C(O)C2 BHQCQFFYRZLCQQ-UHFFFAOYSA-N 0.000 abstract description 16
- 239000004380 Cholic acid Substances 0.000 abstract description 16
- BHQCQFFYRZLCQQ-OELDTZBJSA-N cholic acid Chemical compound C([C@H]1C[C@H]2O)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC(O)=O)C)[C@@]2(C)[C@@H](O)C1 BHQCQFFYRZLCQQ-OELDTZBJSA-N 0.000 abstract description 16
- 235000019416 cholic acid Nutrition 0.000 abstract description 16
- 229960002471 cholic acid Drugs 0.000 abstract description 16
- KXGVEGMKQFWNSR-UHFFFAOYSA-N deoxycholic acid Natural products C1CC2CC(O)CCC2(C)C2C1C1CCC(C(CCC(O)=O)C)C1(C)C(O)C2 KXGVEGMKQFWNSR-UHFFFAOYSA-N 0.000 abstract description 16
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- 239000000243 solution Substances 0.000 description 5
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- 241000978776 Senegalia senegal Species 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
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- 125000001931 aliphatic group Chemical group 0.000 description 1
- 125000003342 alkenyl group Chemical group 0.000 description 1
- 125000000217 alkyl group Chemical group 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 150000001449 anionic compounds Chemical class 0.000 description 1
- 125000000129 anionic group Chemical group 0.000 description 1
- 230000000326 anti-hypercholesterolaemic effect Effects 0.000 description 1
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- IAOZJIPTCAWIRG-QWRGUYRKSA-N aspartame Chemical compound OC(=O)C[C@H](N)C(=O)N[C@H](C(=O)OC)CC1=CC=CC=C1 IAOZJIPTCAWIRG-QWRGUYRKSA-N 0.000 description 1
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- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08B—POLYSACCHARIDES; DERIVATIVES THEREOF
- C08B11/00—Preparation of cellulose ethers
- C08B11/02—Alkyl or cycloalkyl ethers
- C08B11/04—Alkyl or cycloalkyl ethers with substituted hydrocarbon radicals
- C08B11/14—Alkyl or cycloalkyl ethers with substituted hydrocarbon radicals with nitrogen-containing groups
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
- A61K31/716—Glucans
- A61K31/717—Celluloses
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
- A61K31/726—Glycosaminoglycans, i.e. mucopolysaccharides
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Epidemiology (AREA)
- Molecular Biology (AREA)
- Materials Engineering (AREA)
- Organic Chemistry (AREA)
- Polymers & Plastics (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Biochemistry (AREA)
- Engineering & Computer Science (AREA)
- Dermatology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
L'invenzione si riferisce ad un procedimento per la riduzione dei contenuti di colesterolo nel siero in un paziente, che comprende la somministrazione al paziente di una quantità efficace di un derivato cellulosico cationico avente gruppi ammonici quaternari attaccati alle catene cellulosiche. I derivati cellulosici cationici sono efficaci nell'assorbimento di acido colico nell'intestino ma non presentano gli svantaggi quali un sapore sgradevole, associati con medicinali noti che legano l'acido colico, come la resina colestirammina.The invention relates to a process for reducing the serum cholesterol content in a patient, which includes administering to the patient an effective amount of a cationic cellulosic derivative having quaternary ammonium groups attached to the cellulosic chains. Cationic cellulosic derivatives are effective in the absorption of cholic acid in the intestine but do not have the disadvantages such as an unpleasant taste associated with known medicines that bind cholic acid, such as the cholestyramine resin.
Description
DESCRIZIONE dell'invenzione industriale dal titolo: "Derivato cellulosico cationico, relativo uso per la riduzione dei livelli di colesterolo e relativa composizione farmaceutica", DESCRIPTION of the industrial invention entitled: "Cationic cellulosic derivative, relative use for the reduction of cholesterol levels and relative pharmaceutical composition",
DESCRIZIONE DESCRIPTION
La presente invenzione si riferisce a medicinali, più particolarmente medicinali aventi effetto antiipercolesterolemico . L'invenzione si riferisce pure a procedimenti di trattamento ed all'impiego di certi polisaccaridi in terapia e per la preparazione di medicinali. The present invention relates to medicinal products, more particularly medicinal products having an antihypercholesterolemic effect. The invention also relates to treatment processes and the use of certain polysaccharides in therapy and for the preparation of medicines.
L'abbassamento dei contenuti di colesterolo nel plasma è uno scopo importante nella prevenzione dell'aterosclerosi che è una delle cause principali di malattia e di mortalità nel mondo sviluppato. Un approccio che è stato adottato a questo scopo consiste nell'includere nella dieta quantità significative di fibre vegetali non digeribili e si ritiene che queste fibre agiscano assorbendo acido colico (un precursore del colesterolo) nel tratto intestinale, portando così ad un contenuto ridotto di colesterolo nfel sangue. Le fibre vegetali vengono assunte per assorbire l'acido colico mediante un meccanismo non specifico di cattura fisica, e sono quindi non particolarmente efficaci nell'eliminazione dell'acido colico dall'intestino. Lowering plasma cholesterol content is an important aim in the prevention of atherosclerosis which is a major cause of disease and mortality in the developed world. One approach that has been adopted to this end is to include significant amounts of non-digestible plant fibers in the diet and these fibers are believed to work by absorbing cholic acid (a precursor of cholesterol) in the intestinal tract, thus leading to a reduced cholesterol content. nfel blood. Vegetable fibers are taken to absorb cholic acid by a non-specific physical capture mechanism, and are therefore not particularly effective in eliminating cholic acid from the intestine.
Sono anche stati proposti medicinali aventi un effetto più specifico nella rimozione dell’acido colico dall'intestino ed in particolare sono stati usati polimeri cationici per legare l'acido colico nell'intestino per mezzo di un effetto di scambio anionico. L'acido colico è caricato negativamente e può essere fissato da una resina a scambio ionico avente una carica positiva fissa. A questo scopo, per alcuni anni, è stato usato un polimero stirene-divinil benzene al quale sono attaccati gruppi ammonici quaternari fortemente alcalini. Questo prodotto, noto generalmente come resina colestirammina, è attualmente considerato come uno degli agenti più efficaci nel trattamento clinico della ipercolesterolemia (vedi per esempio Levy, Ann. Intern. Med. H , 267 (1972) e Casdorph in Lipid Pharmacology, Volume 2(2), Paoletti e Glueck (Ed), Academic Press, New York, 1976, pagg. 222-256). Medicines have also been proposed having a more specific effect in the removal of cholic acid from the intestine and in particular cationic polymers have been used to bind cholic acid in the intestine by means of an anionic exchange effect. Cholic acid is negatively charged and can be fixed by an ion exchange resin having a fixed positive charge. For this purpose, a styrene-divinyl benzene polymer has been used for some years to which strongly alkaline quaternary ammonium groups are attached. This product, generally known as cholestyramine resin, is currently regarded as one of the most effective agents in the clinical treatment of hypercholesterolemia (see for example Levy, Ann. Intern. Med. H, 267 (1972) and Casdorph in Lipid Pharmacology, Volume 2 ( 2), Paoletti and Glueck (Ed), Academic Press, New York, 1976, pp. 222-256).
Sebbene l'efficacia clinica della resina colestirammina non sia discussa, essa presenta problemi di· uso. Essa ha un sapore sgradevole che dispiace ai pazienti ed è difficile da miscelare con l'acqua il che rende pure la somministrazione difficoltosa. Inoltre, come effetto secondario, si manifesta talvolta stipsi intestinale (vedi Glueck e altri, J. Am. Med . Assoc., 222r 676 (1972)). Although the clinical efficacy of cholestyramine resin is not discussed, it presents problems of use. It has an unpleasant taste that displeases patients and is difficult to mix with water which also makes administration difficult. Furthermore, intestinal constipation sometimes occurs as a secondary effect (see Glueck et al, J. Am. Med. Assoc., 222r 676 (1972)).
Uno scopo della presente invenzione consiste nel provvedere uno scambiatore di ioni adatto per l'assorbimento dell'acido colico nell'intestino, che elimini gli inconvenienti associati con la resina colestirammina . An object of the present invention is to provide an ion exchanger suitable for the absorption of cholic acid in the intestine, which eliminates the drawbacks associated with the cholestyramine resin.
E’ stato ora scoperto che certi derivati cellulosici cationici hanno un effetto comparabile a quello della resina colestirammina nell’assorbimento dell'acido colico, ma presentano, all'uso, proprietà migliorate. I derivati in questione sono derivati cellulosici cationici aventi gruppi ammonici quaternari attaccati alla catena cellulosica. Generalmente questi derivati vengono prodotti facendo reagire cellulosa, per esempio cellulosa fibrosa, con un eccesso di un composto ammonico quaternario contenente almeno un gruppo capace di reagire con un gruppo ossidrilico della cellulosa. Il grado di sostituzione di questi derivati cellulosici è preferibilmente tra 0,5 e 1,1. It has now been discovered that certain cationic cellulosic derivatives have an effect comparable to that of the cholestyramine resin in the absorption of cholic acid, but have improved properties when used. The derivatives in question are cationic cellulosic derivatives having quaternary ammonium groups attached to the cellulosic chain. Generally these derivatives are produced by reacting cellulose, for example fibrous cellulose, with an excess of a quaternary ammonium compound containing at least one group capable of reacting with a hydroxyl group of the cellulose. The degree of substitution of these cellulosic derivatives is preferably between 0.5 and 1.1.
Secondo un aspetto, la presente invenzione provvede un procedimento per la riduzione dei livelli di colesterolo nel siero in un paziente, che comprende la somministrazione al paziente di una quantità efficace di un derivato cellulosico cationico avente gruppi ammonici quaternari attaccati alle catene della cellulosa. According to one aspect, the present invention provides a method for reducing serum cholesterol levels in a patient, which comprises administering to the patient an effective amount of a cationic cellulosic derivative having quaternary ammonium groups attached to the cellulose chains.
Secondo un altro aspetto, la presente invenzione provvede un derivato cellulosico cationico avente gruppi ammonici quaternari attaccati alle catene delia cellulosa, per l'uso in terapia, per esempio per la riduzione dei livelli di colesterolo nel siero . According to another aspect, the present invention provides a cationic cellulosic derivative having quaternary ammonium groups attached to the cellulose chains, for use in therapy, for example for reducing serum cholesterol levels.
Secondo un ulteriore aspetto, la presente invenzione provvede l'uso di un derivato cellulosico cationico avente gruppi ammonici quaternari attaccati alle catene cellulosiche, per la preparazione di ,un medicinale per la riduzione dei livelli di colesterolo nel siero. , According to a further aspect, the present invention provides the use of a cationic cellulosic derivative having quaternary ammonium groups attached to the cellulosic chains, for the preparation of, a medicament for the reduction of serum cholesterol levels. ,
Secondo ancora un altro aspetto, la presente invenzione provvede una composizione farmaceutica, per esempio per l'uso nella riduzione del colesterolo nel siero, che comprende un derivato cellulosico cationico avente gruppi ammonici quaternari attaccati alle catene della cellulosa ed almeno un veicolo o diluente farmaceuticamente accettabile e/oppure uno o più altri ingredienti attivi. According to yet another aspect, the present invention provides a pharmaceutical composition, for example for use in reducing serum cholesterol, which comprises a cationic cellulosic derivative having quaternary ammonium groups attached to the cellulose chains and at least one pharmaceutically acceptable carrier or diluent. and / or one or more other active ingredients.
I derivati cellulosici cationici aventi gruppi ammcnici quaternari attaccati alle catene cellulosiche sono noti, e si può far riferimento in particolare a WO 92/19652. I derivati descritti in tale descrizione sono particolarmente adatti per l'uso secondo la presente invenzione. I derivati cellulosici cationici di US-A-3823133 possono anche essere adatti, ma questi hanno un ds più basso ed hanno quindi proprietà assorbenti più basse rispetto all'acido colico. Cationic cellulosic derivatives having quaternary amino groups attached to the cellulosic chains are known, and reference can be made in particular to WO 92/19652. The derivatives described in this description are particularly suitable for use according to the present invention. The cationic cellulosic derivatives of US-A-3823133 may also be suitable, but these have a lower ds and therefore have lower absorbent properties than cholic acid.
In generale tali derivati possono essere prodotti facendo reagire cellulosa con un eccesso di un composto ammonico quaternario contenente almeno un gruppo capace di reagire con il gruppo ossidrilico della cellulosa in presenza di una base, preferibilmente in soluzione acquosa. In general, these derivatives can be produced by reacting cellulose with an excess of a quaternary ammonium compound containing at least one group capable of reacting with the hydroxyl group of cellulose in the presence of a base, preferably in aqueous solution.
II composto armonico quaternario può essere, per esempio, un composto ammonico glicidilico di formula (I) o (II) The quaternary harmonic compound can be, for example, a glycidyl ammonium compound of formula (I) or (II)
in cui R1, R2 e R3, che possono essere uguali o diversi, sono ciascuno idrogeno o radicali organici, per esempio radicali idrocarburici alifatici o cicloalifatici , saturi o insaturi, opzionalmente sostituiti. Preferibilmente ciascuno tra R1, R2 e R3 viene scelto tra idrogeno, alchile, cicloalchile , idrossialchile, alchenile e arile. Quando R1, R2 o R3 è un radicale organico, il radicale ha preferìbilmente tra 1 e 20 atomi di carbonio, più preferibilmente tra 1 e 10 atomi di carbonio. Più preferibilmente ciascuno di R1, R2 e R3 è metile; wherein R1, R2 and R3, which can be the same or different, are each hydrogen or organic radicals, for example aliphatic or cycloaliphatic, saturated or unsaturated hydrocarbon radicals, optionally substituted. Preferably each of R1, R2 and R3 is selected from hydrogen, alkyl, cycloalkyl, hydroxyalkyl, alkenyl and aryl. When R1, R2 or R3 is an organic radical, the radical preferably has between 1 and 20 carbon atoms, more preferably between 1 and 10 carbon atoms. More preferably each of R1, R2 and R3 is methyl;
X- è un anione farmaceuticamente accettabile adatto, per esempio un anione inorganico o organico, come cloruro, acetato o propionato; e X- is a suitable pharmaceutically acceptable anion, for example an inorganic or organic anion, such as chloride, acetate or propionate; And
Y è alogeno, preferibilmente cloro o bromo. Y is halogen, preferably chlorine or bromine.
Il substrato cellulosico può essere qualsiasi materiale cellulosico adatto, per esempio -fluff, polpa, cellulosa polverizzata, linters di cotone, ecc . The cellulosic substrate can be any suitable cellulosic material, for example -fluff, pulp, pulverized cellulose, cotton linters, etc.
A titolo di esempio, la reazione può essere realizzata ad una temperatura tra 15 e 110°C per un tempo tra 1 e 20 ore in presenza di una base, per esempio idrossido di sodio. Il prodotto può quindi essere purificato per lavaggio fino a neutralità, per esempio con soluzione di cloruro di sodio al 4%, e raccolto per disidratazione con acetone, filtrazione e/oppure centrifugazione. Nel procedimento, si deve avere cura di evitare l'impiego di reagenti che costituirebbero un problema nella somministrazione del prodotto all'uomo e/oppure assicurarsi che i residui di tali agenti vengono allontanati in modo adeguato nella fase di purificazione. By way of example, the reaction can be carried out at a temperature between 15 and 110 ° C for a time between 1 and 20 hours in the presence of a base, for example sodium hydroxide. The product can then be purified by washing to neutrality, for example with a 4% sodium chloride solution, and collected by dehydration with acetone, filtration and / or centrifugation. In the process, care must be taken to avoid the use of reagents which would pose a problem in administering the product to humans and / or to ensure that the residues of such agents are adequately removed in the purification step.
Ulteriori dettagli sulla produzione di derivati cellulosici cationici contenenti gruppi ammonici quaternari vengono forniti in WO 92/19652. Further details on the production of cationic cellulosic derivatives containing quaternary ammonium groups are provided in WO 92/19652.
I derivati cellulosici cationici contenenti gruppi ammonici quaternari possono essere somministrati ad un paziente come tali oppure possono essere formulati come composizione farmaceutica insieme ad uno o più.veicoli o diluenti farmaceuticamente accettabili . The cationic cellulosic derivatives containing quaternary ammonium groups can be administered to a patient as such or can be formulated as a pharmaceutical composition together with one or more pharmaceutically acceptable carriers or diluents.
Composizioni farmaceutiche secondo l'invenzione sono adatte per la somministrazione orale, per esempio come pastiglie. Tipicamente il derivato cellulosico cationico costituirà tra il 10 ed il 95% in peso, per esempio tra il 40 e l'80% in peso della composizione. Secondo una realizzazione, il derivato cellulosico cationico può essere formulato come pastiglia masticabile. Componenti addizionali adatti per pastiglie comprendono cariche come silice colloidale, leganti come gomme, per esempio gomma arabica, coadiuvanti di dispersione, agenti tensioattivi, antiossidanti, agenti aromatizzanti come saccarosio o aspartame, e coloranti. Pharmaceutical compositions according to the invention are suitable for oral administration, for example as tablets. Typically the cationic cellulosic derivative will constitute between 10 and 95% by weight, for example between 40 and 80% by weight of the composition. According to one embodiment, the cationic cellulosic derivative can be formulated as a chewable tablet. Additional components suitable for tablets include fillers such as colloidal silica, binders such as gums, for example gum arabic, dispersing aids, surfactants, antioxidants, flavoring agents such as sucrose or aspartame, and dyes.
Come alternativa alle pastiglie la composizione può essere presentata come preparazione solida, per esempio sotto forma di polvere, destinata ad essere ricostituita con acqua prima dell'uso oppure una preparazione liquida che, come risultato dell'effetto di spessimento del derivato cellulosico, sarà generalmente una soluzione viscosa. La composizione farmaceutica verrà tipicamente prodotta in forma di unità di dosaggio. Per esempio, un regime di dosaggio adatto potrebbe essere tra 2 e 8 g, preferibilmente tra 3 e 5 g, per esempio circa 4 g del derivato cellulosico cationico somministrato,da 2 a 6 volte, per esempio 3 o 4 volte, al giorno. As an alternative to tablets, the composition can be presented as a solid preparation, for example in the form of a powder, intended to be reconstituted with water before use or a liquid preparation which, as a result of the thickening effect of the cellulosic derivative, will generally be a viscous solution. The pharmaceutical composition will typically be produced in dosage unit form. For example, a suitable dosage regimen could be between 2 and 8 g, preferably between 3 and 5 g, for example about 4 g of the cationic cellulosic derivative administered, 2 to 6 times, for example 3 or 4 times, per day.
In precedenza è stato fatto riferimento agli svantaggi delle resine a scambio ionico sintetiche, come colestirammina, e si ritiene che questi svantaggi derivano dal basso potere di idratazione della resina e dalla sua natura completamente sintetica. Reference was previously made to the disadvantages of synthetic ion exchange resins, such as cholestyramine, and it is believed that these disadvantages arise from the resin's low hydration power and its fully synthetic nature.
Una idratazione maggiore può contribuire a mascherare il·sapore sgradevole associato con i gruppi ammonici quaternari ed una maggiore efficienza di scambio ionico permette una riduzione nel volume di materiali che è necessario ingerire (vedi Simone e altri, J. Pharm. Sci. 62, 1695-1698 (1978)). Greater hydration can help mask the unpleasant taste associated with quaternary ammonium groups and greater ion exchange efficiency allows for a reduction in the volume of materials that need to be ingested (see Simone et al., J. Pharm. Sci. 62, 1695 -1698 (1978)).
Senza desiderare legarsi ad alcuna teoria, i derivati cellulosici cationici impiegati secondo la presente invenzione sono intrinsecamente più idrofili delle resine a scambio ionico sintetiche come la colestirammina, e sono quindi più idratabili, il che può avere importanza rendendoli più gradevoli e più facili da formulare e somministrare. I derivati cellulosici cationici vengono ottenuti da un materiale naturale (cellulosa) che è presente in molti alimenti, per cui i derivati cellulosici cationici sono più biocompatibili rispetto alle resine completamente sintetiche. L'idratabilità dei derivati cellulosici cationici risulta ,in .un sapore più accettabile e l'alto grado di sostituzione, ottenibile per esempio nei derivati di WO 92/19652, porta ad una elevata capacità di scambio ionico il che significa che si può somministrare una quantità minore di sostanza. Inoltre, dal punto di vista morfologico e fisico, i derivati cellulosici cationici presentano proprietà tipiche delle fibre vegetali e possono pure presentare capacità di assorbimento di acido colico oltre ed indipendentemente dalle loro proprietà di scambio ionico, e possono avere un effetto favorevole sui movimenti peristaltici intestinali. Without wishing to bind to any theory, the cationic cellulosic derivatives employed in accordance with the present invention are inherently more hydrophilic than synthetic ion exchange resins such as cholestyramine, and are therefore more hydratable, which may matter making them more palatable and easier to formulate and administer. Cationic cellulosic derivatives are obtained from a natural material (cellulose) which is present in many foods, therefore cationic cellulosic derivatives are more biocompatible than fully synthetic resins. The hydratability of the cationic cellulosic derivatives results, in a more acceptable flavor and the high degree of substitution, obtainable for example in the derivatives of WO 92/19652, leads to a high ion exchange capacity which means that a lesser amount of substance. Furthermore, from the morphological and physical point of view, the cationic cellulosic derivatives have properties typical of vegetable fibers and can also have the ability to absorb cholic acid in addition to and independently of their ion exchange properties, and can have a favorable effect on intestinal peristaltic movements. .
La riduzione dei livelli dì colesterolo nel siero può essere utilizzata come misura preventiva primaria nel caso di pazienti particolarmente a rischio di disturbi coronarici del cuore, per esempio pazienti con ipercolesterolemia. Inoltre, la riduzione del colesterolo del siero è pure adatta nel caso di pazienti affetti da ipercolesteremia come pazienti affetti da Fredrickson tipo II (elevato tenore di colesterolo nel plasma associato con trigliceridi a livello normale o leggermente elevato). La riduzione del colesterolo nel siero è pure indicata nelle condizioni seguenti: The reduction of serum cholesterol levels can be used as a primary preventive measure in the case of patients particularly at risk of coronary heart disease, for example patients with hypercholesterolemia. Furthermore, the reduction of serum cholesterol is also suitable in the case of patients with hypercholesteremia such as patients with Fredrickson type II (high plasma cholesterol content associated with normal or slightly elevated triglycerides). The reduction of serum cholesterol is also indicated under the following conditions:
alleviamento di prurito associato con parziale ostruzione biliare ,o .cirrosi biliare primaria; alleviamento di diarrea associata con resezione ileale, malattia di Crohn, vagotomia e neuropatia vagale diabetica; alleviation of itching associated with partial biliary obstruction, or primary biliary cirrhosis; alleviation of diarrhea associated with ileal resection, Crohn's disease, vagotomy and diabetic vagal neuropathy;
cura della diarrea provocata da radiazione. treatment of diarrhea caused by radiation.
I testi precedentemente citati dimostrano che in termini di assorbimento di acido colico in un sistema modello in vitro, un derivato cellulosico cationico è almeno altrettanto efficace della resina colestiramminica . The previously cited texts demonstrate that in terms of the absorption of cholic acid in an in vitro model system, a cationic cellulosic derivative is at least as effective as the cholestyramine resin.
L’invenzione viene illustrata dall'esempio seguente, nel quale si fa riferimento ai disegni allegati, in cui: The invention is illustrated by the following example, in which reference is made to the attached drawings, in which:
la Figura 1 mostra le cinetiche di assorbimento di acido colico. Figure 1 shows the absorption kinetics of cholic acid.
a) Preparazione del derivato cellulosico cationico La procedura generalmente segue l'Esempio 1 di WO 92/19652. 10 g di polpa kraft di cellulosa vengono miscelati con 6,7 g di idrossido di sodio disciolto in 28,5ml di acqua distillata. La miscela viene raffreddata per 30 minuti in bagno di sale e ghiaccio e quindi si aggiungono 46,74 g di cloruro di glicidiltrimetilammonio miscelati con 15 g di acqua distillata. La temperatura viene quindi mantenuta tra 80 e 85°C per 30 minuti sotto continua agitazione. Dopo questo tempo, si aggiungono altri 46,74 g di cloruro di glicidiltrimetilammonio in 15 g di acqua distillata, e la miscela viene mantenuta tra 80 e 85°C per 30 minuti sotto agitazione continua. La procedura viene ripetuta altre sei volte per un totale di otto aggiunte di cloruro di glicidiltrimetilammonio . Completata questa procedura, il campione viene lavato con soluzione acquosa al 4% di cloruro di sodio fino a neutralità e filtrato. Si aggiungono quindi 2,5 1 di acido cloridrico al 4% e si agita il prodotto per 10 ore, dopo di che si filtra, si lava fino a neutralità con acqua distillata e si essicca usando un forte eccesso di acetone. Come fase finale, il prodotto può essere essiccato in una stufa ad aria calda oppure in una stufa sotto vuoto, per allontanare ogni traccia di acetone. Alternativamente, per la fase finale della procedura, si può usare etanolo in sostituzione dell'acetone, a) Preparation of the cationic cellulosic derivative The procedure generally follows Example 1 of WO 92/19652. 10 g of cellulose kraft pulp are mixed with 6.7 g of sodium hydroxide dissolved in 28.5 ml of distilled water. The mixture is cooled for 30 minutes in a salt and ice bath and then 46.74 g of glycidyltrimethylammonium chloride mixed with 15 g of distilled water are added. The temperature is then maintained between 80 and 85 ° C for 30 minutes under continuous stirring. After this time, another 46.74 g of glycidyltrimethylammonium chloride in 15 g of distilled water are added, and the mixture is kept between 80 and 85 ° C for 30 minutes under continuous stirring. The procedure is repeated six more times for a total of eight glycidyltrimethylammonium chloride additions. Once this procedure is completed, the sample is washed with 4% aqueous sodium chloride solution until neutral and filtered. Then 2.5 1 of 4% hydrochloric acid are added and the product is stirred for 10 hours, after which it is filtered, washed to neutrality with distilled water and dried using a strong excess of acetone. As a final step, the product can be dried in a hot air oven or in a vacuum oven, to remove all traces of acetone. Alternatively, for the final step of the procedure, ethanol can be used instead of acetone,
b) Assorbìmento di acido colico b) Absorption of cholic acid
La capacità del prodotto suddetto di assorbire acido colico viene confrontata a quella della resina colestirammina (QUESTRAN, un prodotto della Bristol-Myers-Squibb Co., New York, New York, USA). The ability of the above product to absorb cholic acid is compared to that of the cholestyramine resin (QUESTRAN, a product of Bristol-Myers-Squibb Co., New York, New York, USA).
30 mg del campione da provare vengono incubati in una fiala con,10 ml di soluzione contenente 2 mg/ml di colato di sodio tamponato a pH 6 con tampone fosfato 0,02M. Le incubazioni vengono realizzate in un bagno tipo Dubroff a 25°C. Il colato non legato che rimane nel supernatante viene determinato filtrando il contenuto di ciascuna fiala su carta da filtro senza ceneri tipo Whatman 42, e misurando il colato nel liquido per via spectrofotometrica, con il metodo di Kier (J. Lab. Clin. Med.. ML, 755 (1952)). Il fissaggio di colato sodico è simile nel caso della resina colestiramminica e del derivato cellulosico cationico, che legano rispettivamente il 67% ed il 61,7% del colato sodico presente nella soluzione. La Figura 1 mostra l'assorbanza misurata spectrofotometricamente (come misura della concentrazione residua di colato sodico) in funzione del tempo. Il derivato cellulosico cationico e la resina colestiramminica hanno cinetiche di assorbimento simili. 30 mg of the sample to be tested is incubated in a vial with 10 ml of solution containing 2 mg / ml of sodium cholate buffered at pH 6 with 0.02M phosphate buffer. The incubations are carried out in a Dubroff type bath at 25 ° C. The unbound melt remaining in the supernatant is determined by filtering the contents of each vial on ashless Whatman 42 filter paper, and by measuring the melt in the liquid by spectrophotometry, using the Kier method (J. Lab. Clin. Med. . ML, 755 (1952)). The fixation of sodium cast is similar in the case of the cholestyramine resin and the cationic cellulosic derivative, which bind respectively 67% and 61.7% of the sodium cast present in the solution. Figure 1 shows the absorbance measured spectrophotometrically (as a measure of the residual sodium melt concentration) as a function of time. The cationic cellulosic derivative and the cholestyramine resin have similar absorption kinetics.
Claims (18)
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IT94TO000893A IT1267498B1 (en) | 1994-11-10 | 1994-11-10 | CATIONIC CELLULOSE DERIVATIVE, ITS USE FOR THE REDUCTION OF CHOLESTEROL LEVELS AND ITS PHARMACEUTICAL COMPOSITION. |
PCT/US1995/014733 WO1996014851A1 (en) | 1994-11-10 | 1995-11-13 | Medicaments |
EP95939924A EP0790829A4 (en) | 1994-11-10 | 1995-11-13 | Medicaments |
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IT94TO000893A IT1267498B1 (en) | 1994-11-10 | 1994-11-10 | CATIONIC CELLULOSE DERIVATIVE, ITS USE FOR THE REDUCTION OF CHOLESTEROL LEVELS AND ITS PHARMACEUTICAL COMPOSITION. |
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IT1267498B1 IT1267498B1 (en) | 1997-02-05 |
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US3823133A (en) * | 1972-05-18 | 1974-07-09 | Standard Brands Inc | Method for preparing adsorptive cellulose ethers |
FR2487376B1 (en) * | 1980-07-28 | 1985-10-25 | Showa Sangyo Co | PROCESS FOR THE PRODUCTION OF POLYSACCHARIDES BY CULTURE OF A BACILLUS |
IT1144697B (en) * | 1981-04-06 | 1986-10-29 | Texcontor Ets | SEMI-SYNTHETIC DERIVATIVE OF CHITINA PROCESS FOR ITS PREPARATION AND THERAPEUTIC COMPOSITIONS THAT INCLUDE IT AS AN ACTIVE PRINCIPLE |
SE8103137L (en) * | 1981-05-19 | 1982-11-20 | Pharmacia Ab | POLYMER WITH QUARTER AMINOGRUPS |
US4624743A (en) * | 1983-06-24 | 1986-11-25 | Weyerhaeuser Company | Cationic cellulose product and method for its preparation |
IT1188184B (en) * | 1985-08-14 | 1988-01-07 | Texcontor Ets | QUATERNARY AMMONIC SALTS OF POLYESACCHARIDES WITH HYPO-COLESTEROLEMIZING ACTIVITY |
IT1223362B (en) * | 1987-11-20 | 1990-09-19 | Texcontor Ets | POLYACSACCHARIDE CATIONIZED DERIVATIVES FOR HYPO-COLESTEROLEMIZING ACTIVITY |
US5227481A (en) * | 1989-07-07 | 1993-07-13 | National Starch And Chemical Investment Holding Corporation | Cationic polysaccharides and reagents for their preparation |
IT1249309B (en) * | 1991-05-03 | 1995-02-22 | Faricerca Spa | CATIONIC TYPE POLYSACCHARIDES |
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1995
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ITTO940893A0 (en) | 1994-11-10 |
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WO1996014851A1 (en) | 1996-05-23 |
IT1267498B1 (en) | 1997-02-05 |
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