EP0790829A1 - Medicaments - Google Patents

Medicaments

Info

Publication number
EP0790829A1
EP0790829A1 EP95939924A EP95939924A EP0790829A1 EP 0790829 A1 EP0790829 A1 EP 0790829A1 EP 95939924 A EP95939924 A EP 95939924A EP 95939924 A EP95939924 A EP 95939924A EP 0790829 A1 EP0790829 A1 EP 0790829A1
Authority
EP
European Patent Office
Prior art keywords
cationic cellulose
cellulose derivative
quaternary ammonium
pharmaceutical composition
ammonium compound
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Withdrawn
Application number
EP95939924A
Other languages
German (de)
English (en)
Other versions
EP0790829A4 (fr
Inventor
Benito Casu
Giangiocomo Torri
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Procter and Gamble Co
Original Assignee
Procter and Gamble Co
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Procter and Gamble Co filed Critical Procter and Gamble Co
Publication of EP0790829A1 publication Critical patent/EP0790829A1/fr
Publication of EP0790829A4 publication Critical patent/EP0790829A4/fr
Withdrawn legal-status Critical Current

Links

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

Definitions

  • the present invention relates to medicaments, more particularly medicaments having an antihypercholesterolemic effect.
  • the invention also relates to methods of treatment and the use of certain polysaccharides in therapy and for the manufacture of medicaments.
  • the lowering of plasma cholesterol levels is an important goal in the prevention of atherosclerosis which is a major course of morbidity and mortality in the developed world.
  • One approach which has been used to this end is to include in the diet significant amounts of non-digestible vegetable fibres and it is believed that these fibres act by absorbing cholic acid (a precursor of cholesterol) in the intestinal lumen thereby leading to a reduced cholesterol level in the blood.
  • Vegetable fibres are assumed to absorb cholic acid by a non-specific mechanism of physical entrapment and are thus not particularly effective in removing cholic acid in the intestine.
  • Medicaments have also been proposed having a more specific effect in removing cholic acid in the intestine and in particular cationic polymers have been used to bind cholic acid in the intestine by an anion exchange effect.
  • Cholic acid is negatively charged and can be fixed by an ion exchange resin having a fixed position charge.
  • a styrene- divinyl benzene polymer having strongly basic quaternary ammonium groups attached thereto has been used for this purpose for some years.
  • This material known generically as cholestyramine resin, is currently considered to be one of the most effective agents in the clinical management of hypercholesterolemia (see for example Levy, Ann. Intern.
  • cationic cellulose derivatives have a comparable effect to cholestyramine resin in absorbing cholic acid but have improved properties in use.
  • the derivatives in question are cationic cellulose derivatives having quaternary ammonium groups attached to the cellulose chains.
  • 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 cellulose hydroxyl group.
  • the degree of substitution of these cellulose derivatives is preferably from 0.5 to 1.1.
  • 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 cellulose derivative having quaternary ammonium groups attached to the cellulose chains.
  • the present invention provides a cationic cellulose derivative having quaternary ammonium groups attached to the cellulose chains for use in therapy, for example in reducing serum cholesterol levels.
  • the present invention provides the use of a cationic cellulose derivative having quaternary ammonium groups attached to the cellulose chains for the manufacture of a medicament for the reduction of serum cholesterol levels.
  • the present invention provides a pharmaceutical composition, for example for use in the reduction of serum cholesterol, which comprises a cationic cellulose 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.
  • Cationic cellulose derivatives having quaternary ammonium groups attached to the cellulose chains are known and reference can be made in particular to WO 92/19652.
  • the derivatives described in this specification are particularly suitable for use according to the present invention.
  • the cationic cellulose derivatives of US-A-3823133 may also be suitable but these have a lower ds and may thus have lower absorbing properties with respect to cholic acid.
  • such 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 cellulose hydroxyl group in the present of base, preferably in aqueous solution.
  • the quaternary ammonium compound can be, for example, a glycidyl ammonium compound of formula (I) or (II)
  • wwhheerreeiinn RR 1 ,, RR 2 ⁇ aanndd RR 3 ,, wwhhiicchh mmaa'yv be the same or different, are each hydrogen or organic radicals, for example optionally substituted saturated or unsaturated aliphatic or cycloaliphatic hydrocarbon radicals.
  • R 1 , R 2 and R 3 are selected from hydrogen, alkyl, cycloalkyl, hydroxyalkyl, alkenyl and aryl.
  • R 1 , R 2 or R 3 is an organic radical, the radical preferably has 1 to 20 carbon atoms, more preferably 1 to 10 carbon atoms.
  • R 1 , R 2 and R 3 are each methyl;
  • X " is a suitable pharmaceutically acceptable anion, for example an inorganic or organic anion, such as chloride, acetate or propionate,- and
  • Y is halogen, preferably chlorine or bromine.
  • the cellulose substrate may be any suitable cellulose material, for example fluff, pulp, pulverized cellulose, cotton linters, etc.
  • the reaction may be carried out at a temperature of from 15 to 110°C for l to 20 hours in the presence of base, for example sodium hydroxide.
  • base for example sodium hydroxide.
  • the product may then be purified by washing to neutrality, for example with 4% NaCl and recovered by dehydration with acetone, filtration and/or centrifugation.
  • care must be taken to avoid the use of reagents which would present a problem in the administration of the product to humans and/or to ensure that residues of such reagents are removed to an adequate level in the purification step.
  • the cationic cellulose 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.
  • compositions according to the invention are adapted for oral administration, for example as tablets.
  • the cationic cellulose derivative will make up from 10 to 95% by weight, for example 40 to 80% by weight of the composition.
  • the cationic cellulose derivative can be formulated as a chewable tablet.
  • suitable additional components for tablets include fillers such as colloidal silica, binders such as gums for example acacia, dispersion aids, surface active agents, anti oxidants, flavouring agents such as sucrose or aspartame, and colourings.
  • the composition may 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 cellulose derivative, will generally be a viscous solution.
  • the pharmaceutical composition will typically be produced in unit dosage form.
  • a suitable dosage regime would be from 2 to 8 grams, preferably 3 to 5 grams, for example about 4 grams of the cationic cellulose derivative administered 2 to 6 times, for example 3 or 4 times, per day.
  • the cationic cellulose derivatives used according to the present invention are intrinsically more hydrophilic than synthetic ion- exchange resins such as cholestyramine and are thus more hydratable which may account for their being more palatable and easier to formulate and administer.
  • the cationic cellulose derivatives are obtained from a natural material (cellulose) which is present in many foods so that the cationic cellulose derivatives are more biocompatible than completely synthetic resins.
  • the hydratability of the cationic cellulose derivatives results in a more acceptable taste 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 less of the material need be administered.
  • the cationic cellulose derivatives show properties typical of vegetable fibres and may well show a capacity to absorb colic acid in addition to and independent of their ion exchange properties, and may have a favourable effect on intestinal peristaltic movements.
  • Reduction of serum cholesterol levels may be of use as a primary preventative measure in the case of patients particularly at risk of coronary heart disease, for example patients with hypercholesterolaemia.
  • reduction of serum cholesterol is also appropriate in the case of patients diagnosed as having hypercholesteraemia such a patients diagnosed as Fredrickson's Type II (high plasma cholesterol associated with normal or slightly elevated triglycerides) .
  • Reduction of serum cholesterol is also indicated in the following conditions: relief of pruritus associated with partial biliary obstruction or primary biliary cirrhosis; relief of diarrhoea associated with ileal resection, Crohn's disease, vagotomy and diabetic vagal neuropathy; - management of radiation - induced diarrhoea.
  • Figure 1 shows absorption kinetics of cholic acid.
  • the procedure was repeated another six times for a total of eight additions of glycidyltrimethylammonium chloride.
  • the sample was washed with 4% aqueous NaCl to neutrality and filtered. 2.5 litres of 4% hydrochloric acid were then added and the product stirred for 10 hours after which it was filtered, washed to neutrality with distilled water and dried using a large excess of acetone.
  • the product may be dried in a ventilated oven or a vacuum oven to remove all traces of acetone. Alternatively, ethanol can be used in place of acetone for the final stage of the procedure.
  • Figure 1 shows absorbence measured spectrophotometrically (as a measure of residual sodium cholate concentration) against time.
  • the cationic cellulose derivative and cholestyramine resin show similar absorption kinetics.

Landscapes

  • 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'invention concerne un procédé permettant de réduire les taux sériques de cholestérol chez un patient. Ledit procédé consiste à administrer au patient une quantité efficace d'un dérivé cellulosique cationique comportant des groupes ammonium quaternaires liés aux chaînes cellulosiques. Les dérivés cellulosiques cationiques absorbent efficacement l'acide cholique dans les intestins mais ne présentent pas les inconvénients (goût désagréable par exemple) associés aux médicaments connus qui lient l'acide cholique, tels que la résine de cholestyramine.
EP95939924A 1994-11-10 1995-11-13 Medicaments Withdrawn EP0790829A4 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
IT94TO000893A IT1267498B1 (it) 1994-11-10 1994-11-10 Derivato cellulosico cationico, relativo uso per la riduzione dei livelli di colesterolo e relativa composizione farmaceutica.
ITTO940893 1994-11-10
PCT/US1995/014733 WO1996014851A1 (fr) 1994-11-10 1995-11-13 Medicaments

Publications (2)

Publication Number Publication Date
EP0790829A1 true EP0790829A1 (fr) 1997-08-27
EP0790829A4 EP0790829A4 (fr) 2001-08-08

Family

ID=11412883

Family Applications (1)

Application Number Title Priority Date Filing Date
EP95939924A Withdrawn EP0790829A4 (fr) 1994-11-10 1995-11-13 Medicaments

Country Status (3)

Country Link
EP (1) EP0790829A4 (fr)
IT (1) IT1267498B1 (fr)
WO (1) WO1996014851A1 (fr)

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
ITFI20120268A1 (it) 2012-12-03 2014-06-04 Diopeite Consulting Ltd Composizioni farmaceutiche per il trattamento dell'obesita'

Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3823133A (en) * 1972-05-18 1974-07-09 Standard Brands Inc Method for preparing adsorptive cellulose ethers
GB2080818A (en) * 1980-07-28 1982-02-10 Showa Sangyo Co A microbiological process for the production of a polysaccharide and its cationic salt and their use in depressing serum and liver cholesterol levels and the atherogenic index
US4436731A (en) * 1981-04-06 1984-03-13 Etablissement Texcontor Semi-synthetic chitin derivative, the process for its preparation, and therapeutic compositions which contain it as active principle
US4591638A (en) * 1981-05-19 1986-05-27 Pharmacia Ab Dextran or crosslinked dextran having quaternary amino groups
EP0212145A1 (fr) * 1985-08-14 1987-03-04 Etablissement TEXCONTOR Sels d'ammonium quaternaires de polysaccharides naturels ayant une activité hypocholestérolémique
EP0319645A1 (fr) * 1987-11-20 1989-06-14 Etablissement TEXCONTOR Dérivés cationiques de polysaccharides ayant une activité hypocholestérolémique
WO1992019652A1 (fr) * 1991-05-03 1992-11-12 Società Consortile Ricerche Angelini S.P.A. Polysaccharides cationiques

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4624743A (en) * 1983-06-24 1986-11-25 Weyerhaeuser Company Cationic cellulose product and method for its preparation
US5227481A (en) * 1989-07-07 1993-07-13 National Starch And Chemical Investment Holding Corporation Cationic polysaccharides and reagents for their preparation

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3823133A (en) * 1972-05-18 1974-07-09 Standard Brands Inc Method for preparing adsorptive cellulose ethers
GB2080818A (en) * 1980-07-28 1982-02-10 Showa Sangyo Co A microbiological process for the production of a polysaccharide and its cationic salt and their use in depressing serum and liver cholesterol levels and the atherogenic index
US4436731A (en) * 1981-04-06 1984-03-13 Etablissement Texcontor Semi-synthetic chitin derivative, the process for its preparation, and therapeutic compositions which contain it as active principle
US4591638A (en) * 1981-05-19 1986-05-27 Pharmacia Ab Dextran or crosslinked dextran having quaternary amino groups
EP0212145A1 (fr) * 1985-08-14 1987-03-04 Etablissement TEXCONTOR Sels d'ammonium quaternaires de polysaccharides naturels ayant une activité hypocholestérolémique
EP0319645A1 (fr) * 1987-11-20 1989-06-14 Etablissement TEXCONTOR Dérivés cationiques de polysaccharides ayant une activité hypocholestérolémique
WO1992019652A1 (fr) * 1991-05-03 1992-11-12 Società Consortile Ricerche Angelini S.P.A. Polysaccharides cationiques

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See also references of WO9614851A1 *

Also Published As

Publication number Publication date
IT1267498B1 (it) 1997-02-05
ITTO940893A1 (it) 1996-05-10
ITTO940893A0 (it) 1994-11-10
EP0790829A4 (fr) 2001-08-08
WO1996014851A1 (fr) 1996-05-23

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