EP0790829A1 - Medicaments - Google Patents
MedicamentsInfo
- 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- Withdrawn
Links
- 239000003814 drug Substances 0.000 title claims abstract description 9
- 229920002678 cellulose Polymers 0.000 claims abstract description 66
- 239000001913 cellulose Substances 0.000 claims abstract description 66
- 125000002091 cationic group Chemical group 0.000 claims abstract description 38
- 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 claims abstract description 18
- 125000001453 quaternary ammonium group Chemical group 0.000 claims abstract description 14
- 239000008194 pharmaceutical composition Substances 0.000 claims description 12
- 150000003856 quaternary ammonium compounds Chemical class 0.000 claims description 9
- 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
- 238000006243 chemical reaction Methods 0.000 claims description 4
- 229910052736 halogen Inorganic materials 0.000 claims description 4
- 238000004519 manufacturing process Methods 0.000 claims description 4
- AFEQENGXSMURHA-UHFFFAOYSA-N oxiran-2-ylmethanamine Chemical compound NCC1CO1 AFEQENGXSMURHA-UHFFFAOYSA-N 0.000 claims description 4
- 239000003085 diluting agent Substances 0.000 claims description 3
- 239000003937 drug carrier Substances 0.000 claims description 3
- 238000002560 therapeutic procedure Methods 0.000 claims description 3
- 239000004480 active ingredient Substances 0.000 claims description 2
- 125000005843 halogen group Chemical group 0.000 claims 3
- 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 15
- 239000004380 Cholic acid Substances 0.000 abstract description 15
- 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 15
- 229960002471 cholic acid Drugs 0.000 abstract description 15
- 235000019416 cholic acid Nutrition 0.000 abstract description 15
- 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 15
- 229940107170 cholestyramine resin Drugs 0.000 abstract description 9
- 238000000034 method Methods 0.000 abstract description 9
- 210000000936 intestine Anatomy 0.000 abstract description 5
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 7
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 238000010521 absorption reaction Methods 0.000 description 5
- 239000000463 material Substances 0.000 description 5
- 239000000047 product Substances 0.000 description 5
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- 239000012153 distilled water Substances 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- NRHMKIHPTBHXPF-TUJRSCDTSA-M sodium cholate Chemical compound [Na+].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 NRHMKIHPTBHXPF-TUJRSCDTSA-M 0.000 description 4
- 229920001268 Cholestyramine Polymers 0.000 description 3
- 208000035150 Hypercholesterolemia Diseases 0.000 description 3
- 230000000968 intestinal effect Effects 0.000 description 3
- 238000005342 ion exchange Methods 0.000 description 3
- 239000003456 ion exchange resin Substances 0.000 description 3
- 229920003303 ion-exchange polymer Polymers 0.000 description 3
- 238000002360 preparation method Methods 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- 239000003826 tablet Substances 0.000 description 3
- PUVAFTRIIUSGLK-UHFFFAOYSA-M trimethyl(oxiran-2-ylmethyl)azanium;chloride Chemical compound [Cl-].C[N+](C)(C)CC1CO1 PUVAFTRIIUSGLK-UHFFFAOYSA-M 0.000 description 3
- 235000013311 vegetables Nutrition 0.000 description 3
- 206010012735 Diarrhoea Diseases 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 125000004432 carbon atom Chemical group C* 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- BHQCQFFYRZLCQQ-OELDTZBJSA-M cholate 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-M 0.000 description 2
- 229940099352 cholate Drugs 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 230000036571 hydration Effects 0.000 description 2
- 238000006703 hydration reaction Methods 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 238000006467 substitution reaction Methods 0.000 description 2
- NWUYHJFMYQTDRP-UHFFFAOYSA-N 1,2-bis(ethenyl)benzene;1-ethenyl-2-ethylbenzene;styrene Chemical compound C=CC1=CC=CC=C1.CCC1=CC=CC=C1C=C.C=CC1=CC=CC=C1C=C NWUYHJFMYQTDRP-UHFFFAOYSA-N 0.000 description 1
- CHRJZRDFSQHIFI-UHFFFAOYSA-N 1,2-bis(ethenyl)benzene;styrene Chemical compound C=CC1=CC=CC=C1.C=CC1=CC=CC=C1C=C CHRJZRDFSQHIFI-UHFFFAOYSA-N 0.000 description 1
- 208000004998 Abdominal Pain Diseases 0.000 description 1
- 241000220479 Acacia Species 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- 108010011485 Aspartame Proteins 0.000 description 1
- 201000001320 Atherosclerosis Diseases 0.000 description 1
- 208000008439 Biliary Liver Cirrhosis Diseases 0.000 description 1
- 208000033222 Biliary cirrhosis primary Diseases 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- 239000004215 Carbon black (E152) Substances 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- 208000002881 Colic Diseases 0.000 description 1
- 206010010774 Constipation Diseases 0.000 description 1
- 229920000742 Cotton Polymers 0.000 description 1
- 208000011231 Crohn disease Diseases 0.000 description 1
- 206010014486 Elevated triglycerides Diseases 0.000 description 1
- 235000010643 Leucaena leucocephala Nutrition 0.000 description 1
- 208000012654 Primary biliary cholangitis Diseases 0.000 description 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 1
- 208000003251 Pruritus Diseases 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
- 229930006000 Sucrose Natural products 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 238000007792 addition Methods 0.000 description 1
- 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
- 238000005349 anion exchange Methods 0.000 description 1
- 150000001449 anionic compounds Chemical class 0.000 description 1
- 230000000326 anti-hypercholesterolaemic effect Effects 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 230000003078 antioxidant effect Effects 0.000 description 1
- 235000006708 antioxidants Nutrition 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 239000000605 aspartame Substances 0.000 description 1
- 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
- 229960003438 aspartame Drugs 0.000 description 1
- 235000010357 aspartame Nutrition 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 229920006317 cationic polymer Polymers 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 239000007910 chewable tablet Substances 0.000 description 1
- 229940068682 chewable tablet Drugs 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 235000012000 cholesterol Nutrition 0.000 description 1
- 239000008119 colloidal silica Substances 0.000 description 1
- 238000004040 coloring Methods 0.000 description 1
- 230000001609 comparable effect Effects 0.000 description 1
- 208000029078 coronary artery disease Diseases 0.000 description 1
- 125000000753 cycloalkyl group Chemical group 0.000 description 1
- 230000018044 dehydration Effects 0.000 description 1
- 238000006297 dehydration reaction Methods 0.000 description 1
- 206010012601 diabetes mellitus Diseases 0.000 description 1
- 235000005911 diet Nutrition 0.000 description 1
- 230000037213 diet Effects 0.000 description 1
- 239000006185 dispersion Substances 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- 235000013355 food flavoring agent Nutrition 0.000 description 1
- 150000004676 glycans Chemical class 0.000 description 1
- 150000002367 halogens Chemical group 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
- 150000002431 hydrogen Chemical class 0.000 description 1
- 125000002768 hydroxyalkyl group Chemical group 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 239000002655 kraft paper Substances 0.000 description 1
- 150000002632 lipids Chemical class 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 230000000877 morphologic effect Effects 0.000 description 1
- 239000005445 natural material Substances 0.000 description 1
- 201000001119 neuropathy Diseases 0.000 description 1
- 230000007823 neuropathy Effects 0.000 description 1
- 150000002891 organic anions Chemical class 0.000 description 1
- 239000000123 paper Substances 0.000 description 1
- 208000033808 peripheral neuropathy Diseases 0.000 description 1
- 230000002572 peristaltic effect Effects 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 229920001282 polysaccharide Polymers 0.000 description 1
- 239000005017 polysaccharide Substances 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 229940073095 questran Drugs 0.000 description 1
- 230000005855 radiation Effects 0.000 description 1
- 238000002271 resection Methods 0.000 description 1
- 239000011347 resin Substances 0.000 description 1
- 229920005989 resin Polymers 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 239000000057 synthetic resin Substances 0.000 description 1
- 229920003002 synthetic resin Polymers 0.000 description 1
- 230000008719 thickening Effects 0.000 description 1
- 230000001515 vagal effect Effects 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
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
The invention relates to 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 cationic cellulose derivatives are effective in absorbing cholic acid in the intestine but do not have the disadvantages such as unpleasant taste associated with known medicaments which bind cholic acid such as cholestyramine resin.
Description
MEDICAMENTS
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.
Med., 2 , 267 (1972) and Casdorph in Lipid Pharmacology,
Volume 2(2), Paoletti and Glueck (Eds), Academic Press, New
York, 1976, pages 222-256) .
Although the clinical efficacy of cholestyramine resin is not disputed, it presents problems in use. It has an unpleasant taste which is disliked by patients and it is difficult to mix with water which also makes administration difficult. In addition, intestinal constipation is sometimes seen as a side effect (see Glueck et al., J. Am. Med. Assoc. , 222. 676 (1972) ) .
It is an object of the present invention to provide an ion exchanger suitable for absorption of cholic acid in the intestine which obviates the disadvantages associates with cholestyramine resin.
It has now been found that certain 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. 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 cellulose hydroxyl group. The degree of substitution of these cellulose derivatives is preferably from 0.5 to 1.1.
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 cellulose derivative having quaternary ammonium groups attached to the cellulose chains.
According to another aspect 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.
According to a further aspect, 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.
According to a still further aspect, 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.
In general 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 RR1,, RR2^ aanndd RR3,, 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. Preferably each of R1, R2 and R3 are selected from hydrogen, alkyl, cycloalkyl, hydroxyalkyl, alkenyl and aryl. Where R1, R2 or R3 is an organic radical, the radical preferably has 1 to 20 carbon atoms, more preferably 1 to 10 carbon atoms. Most preferably R1, R2 and R3 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.
By way of example, 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. 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. In the process, 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.
Further details of the production of cationic cellulose derivatives containing quaternary ammonium groups are given
.
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.
Pharmaceutical compositions according to the invention are adapted for oral administration, for example as tablets. Typically the cationic cellulose derivative will make up from 10 to 95% by weight, for example 40 to 80% by weight of the composition. According to one embodiment, 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.
As an alternative to tablets 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. For example 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.
Reference has been made above to the disadvantages of synthetic ion exchange resins such as cholestyramine and it is believed that these disadvantages stem from the low hydration power of the resin and its completely synthetic nature. Greater hydration may help to mask the unpleasant
taste associates with quaternary ammonium groups and a greater efficiency of ion-exchange permits a reduction in the volume of the material which needs to be ingested (see Simone et al . , J. Pharm. Sci. , _ 1_, 1695-1698 (1978)) .
Without wishing to be bound by any theory, 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. Furthermore, from the morphological and physical point of view, 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. In addition 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.
Tests reported hereinafter demonstrate that in terms of absorption of cholic acid in a model in vi tro system, a cationic cellulose derivative was at least as effective as cholestyramine resin.
The invention is illustrated by the following example in which reference is made to the accompanying drawings in which:
Figure 1 shows absorption kinetics of cholic acid.
Example
a) Preparation of cationic cellulose derivative
The procedure generally follows Example 1 of WO 92/19652. 10 g of cellulose kraft pulp were mixed with 6.7 g sodium hydroxide dissolved in 28.5 ml of distilled water. The mixture was cooled for 30 minutes in an ice salt bath and 46.74 g of glycidyltrimethylammonium chloride mixed with 15 g distilled water were added. The temperature was then maintained at 80 to 85°C for 30 minutes with continuous stirring. At the end of this time, another 46.74 g of glycidyltrimethylammonium chloride in 15 g distilled water was added and the mixture maintained at 80 to 85°C for 30 minutes with continuous stirring. The procedure was repeated another six times for a total of eight additions of glycidyltrimethylammonium chloride. At the end of this procedure, 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. As a final stage 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.
b) Absorption of Cholic Acid
The ability of the above material to absorb cholic acid was compared to that of cholestyramine resin (QUESTRAN - a product of Bristol-Myers-Squibb Co., New York, New York, USA) '.
30 mg of the sample under test was incubated in a vial with 10ml of a solution containing 2 mg/ml sodium cholate buffered to pH 6 with 0.02M phosphate buffer. Incubations were carried out in a Dubroff-type bath at 25°C. Unbound cholate in the supernatant was determined by filtering the contents of each vial on Whatman Type 42 ashless filter paper and measuring cholate in the liquid spectrophotometrically by the method of Kier (J. Lab. Clin. Med. , 4_0, 755 (1952)) . Binding of sodium cholate was similar in the case of cholestyramine resin and the cationic cellulose derivative which bound 67% and 61.7% respectively of the sodium cholate in the solution.
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.
Claims
1. A cationic cellulose derivative having quaternary ammonium groups attached to the cellulose chains for use in therapy.
2. A cationic cellulose derivative as claimed in claim 1 for use in reducing serum cholesterol levels.
3. A cationic cellulose derivative as claimed in claim 1 or 2 which has been produced by reaction of cellulose with an excess of a quaternary ammonium compound containing at least one group capable of reacting with the cellulose hydroxyl group in the presence of base.
4. A cationic cellulose derivative as claimed in claim 3 wherein the quaternary ammonium compound is a glycidyl ammonium compound of formula (I) or (II) :
wherein R1, R2 and R3, which may be the same or different, are each hydrogen or organic radicals; X is a suitable pharmaceutically acceptable anion and Y is halogen. 5. A cationic cellulose derivative as claimed in any of claims 1 to 4 having a ds of 0.
5 to 1.1.
6. 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.
7. Use according to claim 6 wherein the cationic cellulose derivative has been produced by reaction of cellulose with an excess of a quaternary ammonium compound containing at least one group capable of reacting with the cellulose hydroxyl group in the presence of base.
8. Use according to claim 7 wherein the quaternary ammonium compound is a glycidyl ammonium compound of formula (I) or (ID :
wherein R1, R2 and R3, which may be the same or different, are each hydrogen or organic radicals; X is a suitable pharmaceutically acceptable anion and Y is halogen.
9. Use according to any of claims 6 to 8 wherein the cationic cellulose derivative has a ds of 0.5 to 1.1.
10. Use according to any of claims 6 to 9 wherein the cationic cellulose derivative is administered in a unit dose of from 2 to 8 grams 2 to 6 times per day.
11. A pharmaceutical composition comprising 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.
12. A pharmaceutical composition as claimed in claim 11 in a form adapted for oral administration.
13. A pharmaceutical composition as claimed in claim 12 in the form of a tablet.
14. A pharmaceutical composition as claimed in any of claims 11 to 13 containing from 10 to 95% by weight of the cationic cellulose derivative.
15. A pharmaceutical composition as claimed in any of claims 11 to 14 in unit dose form containing from 2 to 8 grams of the cationic cellulose derivative.
16. A pharmaceutical composition as claimed in any of claims 11 to 15 wherein the cationic cellulose derivative has been produced by reaction of cellulose with an excess of a quaternary ammonium compound containing at least one group capable of reacting with the cellulose hydroxyl group in the presence of base.
17. A pharmaceutical composition as claimed in claim 16 wherein the quaternary ammonium compound is a glycidyl ammonium compound of formula (I) or (II) :
wherein R1, R2 and R3, which may be the same or different, are each hydrogen or organic radicals; X is a suitable pharmaceutically acceptable anion and Y is halogen.
18. A pharmaceutical composition as claimed in any of claims 11 to 17 wherein the cationic cellulose derivative has a ds of 0.5 to 1.1.
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
IT94TO000893A IT1267498B1 (en) | 1994-11-10 | 1994-11-10 | CATIONIC CELLULOSE DERIVATIVE, ITS USE FOR THE REDUCTION OF CHOLESTEROL LEVELS AND ITS PHARMACEUTICAL COMPOSITION. |
ITTO940893 | 1994-11-10 | ||
PCT/US1995/014733 WO1996014851A1 (en) | 1994-11-10 | 1995-11-13 | Medicaments |
Publications (2)
Publication Number | Publication Date |
---|---|
EP0790829A1 true EP0790829A1 (en) | 1997-08-27 |
EP0790829A4 EP0790829A4 (en) | 2001-08-08 |
Family
ID=11412883
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP95939924A Withdrawn EP0790829A4 (en) | 1994-11-10 | 1995-11-13 | Medicaments |
Country Status (3)
Country | Link |
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EP (1) | EP0790829A4 (en) |
IT (1) | IT1267498B1 (en) |
WO (1) | WO1996014851A1 (en) |
Families Citing this family (1)
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ITFI20120268A1 (en) | 2012-12-03 | 2014-06-04 | Diopeite Consulting Ltd | PHARMACEUTICAL COMPOSITIONS FOR THE TREATMENT OF OBESITY |
Citations (7)
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 (en) * | 1985-08-14 | 1987-03-04 | Etablissement TEXCONTOR | Quaternary ammonium salts of natural polysaccharides possessing hypocholesterolemic activity |
EP0319645A1 (en) * | 1987-11-20 | 1989-06-14 | Etablissement TEXCONTOR | Cationized polysaccharide derivatives with hypocholesterolemic activity |
WO1992019652A1 (en) * | 1991-05-03 | 1992-11-12 | Società Consortile Ricerche Angelini S.P.A. | Cationic polysaccharides |
Family Cites Families (2)
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 |
-
1994
- 1994-11-10 IT IT94TO000893A patent/IT1267498B1/en active IP Right Grant
-
1995
- 1995-11-13 EP EP95939924A patent/EP0790829A4/en not_active Withdrawn
- 1995-11-13 WO PCT/US1995/014733 patent/WO1996014851A1/en not_active Application Discontinuation
Patent Citations (7)
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 (en) * | 1985-08-14 | 1987-03-04 | Etablissement TEXCONTOR | Quaternary ammonium salts of natural polysaccharides possessing hypocholesterolemic activity |
EP0319645A1 (en) * | 1987-11-20 | 1989-06-14 | Etablissement TEXCONTOR | Cationized polysaccharide derivatives with hypocholesterolemic activity |
WO1992019652A1 (en) * | 1991-05-03 | 1992-11-12 | Società Consortile Ricerche Angelini S.P.A. | Cationic polysaccharides |
Non-Patent Citations (1)
Title |
---|
See also references of WO9614851A1 * |
Also Published As
Publication number | Publication date |
---|---|
EP0790829A4 (en) | 2001-08-08 |
ITTO940893A0 (en) | 1994-11-10 |
IT1267498B1 (en) | 1997-02-05 |
ITTO940893A1 (en) | 1996-05-10 |
WO1996014851A1 (en) | 1996-05-23 |
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