WO1996014851A1

WO1996014851A1 - Medicaments

Info

Publication number: WO1996014851A1
Application number: PCT/US1995/014733
Authority: WO
Inventors: Benito Casu; Giangiocomo Torri
Original assignee: The Procter & Gamble Company
Priority date: 1994-11-10
Filing date: 1995-11-13
Publication date: 1996-05-23
Also published as: EP0790829A1; ITTO940893A1; EP0790829A4; IT1267498B1; ITTO940893A0

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) :

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.