ZA200106447B

ZA200106447B - Pharmaceutical composition.

Info

Publication number: ZA200106447B
Application number: ZA200106447A
Authority: ZA
Inventors: Lawrence John Penkler
Original assignee: Aspen Pharmacare Holdings Ltd
Priority date: 2000-08-17
Filing date: 2001-08-06
Publication date: 2002-02-13

Description

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PHARMACEUTICAL COMPOSITION

BACKGROUND OF THE INVENTION

This invention relates to an oral controlled release pharmaceutical composition containing chitosan for use as a dietary additive for reducing the absorption of dietary fat.

Chitosan is derived from chitin, the structural biopolymer making up the ) exoskeleton of crustaceans and insects. Partial removal of the N-acetyl groups of chitin results in a complex mixture of polysaccharides based on glucoseamine, collectively known as “chitosan”.

Chitosan has been used in the pharmaceutical industry as a coating agent, ~ bioadhesive or controlled release polymer (1).

The effects of chitosan as a dietary additive on fat binding and cholesterol lowering have been well established through in-vitro and in-vivo studies (2-9).

Through a variety of mechanisms including ionic and non-bonded interactions, chitosan is capable of complexing over five times its mass of dietary fats dependent on the degree of N-de-acetylation. Several products have been

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Coe w0016447 commercialised based on this property for the reduction of dietary fat absorption. Up to four chitosan tablets or capsules containing 250 mg chitosan are recommended with each meal of the day.

Chitosan is soluble in acidic media but sparingly soluble in alkaline media based on protonation of the free amino functionality. Consequently a dose of chitosan will be instantly released in the low pH environment of the stomach.

Dietary fats are predominantly composed of triglycerides which are broken down to free fatty acids by the action of lipases. The main action of lipases occurs in the intestines as opposed to the stomach. Anionic lipids are strongly bound by chitosan even at intestinal pH of 6.8. (10).

Up to 95% of dietary fats are absorbed throughout the intestinal tract with only about 5% being unabsorbed.

SUMMARY OF THE INVENTION

According to a first aspect of the invention, there is provided a controlled release pharmaceutical composition for oral administration comprising: (a) an amount of chitosan; and (b) an amount of a pharmaceutically acceptable non-ionic polymer effective to control the release of the chitosan.

According to a second aspect of the invention, there is provided a dose of a pharmaceutical composition for oral administration before a meal to reduce absorption of dietary fat, the dose comprising one or more, preferably two tablets or capsules comprising:

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Loe | 0016447 (a) an amount of chitosan; and (b) an amount of a pharmaceutically acceptable non-ionic polymer effective to control the release of the chitosan.

According to a third aspect of the invention, there is provided the use of chitosan in the manufacture of a medicament for oral administration comprising: (a) an amount of chitosan; and (b) an amount of a pharmaceutically acceptable non-ionic polymer effective to control the release of the chitosan; for the promotion of weight loss or for the maintenance of body weight.

BRIEF DESCRIPTION OF THE DRAWING ]

Figure 1 shows the dissolution rate of a tablet prepared according to

Example 1.

DESCRIPTION OF EMBODIMENTS

The invention relates to an oral controlled release pharmaceutical composition of chitosan for use as a dietary additive for reducing the absorption of dietary fat over extended periods.

The chitosan is preferably greater than 70% N-deacetylated (i.e. the average number of D-glucoseamine units per 100 monomers is greater than 70). More preferably, the chitosan is from 80% to 95% inclusive N-deacetylated and most preferably from 85% to 95% inclusive N-deacetylated. The average molecular weight of the chitosan is preferably greater than 50 000 g.mol”. More preferably the average molecular weight of the chitosan is greater than i ———— ee v

EER 20016447 4. 100 000 g.mol™. Most preferably the average molecular weight of the chitosan is about 140 000 g.mol™. The chitosan is preferably in a finely divided state, i.e 90% under 500 microns.

The chitosan may be in the form of a pharmaceutically acceptable salt. For : example: hydrochloride, glutamate, and the like.

An effective dose of chitosan for weight maintenance or loss is greater than 600mg chitosan before each main meal. Thus, in the pharmaceutical composition of the invention preferably each pharmaceutical unit, e.g. each tablet or capsule or the like, contains 250mg or greater of chitosan, more preferably 300mg or greater of chitosan, most preferably 500mg or greater of chitosan.

The non-ionic polymer may be selected from the group consisting of hydroxypropylmethylicelluloses ~~ (HPMC), polyvinylpyrrolidones (PVP), hydroxypropylcelluloses, hydroxyethylcelluloses, polyethyleneglycols, polyvinyl alcohols, and polyethylene oxides, and a mixture of two or more thereof.

The polymer or mixture of polymers is preferably selected from those with viscosity grades with a nominal viscosity in water of a 2% solution of between 4 000 and 100 000 poise.

The mass ratio of polymer to chitosan is preferably from 1:5 to 1:20, inclusive.

The pharmaceutical composition may also contain an effective amount of an : appetite suppressant such as for example a chromium salt, e.g chromium picolinate, or nor-pseudoephedrine. A typical dose of chromium picolinate is 0,625 milligrams.

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The chitosan may be blended with the polymer and granulated with a hydroalcoholic granulating solution in a high shear granulator according to methods known in the art. The granulating solution is preferably a mixture of purified deionised water and ethanol in the ratio 70:30.

In order to improve granule strength pharmaceutical binders selected from the group copolyvidone, primojel and pregelatinised starch may be used in quantities known in the art.

The granules are dried in an oven and calibrated, blended with other excipients such as lubricant and preservative and finally compressed into tablets.

Sodium carboxymethyicellulose or microcrystalline cellulose may optionally be added to improve compressibility.

The preferred dosage form of the invention is tablets containing at least 250mg chitosan and most preferably 500mg or greater of chitosan.

The tablets may be coated with pharmaceutically acceptable coating agents including enteric coating compounds such as methacrylic acid copolymers, waxes and the like to prevent the tablet from dissolving in the gastric juice.

For a weight loss program, preferably four tablets are taken daily, 2 before lunch and 2 before dinner in combination with a hypocaloric diet where daily fat intake is limited to 400 kilocalories.

For weight maintenance, preferably two tablets are taken before the main meal of the day.

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Other pharmaceutical dosage forms, e.g. capsules or powders may also be formulated.

An example of the invention will now be given.

EXAMPLE 1

Chitosan with a degree of N-de-acetylation of 85% and average molecular weight of 140 000 g.mol™ (20kg) is blended with 2.5 kg HPMC E86. The mixture is granulated at 200 rpm with 15,2 litres of a 70:30 water:ethanol solution containing copolyvidone (1,0 kg) in a high shear granulator. The granules are dried to constant mass at 80°C in an oven and calibrated. The granules are blended with sodium carboxymethylcellulose (0,5 kg) and preservative

Nipastat (5g) prior to compression into tablets.

The unit composition of a tablet is as follows:

Chitosan 500 mg

HPMC E6 62,5 mg

Sodium carboxymethylcellulose 12,5 mg

Copolyvidone 25 mg

Nipastat 0,125 mg

A tablet prepared according to this example was subjected to a dissolution test and the results thereof are shown in Figure 1. The dissolution test was performed in 900ml medium at pH 1,2 and 37°C with a paddle speed of 50 rpm.

EXAMPLE 2

Double Blind Placebo-controlled Study to Determine Weight Loss, with

Controlled Release Chitosan as Active Ingredient v

The aim of the study was to determine weight loss in 40 overweight female volunteers over a six week period. The 40 overweight women, between the ages of 18 and 60 years, were randomly divided into a placebo and active group. The active treatment group was given tablets formulated according to

Example 1, in an amount of 2 500 mg chitosan tablets, taken twice daily before the main meals of the day.

Diet Treatment:

All the subjects’ diets were calculated individually according to their own body measurements, age, sex, current body weight and activity levels. The Harris

Benedict Formula was used to determine Basal metabolic requirements (BMR), with an activity factor of 1.3. Total daily calories was then reduced with 2 000 kJ daily. This adjustment was made to ensure an expected equal weight loss in all subjects, regardless of whether they were taking the active drug or placebo. Seeing that BMR was calculated using current body weight, the diet was revised with each visit according to the subject's weight loss during the preceding 2 weeks. This ensures that a comparison can be made between the two groups.

The active treatment group showed an average weight loss of 3.4 ka/person and the placebo group 1.6 kg/person. The composition according to the invention achieved a maximum weight loss of 5.8 kg over 6 weeks treatment.

EXAMPLE 3

Tablets were formulated according to the method of Example 1, but with the following unit composition:

Chitosan 500 mg

Chromium picolinate 0,625 mg

HPMC E6 62,5 mg

Sodium carboxymethylcellulose 12,5 mg

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Copolyvidone 25mg

Nipastat 0,125 mg

List of References 1. Felt O. etal

Chitosan: A unique Polysaccharide for Drug Delivery. Drug Dev. Ind.

Pharm. 1998, 24(11), 979-993 2. Pittler MH et al

Randomized, double blind trial of chitosan for body weight reduction.

Eur. J. Clin. Nutr 1999, 53, 379-81 3. Macchi G.

A new approach to the treatment of obesity: Chitosan’s effects on body weight reduction and plasma cholesterol levels. Acta Toxicol. Ther. 1996, 17(4), 303-320 4. Sciutto AM et al

Lipid lowering effect of Chitosan dietary integrator and hypocaloric diet in obese subjects. Acta Toxicol. Ther. 1995, 16(4), 215-229 5. Veneroni G. et al

Effect of a new chitosan on hyperlipidemia and overweight in obese patients. Chitin Enzymology 1996, 2 (1), 55-62 6. Giustina A et al

Weight reducing regimens in obese subjects. Acta Toxicol. Ther. 1995, 16(4), 199-214 7. Ebihara K. et al

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Interaction of bile acids, phospholipids, cholesterol and triglyceride with dietary fibers in the small intestine of the rat. J Nutr 1989, 119, 1100- 1106 8. Jing SB et al

Effect of Chitosan on renal function in patients with chronic renal failure. J Pharm Pharmacol 1997, 49, 721-3 9. Kanauchi O et al

Mechanism for the inhibition of fat digestion by chitosan and for the synergistic effect of ascorbate. Biosci Biotechnol Biochem 1995, 59, 786-790 10. Nauss J.L. et al

The binding of micellar lipids to chitosan. Lipids 1998, 18, 714-719.

Claims

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CLAIMS 1 A controlled release pharmaceutical composition for oral administration comprising: (@) an amount of chitosan; and (b) an amount of a pharmaceutically acceptable non-ionic polymer effective to control the release of the chitosan.
2 A pharmaceutical composition according to claim 1 wherein the chitosan is greater than 70% N-deacetylated.
3 A pharmaceutical composition according to claim 2 wherein the chitosan is from 85% to 95% inclusive N-deacetylated.
4 A pharmaceutical composition according to any one of claims 1 to 3 wherein the chitosan has an average molecular weight of greater than 50 000 g. mol.

A pharmaceutical composition according to claim 4 wherein the chitosan has an average molecular weight of greater than 100 000 g-mol™.

6 A pharmaceutical composition according to any one of claims 1 to 5 wherein the non-ionic polymer is selected from the group consisting of hydroxypropylmethyicelluloses, polyvinylpyrrolidones, hydroxypropyicelluloses, hydroxyethyicelluloses, polyethyleneglycols, polyvinyl alcohols, and polyethylene oxides, and a mixture of two or more thereof.

7 A pharmaceutical composition according to claim 6 wherein the non-ionic polymer has a nominal viscosity in water of a 2% solution of between 4 000 and 100 000 poise.

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8 A pharmaceutical composition according to any one of claims 1 to 7 wherein the mass ratio of the non-ionic polymer to the chitosan is from 1:5 to 1:20 inclusive.

9 A pharmaceutical composition according to any one of claims 1 to 8 which includes:

(c) an effective amount of an appetite suppressant.

A pharmaceutical composition according to claim 9 wherein the appetite suppressant is chromium picolinate.

11 A pharmaceutical composition according to any one of claims 1 to 10 in the form of a tablet or a capsule or a powder, wherein each tablet or capsule or dose of powder contains 250 mg or greater of the chitosan.

12 A dose of a pharmaceutical composition for oral administration before a meal to reduce absorption of dietary fat, the dose comprising one or more tablets or capsules comprising:

(@) an amount of chitosan; and (b) an amount of a pharmaceutically acceptable non-ionic polymer effective to control the release of the chitosan.

13 Adose according to claim 12 wherein the chitosan is greater than 70% N-deacetylated.

14 A dose according to claim 13 wherein the chitosan is from 85% to 95% inclusive N-deacetylated.

A dose according to any one of claims 12 to 14 wherein the chitosan has an average molecular weight of greater than 50 000 g. mol".

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16 A dose according to claim 15 wherein the average chitosan has an molecular weight of greater than 100 000 g.mol".

17 A dose according to any one of claims 12 to 16 wherein the non-ionic polymer is selected from the group consisting of hydroxypropylmethylcelluloses, polyvinylpyrrolidones, hydroxypropylcelluloses, hydroxyethylcelluloses, ~~ polyethyleneglycols, polyvinyl alcohols, and polyethylene oxides, and a mixture of two or more thereof.

18 A dose according to claim 17 wherein the non-ionic polymer has a nominal viscosity in water of a 2% solution of between 4 000 and 100 000 poise. 19 A dose according to any one of claims 12 to 18 wherein the mass ratio of the non-ionic polymer to the chitosan is from 1:5 to 1:20 inclusive.

A dose according to any one of claims 12 to 19 which includes: (c) an amount of an appetite suppressant.

21 A dose according to claim 20 wherein the appetite suppressant is chromium picolinate.

22 A dose according to any one of claims 12 to 21 wherein each tablet or capsule contains 250 mg or greater of the chitosan.

23 A dose according to claim 22 comprising two or three tablets or capsules.

24 The use of chitosan in the manufacture of a medicament for oral administration comprising:

(a) an amount of chitosan; and

" Sy t " -13 - (b) an amount of a pharmaceutically acceptable non-ionic polymer i effective to control the release of the chitosan; ’ for the promotion of weight loss or for the maintenance of body weight.

The use according to claim 24 wherein the chitosan is greater than 70% N-deacetylated.

26 The use according to claim 25 wherein the chitosan is from 85% to 95% inclusive N-deacetylated.

27 The use according to any one of claims 24 to 26 wherein the chitosan has an average molecular weight of greater than 50 000 g. mol”.

28 The use according to claim 27 wherein the chitosan has an average molecular weight of greater than 100 000 g.mol™.

29 The use according to any one of claims 24 to 28 wherein the non-ionic polymer is selected from the group consisting of hydroxypropylmethylcelluloses, polyvinylpyrrolidones, hydroxypropylcelluloses, hydroxyethylcelluloses, polyethyleneglycols, polyvinyl alcohols, and polyethylene oxides, and a mixture of two or more thereof.

The use according to claim 29 wherein the non-ionic polymer has a nominal viscosity in water of a 2% solution of between 4 000 and 100 000 poise.

31 The use according to any one of claims 24 to 30 wherein the mass ratio of the non-ionic polymer to the chitosan is from 1:5 to 1:20 inclusive.

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DATED THIS 6™ DAY OF AUGUST 2001 SPOOR & FISHER APPLICANTS PATENT ATTORNEYS