WO2003013471A2

WO2003013471A2 - Pharmaceutical enteric coated composition comprising chitosan

Info

Publication number: WO2003013471A2
Application number: PCT/IB2002/003117
Authority: WO
Inventors: Paolina Galvao
Original assignee: Paolina Galvao
Priority date: 2001-08-08
Filing date: 2002-08-08
Publication date: 2003-02-20
Also published as: AU2002321707A8; WO2003013471A3; AU2002321707A1

Abstract

An enteric coated pharmaceutical composition containing chitosan is protected from the acidic stomach environment and exposed in the alkaline environment of the small intestine where it can bind fat. An activator, typically a pharmaceutically acceptable acid, is included in the composition to create an acidic micro-environment in the alkaline medium of the small intestine to increase the solubility of the chitosan and hence its ability to bind fat.

Description

PHARMACEUTICAL ENTERIC COATED COMPOSITION COMPRISING CHITOSAN

BACKGROUND OF THE INVENTION

This invention relates to an oral pharmaceutical composition containing chitosan for use as a fat binder in reducing the absorption of dietary fats.

Chitosan is a well-known dietary additive and its use as a fat binder is well established. To properly understand the action of chitosan, it is important to understand the process of fat digestion. Dietary fats are composed mainly of triglycerides (TG). The triglycerides are uncharged or have a zero charge when the dietary fats are ingested. They enter and leave the stomach unchanged. Upon entering the small intestine, lipase fat splitting enzymes break the triglycerides down into fatty acids and monoglycerides. The fatty acids are absorbed into the body and stored in the adipose tissue of the body in areas such as hips, thighs, waist and buttocks.

Chitosan is a fibre found in the outer skeleton of shellfish. It has a positive charge and thus binds to any negatively charged molecules. As triglycerides are broken down into negatively charged fatty acids, the positively charged chitosan is ideally suited for binding the fatty acids so that the fat is eliminated from the body with the chitosan.

However, traditional products containing chitosan release the chitosan in the low pH environment of the stomach due to its solubility in acidic media. In the stomach the chitosan will not be attracted to the non-charged dietary fats and will instead bind to other negatively charged compounds. For example, carbonate groups from fizzy drinks, sulphate groups from eggs and the like will be bound by the chitosan. As a result there will be a lot less chitosan (if any at all) left to bind the fatty acids when they are released from the triglycerides in the small intestine.

In order to address this problem, Aspen Pharmacare Holdings Limited developed an oral controlled release pharmaceutical composition containing chitosan and a pharmaceutically acceptable non-ionic polymer effective to control the release of the chitosan, as disclosed in their South African Patent 2001/6447. By having a slow release formulation, it is presumed that sufficient chitosan will remain in the product in order to bind the fatty acids in the small intestine. In this regard, it is also mentioned that the tablets may be coated with pharmaceutically acceptable coating agents, including enteric coating compounds such as methacrylic acid co-polymers, waxes and the like to prevent the tablet from dissolving in the gastric juice.

A problem with this approach, is that chitosan is soluble in acidic media but sparingly soluble in alkaline media based on protonation of the free amino functionality. As a result, even though the chitosan may be protected from the acidic media in the stomach, once in the higher pH environment of the intestine, the chitosan is sparingly soluble and hence its effectiveness in binding fatty acids is substantially reduced.

SUMMARY OF THE INVENTION

According to a first aspect of the invention there is^' provided an enteric coated pharmaceutical composition for oral administration comprising:

(a) a core containing as active ingredient an amount of chitosan and an effective amount of a pharmaceutically acceptable activator for activating the chitosan in an alkaline medium; and

(b) an outer layer of an enteric coating. According to a second aspect of the invention, there is provided the use of chitosan in the manufacture of a medicament for oral administration comprising:

(b) an outer layer of an enteric coating.

According to a third aspect of the invention, there is provided a method of reducing the absorption of dietary fat in a patient comprising administering to the patient an effective amount of chitosan, together with an effective amount of a pharmaceutically acceptable activator for activating the chitosan in an alkaline medium, wherein the medicament is enteric coated to prevent or reduce release of the chitosan in the acidic medium of the stomach, but allow rapid release thereof in the intestine.

By "pharmaceutically acceptable activator" is meant any compound that is capable of activating the chitosan, i.e. by improving its solubility in an alkaline medium. Preferably, the pharmaceutically acceptable activator is a pharmaceutically acceptable acid that is capable of creating an acidic-micro environment in the alkaline medium, which improves the solubility of the chitosan and hence its ability to absorb fatty acids. The pharmaceutically acceptable activator is preferably ascorbic acid.

The chitosan is typically combined with the ascorbic acid in a weight ratio of about 4:1 to about 2:1 , in particular a weight ratio of 4:1. The typical dosage of chitosan is 500 mg - 6000 mg per day, and the dosage of ascorbic acid is typically 125 mg - 3000 mg per day. Less ascorbic acid could be included if it is being used only to create an acidic micro-environment and not also for its additive effect on the chitosan.

DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS

The crux of the invention is to provide an enteric coated pharmaceutical composition containing chitosan in order to protect it from the acidic stomach environment and expose it in the alkaline environment of the small intestine where it can bind fat, and to include an activator for activating the chitosan in this environment.

The enteric coating must be such that the chitosan is protected in the acidic pH of the stomach but when it passes into the alkaline pH of the small intestine the enteric coating must disintegrate to expose the chitosan. Thus, the enteric coating must have a pka (dissociation constant) to ensure that it stays intact in an acidic environment but that it dissociates thus exposing the chitosan in an alkaline environment.

The enteric coating is usually applied as a film by spray drying in a pan or by the air-suspension technique. Although various approaches have been followed to obtain an enteric coat that is able to resist gastric fluid and to permit penetration of intestinal fluid, the most common is to use pH-sensitive materials. Cellacephate (CAP) is an enteric coating material that is soluble in fluids of pH 6 or above and is also readily digested by the enzymes in the intestinal fluid. It has been found to be a particularly useful enteric coating material in respect of the pharmaceutical composition of the invention. When using cellacephate, diethyl phthalate may be used as a solvent and plasticiser therefor. Other enteric coats which may be used include Eudragit L100 and Eudragit S100. Eudragit L and S are anionic polymers based on methacrylic acid and methylacrylate. These products are described in USP/NF as a methacrylic acid co-polymer type A (Eudragit L) and type B (Eudragit S). The ratio of free carboxyl groups to the ester groups is approximately 1.1 in Eudragit L and 1 :2 in Eudragit S. Another suitable enteric coating is Acryl- Eze™, a dry enteric coating system dispersible in water for the application of enteric film coating to solid dosage forms such as tablets, granules and beads. Sureteric is another suitable enteric coating. Both Acryl-Eze™ and Sureteric rely on ionisable phthalate groups for their functionality. The use of a HPMC based sub-coat would be preferable to isolate the chitosan from the coating. Polyvinyl acetate phthalate (PVAP), a further suitable enteric coating, is less permeable to moisture and gastric fluid, more stable to hydrolysis and able to ionise at a lower pH, resulting in earlier release of actives in the duodenum. Hydroxypropyl methycellulose phthalate is a similar enteric coating with similar properties to that of PVAP. Other suitable enteric coatings include cellulose acetate trimellitete (CAT), which has similar properties to CAP, carboxymethyl ethylcellulose (CMEC), hydroxypropyl methycellulose acetate succinate (HPMCAS) and methacrylic acid or methyacrylic acid ester co-polymers. Enteric coats that were tested but failed to pass the disintegration test include formalin treated gelatin and shellac. With these two enteric coats polymerisation could not be controlled and this resulted in failure to release the active ingredient. It should be noted however that the activity of the chitosan is enhanced if a sub-coat is used to protect the chitosan from the enteric coat. An HPMC sub-coat or any other similar sub-coat could be used.

In order to identify an enteric coating for the pharmaceutical composition of the invention, it must comply with the disintegration test for enteric-coated tablets as set out on page A 41 of British Pharmacopoeia 1988, Appendix X11 B, for example. In terms of this test, the time of resistance to the acidic medium varies according to the formulation of the tablets to be examined. It is usually three hours but even with authorised deviations it is not less than one hour. If the preparation being examined in accordance with this test procedure fails to comply because of adherence of the tablets to the discs used, the test may be repeated on a further six tablets emitting the discs. The preparation being examined is deemed to comply with the test if all six tablets disintegrate in a pH environment of 6.8, but not an acidic environment.

By protecting the chitosan in the stomach environment it is prevented from being wasted by binding to other negative ions in the stomach. Accordingly, the chitosan is available to bind the negatively charged fatty acids in the small intestine once they are released from the triglycerides under the action of lipase. However, chitosan is sparingly soluble in alkaline media. Thus, unless it is rendered more soluble in the small intestine, its efficiency is reduced. It is therefore necessary to include in the pharmaceutical composition a pharmaceutically acceptable activator to activate or enhance the solubility of the chitosan, thereby improving its efficiency.

As chitosan is readily soluble in an acidic medium, by creating an acidic micro- environment in the small intestine, it has been found that the chitosan is activated and is capable of binding fatty acids. This acidic micro-environment is created when a pharmaceutically acceptable acid, in particular ascorbic acid, is provided as the activator.

The synergistic effect of vitamin C (ascorbic acid) on chitosan appears to be well documented. Whereas on its own 90 to 95% N-deacylated chitosan (pharmaceutical grade chitosan) is able to absorb 10 to 12 times its own weight of fatty acids, this is doubled with the addition of ascorbic acid. Vitamin C is available with chitosan in the products Cheat and Eat; Fat Trapper; Stacker 3 with Chitosan and Bindasal, none of which is an enteric coated product.

However, by combining ascorbic acid with chitosan in an enteric-coated dosage form, in addition to the abovementioned advantage, the chitosan is suprisingly activated in the small intestine for optimum binding of the fatty acids by the ascorbic acid.

The following examples are provided to illustrate the invention, and should not be construed as limiting on the scope of protection thereof.

Example 1

A batch of enteric coated tablets, in which diethylphthalate and cellacephate were used as the coating agents, were made as follows.

278 g of chitosan with a degree of N-deacetylation of 90% were blended in a planetary mixer at 45 rpm for 15 minutes with 62,50 g vitamin C, 18 g povidone K30, 40 g calcium phosphate dibasic, 68 g lactose and 78 g maize starch. Once the desired LOD at 80°C was obtained, the blend was granulated with 360 ml methylated spirits to form suitable granules, which were dried in a conventional oven at 45°C. The dried granules were then screened through a 850 micron screen and as the LOD was still suitable at 80°C, the granules were finally blended with 5,5 g magnesium stearate at 30rpm for 5 minutes. The final blend was then compressed into tablet cores on a rotary press. 300 mg to 500 mg tablet cores were transferred into a fluidbed dryer. In a separate container an enteric coating was formulated by mixing 7 g methylated spirits, 60 g acetone, 170 g dichloromethane, 10 g diethylphthlate, and 34 g cellacephate. The tablet cores were heated to 35°C and the enteric coating sprayed onto the tablets to produce the enteric coated tablets of the invention.

The unit composition of an enteric coated tablet so produced is as follows: Core:

Chitosan 90% 278 mg

Vitamin C 62,5 mg

Povidone K30 18 mg Calcium phosphate dibasic 40 mg

Lactose 68 mg

Maize starch 78 mg

Magnesium stearate 5,5 mg

Coating:

Diethylphthalate ' 10 mg

Cellacephate 34 mg

Example 2

A study to determine the efficacy of the pharmaceutical composition of the invention was conducted as follows:

Four, healthy females aged between 20 and 30 years, all having moderate activity levels and not taking any medication or supplements, were tested. All the test candidates were given a healthy eating plan to follow.

Patient A and Patient B were given tablets containing 500 mg of chitosan. These tablets had not been subjected to any specialised manufacturing procedure. Patient C and Patient D were given tablets which were enteric coated containing 250 mg of chitosan and 62.5 mg of ascorbic acid each.

All the patients were told to take one tablet three times daily. After four weeks the results were as follows: 1. Patient A lost 3.1 kg and 28 cm;

2. Patient B lost 2.9 kg and 25 cm;

3. Patient C lost 3.9 kg and 36 cm; and

4. Patient D lost 4.0 kg and 31 cm.

As a result of the enteric coated dosage form and the addition of ascorbic acid, the chitosan is only released in the alkaline environment of the small intestine where it is activated by the ascorbic acid to provide for optimum fat binding capabilities.

Claims

1. An enteric coated pharmaceutical composition for oral administration comprising:

(b) an outer layer of an enteric coating.

2. A composition according to claim 1 , wherein the activator is a pharmaceutically acceptable acid capable of creating an acidic micro- environment in the alkaline medium of the intestine to increase the solubility of the chitosan.

3. A composition according to claim 2, wherein the activator is a pharmaceutically acceptable acid.

4. A composition according to claim 3, wherein the pharmaceutically acceptable acid is ascorbic acid.

5. A composition according to claim 4, wherein the weight ratio of chitosan to ascorbic acid is in the range of about 2:1 to about 4:1.

6. A composition according to claim 5, wherein the weight ratio of chitosan to ascorbic acid is about 4:1.

7. A composition according to any one of the preceding claims, wherein the enteric coating is selected from the group comprising cellacephate, methacrylic acid and acid ester polymers, polyvinyl acetate phthalate, hydroxypropyl methylcellulose phthalate, cellulose acetate trimellitrate, carboxymethyl ethylcellulose, and hydroxypropyl methylcellulose acetate succinate.

8. A composition according to claim 7, wherein the enteric coating is cellacephate.

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

(b) an outer layer of an enteric coating.

10. The use of claim 9, wherein the activator is a pharmaceutically acceptable acid capable of creating an acidic micro-environment in the alkaline medium of the intestine to increase the solubility of the chitosan.

11. The use of claim 10, wherein the activator is ascorbic acid.

12. The use of claim 9, wherein the enteric coating is selected from the group comprising cellacephate, methacrylic acid and acid ester polymers, polyvinyl acetate phthalate, hydroxypropyl methylcellulose phthalate, cellulose acetate trimellitrate, carboxymethyl ethylcellulose, and hydroxypropyl methylcellulose acetate succinate.

13. The use of claim 9, wherein the medicament is an enteric coated tablet or pellet.

14. A method of reducing the absorption of dietary fat in a patient comprising administering to the patient an effective amount of chitosan, together with an effective amount of a pharmaceutically acceptable activator for activating the chitosan in an alkaline medium, wherein the medicament is enteric coated to prevent or reduce release of the chitosan in the acidic medium of the stomach, but allow rapid release thereof in the intestine.

15. A method according to claim 14, wherein the activator is a pharmaceutically acceptable acid capable of creating an acidic micro- environment in the alkaline medium of the intestine to increase the solubility of the chitosan.

16. A method according to claim 15, wherein the activator is ascorbic acid.

17. A method according to claim 16, wherein the dose of chitosan is about 500mg to 6000mg per day and the dose of ascorbic acid is about 125mg to 3000mg per day.