GB2113998A - Lactitol for the treatment of liver disease - Google Patents

Abstract

Lactitol (4-???-D-galactopyranosyl- D-sorbitol) is used in a method of treatment of the human or animal body, particularly for treating liver disease, and especially portal systemic encephalopathy (P.S.E.). Pharmaceutical compositions for use in the method comprise lactitol and an orally acceptable carrier.

Description

SPECIFICATION Pharmaceutical compositions The invention relates to pharmaceutical compositions for effective treatment of liver diseases like portal systemic encephalopathy.

Portal systemic encephalopathy (PSE) is a disorder of the central nervous system that occurs as a complication of advanced hepatic cirrhosis. In patients suffering from this disease, toxic nitrogenous substances in portal blood, among which ammonia may be important, produced by bacteria in the colon are no longer detoxified by the liver but enter freely into the systemic blood circulation and reach the brain where they damage the nervous cells. PSE patients show psychiatric and neurological disturbances progressing from mild mental aberration to coma.

In 1 966 lactulose has been introduced for treatment of PSE. Until then this condition was treated with dietary protein restriction, purging and the administration of broad spectrum antibiotics. Lactulose is a dissaccharide that cannot be hydrolized and resorbed by the small intestines; it passes unchanged to the ileum and colon where it provides a fermentable carbohydrate for the colon flora.

Also isomaltitol has been suggested for this purpose (German Offenlegungsschrift 2 307 251), but this product is difficult to produce, as can be deduced from the number of production steps involved. The production process for isomaltitol starts from saccharose which is converted enzymatically to isomaltulose. Isomaltulose is then hydrogenated to a mixture of isomaltitol and a-D glucopyranosido-1,6 mannitol.From this mixture isomaltitol is separated by fractionated crystailization. The presence of fermentable carbohydrate, providing readily available carbon and energy is inducing the growth of Lactobacilli, converting lactulose and ammonia into biomass and organic acids, resulting in a reduction of the ammonia concentration in the colonic environment -- and thus reduces the diffusion of ammonia from the lumen to the portal blood - in two ways: 1) The preferential use of lactulose as a carbon and energy source exerts a sparing effect on the metabolism of aminated compounds thus decreasing the amount of ammonia and other basic nitrogenous substances literated as a byproduct of these processes.

2) A readily available energy source will enhance assimilation of ammonia, an energy requiring process which will not occur so readily under conditions of carbohydrate limitations.

Lactulose, however, shows a number of distinct disadvantages: it can only be obtained in a syrup form with relatively large amounts of impurities (lactose, galactose, glucose).

these impurities do not possess any therapeutic effect but may cause problems for diabetic patients and will give rise to dental caries.

- the main disadvantage, however, is that lactulose syrup has an unpleasantly sweet taste.

The aversion to the product of patients who have to take large doses over a prolonged period of time can go that far that it occurs that the patients stop using lactulose, with the risk of coma and subsequently even death.

It has now been found that the disaccharide alcohol lactitol (4P-D-galactosyl-D-sorbitol) has the same therapeutic effect against p.s.e. as lactulose, but, surprisingly, does not show the undesired side effects. In particular the aversion to sweet taste and the nausea, often experienced after taking high doses of Lactulose, does not occur. Accordingly the ratio of beneficial to adverse effect of Lactitol is superior to the one of Lactulose. Lactitol is derived from lactose, which is abundantly available as a by-product of cheese manufacture. It can be obtained in a very pure crystalline form, as monohydrate or as dihydrate (European Patent Application 0039981).The crystalline forms offer the advantage of incorporating it in many dosage forms; depending on the product and production process the low melting dihydrate (m.p. 760C) or the higher melting monohydrate (m.p. 1 100C) can be used.

A great benefit of the treatment with lactitol is that lactitol has not the disagreeable taste of lactulose. A further benefit is that the pharmaceutical composition is chemically pure and can be prepared in the shape of a tablet, in a unidose bag or controlled amount powder dispenser, these are the most convenient forms of administration of such a drug.

A suitable dose is 20-200 g of lactitol per day, especially 30-75 g of lactitol per day. The absence of impurities in lactitol is an advantage over lactulose in view of the necessarily prolonged administration of the drug. It appeared from tests that patients treated with lactitol instead of lactulose remain at least in a similarly satisfactory clinical condition as appears from EEG and clinical characteristics such as flapping tremor, but may obtain a better result in the number connection test. (This is a test for organic brain disease in which points are to be connected in a certain sequence by means of a pencil. Healthy, intelligent people perform this test in 30 to 40 seconds).

Tablets can be prepared from lactitolmonohydrate and lactitoldihydrate.

Crystalline mono- or dihydrate (particle size 0.5-1.4 mm) can be compressed directly into tablets using 0.5 percent lubricant (e.g. stearic acid). Lactitol mono- or dihydrate in powder form (particle size less than 0.7 mm) has to be granulated with usual binders (starch, natural gums, conc. 0.5-1.0 per cent) to make it suitable for tabletting. Tablets thus obtained are of better quality (hardness, friability) but as the amount of additives has to be kept as low as possible the direct compression is preferred. It is also possible to administer lactitol in foods or drinks, so that it is not necessary to take tablets. Examples of such foods are tea, coffee, yoghurt, fruit salad, etc. All these possibilities of dispensing the drug are found to increase patients compliance as compared to lactulose.

Experimental Results In a patient suffering from PSE (male of 61 years, weight 62 kg) who was treated with 100 g of lactulose per day, the lactulose was replaced by 40.5 g of lactitol (d.s.) per day. At this dose of lactitol, the arterial blood ammonia content (127 jug/dl) was higher than with the dose of 100 g lactulose a day (120 yg/dl), however, the further tests (i.e. clinical coma grade, number connection test and EEG grade) were the same.

The lactitol dose was then increased to 3 x 8 tablets (64.8 g d.s.) afteFtwo weeks. The patient did not exhibit side-effects, such as diarrhea, however, did exhibit positive effect, such as an improvement of the number connection test. The patient required more than 120 seconds both with a dose of 100 g lactulose and 40.5 g lactitol.

When 64.8 g lactitol administered the time required was 110 seconds and after a week of said dose the time was 102 seconds. Blood ammonia (158 jug/dl) remained somewhat above the contents observed during treatment with 100 g lactulose per day.

The lactitol tablets were prepared by compressing a mixture of crystalline lactitoldihydrate and 0.5 per cent of stearic acid to tablets of 3 g each in the usual way.

With respect to the test it is observed that it is ethically not justifiable to compare the test substance with a placebo in view of the fact that this might cause coma and represent an unacceptable risk for the patient. For this reason, it is now usual to compare with the best known compound, i.e. lactulose in the present case.

Claims (7)

1. Lactitol for use in a method of treatment of the human or animal body.

2. Lactitol for use in a method as claimed in claim 1, wherein said treatment is a treatment of liver disease.

3. Lactitol for use in a method as claimed in either claim 1 or claim 2, wherein said treatment is a treatment of portal systemic encephalopathy.

4. A composition comprising lactitol for use in treatment of liver disease.

5. A composition as claimed in claim 4, wherein the lactitol is admixed with one or more pharmaceutically acceptable carriers.

6. A process for the production of a pharmaceutical composition for treatment of liver disease, comprising the step of bringing lactitol with or without additives into a suitable form.

7. A use of lactitol substantially as described herein with reference to the Examples.