NL8300374A - PHARMACEUTICAL PREPARATIONS FOR THE TREATMENT OF LIVER DISEASES. - Google Patents

Description

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Pharmaceutical preparations for the treatment of liver diseases *

The invention relates to pharmaceutical compositions for the effective treatment of liver diseases such as portal systemic encephalopathy.

Portal systemic encephalopathy (PSE) is a disease of the central nervous system. occurs as a complication of advanced hepatitis cirrhosis. In patients suffering from this disease, toxic nitrogen-containing compounds in the portal blood, including ammonia, which are formed by bacteria in the colon, are no longer detoxified by the liver, but are released into the systemic circulation and to the brain where they affect the nerve cells. PSE patients show psychiatric neurological disturbances that progress from a mild mental disorder to a coma.

Lactulose was introduced in 1966 for the treatment of PSE.

Until then, this condition was treated by a diet with a limited protein content, rinsing and the administration of antibiotics with a broad spectrum of action. Lactulose is a disaccharide that cannot be hydrolyzed and absorbed by the small intestine; it passes unchanged to the colon and colon where it forms a fermentable hydrocarbon for the flora of the colon.

Isomaltitol has also been proposed for this purpose (German Offenlegungsschrift 2 302 251), but this product is difficult to prepare as evidenced by the number of preparation steps required. The preparation method for isomaltitol is based on sucrose which is enzymatically converted into iso-maltulose. Isomaltulose is then hydrogenated to a mixture of isomaltitol and α-D glucopyranosido-1,6 mannitol. Isomaltitol is separated from this mixture by fractional crystallization. The presence of fermentable hydrocarbon, which is an easily accessible source of carbon and energy, induces the growth of Lactobacilli, which convert lactulose and ammonia into biomass and organic acids, resulting in a reduction of the ammonia concentration in the colon - and thus the diffusion of ammonia from * the lumen to the portal blood decreases - in two ways: 1) Preferably using lactulose as a carbon source and as an energy source exerts a sparing influence on the metabolism of aminated compounds thereby reducing the amount of ammonia and other basic nitrogen compounds which is released as a by-product of these processes is reduced.

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** »» 5 2) An easily available energy source improves the assimilation of ammonia, an energy-demanding process that does not occur as readily under the conditions where hydrocarbon is only present to a limited extent.

Lactulose, however, has a number of obvious disadvantages: - it can only be obtained in the form of a syrup with a relatively large amount of impurities (lactose, galactose, glucose).

these impurities do not have any therapeutic effect, but can cause problems for diabetic patients and can cause dental caries.

- the main drawback, however, is that lactulose syrup has an unpleasant sweet taste. The reluctance to the product of patients who have to take large doses for a long time can become so strong that patients end the use of lactulose with the risk of coma and possibly death.

It has now been found that the disaccharide alcohol lactitol (4- $ D-galactosyl-D-sorbitol) has the same therapeutic effect against PSE as lactulose, but surprisingly does not exhibit the undesirable side effects. In particular, the aversion to the sweet taste and nausea, which often occur after taking a large dose of lactulose, does not occur. As a result, the favorable to adverse effect ratio of lactitol is superior to that of lactulose. Lactitol is derived from lactose, which is available in large quantities as a by-product of cheese production. It can be obtained in very pure crystalline form as monohydrate or as dihydrate (European Patent Application 0039981). The crystalline form offers the advantage that it can be included in many dosage forms; depending on the product and the method of preparation, the low melting dihydrate (melting point 76 ° C) or the higher melting monohydrate (melting point 110 ° C) can be used.

A big advantage of the treatment with lactitol is that lactitol does not have the unpleasant taste of lactulose. Another advantage is that the pharmaceutical preparation is chemically pure and can be presented in the form of a tablet, a unit dose pouch or a dispenser delivering a set amount of powder. These are the most suitable forms of administration of such a drug.

A suitable dose is 20-100 g of lactitol per day, in particular 30-75 g of lactitol per day. The absence of impurities in lac-40 titol is an advantage over lactulose given the necessarily long-term administration of this drug, 8300374 * ...............- mr * 3, studies have shown that patients those treated with lactitol rather than lactulose remain in a similar satisfactory clinical condition as evidenced by EEG and clinical features such as its asterixis, but obtain a better result in the number compound test. (This is an organic brain disease test in which points have to be connected with a pencil in a certain order. Healthy, intelligent people complete this test in 30 to 40 seconds).

Tablets can be prepared from lactitol monohydrate and lactitol dihydrate. 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). Powdered lactitol mono- or dihydrate (particle size less than 0.7 mm) is granulated with conventional binders (starch, natural gums, at a concentration of 0.5-1.0 percent) to make it suitable for tabletting. The tablets obtained in this way are of better quality (hardness, possibility of crumbling), but since the amount of additives must be kept as small as possible, direct compression is preferred. It is also possible to add lactitol in foods or drinks, so that it is not necessary to take tablets. Examples of such foods are tea, coffee, yogurt, fruit salad, etc. All of these options for administering this drug promote patient compliance compared to lactulose.

25 Experimental results

In a patient suffering from PSE (61-year-old man, weight 62 kg) who was treated with 100 g lactulose per day, the lactulose was replaced by 40.5 g lactitol (d.s.) per day. At this lactitol dose, the ammonia content of the venous bleod (127 yg / dl) was higher than 30 with the dose of 100 g lactulose per day (120 yg / dl), the further tests (ie clinical coma grade, number connection test and quality of the EEC) were the same. The dose of lactitol was then increased to 3x8 tablets (64.8 g d.s.) after two weeks. The patient showed no side effects, such as diarrhea, but showed a positive effect, such as an improvement in the number connection test. The patient took more than 120 seconds with both a dose of 100 g lactulose and 40.5 g lactitol. When 64.8 g lactitol was administered, the time required was 110 seconds and after a week with this dose, the time was 102 seconds. The blood content of ammonia (158 yg / dl) remained slightly above the level observed during treatment with 8300374 4 »............. _ _ _ _ ....... .......

100 g of lactulose per day.

The lactitol tablets were prepared by pressing a mixture of crystalline lactitol dihydrate and 0.5 percent stearic acid into tablets of 3 g each in the usual manner.

Regarding the trial, it is noted that it is ethically unjustified to compare the test compound to a placebo given that it may cause a coma and represents an unacceptable risk to the patient. Therefore, it is usual to compare with the best known compound, ie in the present case, lactulose.

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Claims (7)

1. The use of lactitol for the treatment of the human or animal body. The use of lactitol in the method of claim 5 1, wherein said treatment is a treatment of the liver disease. Use of lactitol in a method according to claim 1 or 2, wherein the treatment is a treatment of portal systemic encephalopathy. 4. Lactitol-containing preparation for use in the treatment of liver disease. The formulation of claim 4, wherein the lactitol is mixed with one or more pharmaceutically acceptable carriers. 6 * A process for the preparation of a pharmaceutical composition for the treatment of a liver disease, wherein lactitol with or without additives is brought into a suitable form with or without additives. 7. Use of lactitol as described in the examples. ********** 8300374