Stable Granulates Containing S-adenosylmethionine and Process for Preparation Thereof

Abstract

A fluid bed granulation process for manufacturing non-hygroscopic, stable granulates containing a water-soluble salt of S-adenosylmethionine is described. Said process comprises:a) the simultaneous, sequential or alternate dispersion of at least a solution of a water-soluble salt of SAMe (A) and of a solution of a coating agent (B), on a fluid bed granulation carrier (C) andb) the fluid bed granulation of the mixture.Granulates obtainable by said process and solid oral pharmaceutical forms obtainable by said granulates are disclosed.

Description

[0001]This application is a continuation of Ser. No. 11 / 277,722 filed Mar. 28, 2006; which was a continuation of Ser. No. 10 / 432,338 filed May 20, 2003 now issued as U.S. Pat. No. 7,048,948; which was a 371 of PCT / EP02 / 13568 filed Nov. 29, 2002; the disclosures of which are incorporated herein by reference.[0002]The present invention relates to a granulation process and, more particularly, it relates to a granulation process for preparing stable granulates containing S-adenosylmethionine.[0003]S-adenosylmethionine, in short SAMe, is a known compound of formulabroadly used in therapy, especially for its anti-inflammatory properties and in the treatment of chronic hepatic diseases (Merck Index, 1996, n. 155).[0004]It is generally prepared by fermentation and isolated as a salt, as described for example in the U.S. Pat. No. 4,562,149.[0005]The molecule is characterized by a significant intrinsic instability, mainly due to the intramolecular attack of the carboxylate ion onto the methyl...

AI Technical Summary

Benefits of technology

[0011]The instability of SAMe is accelerated, besides the heating, by an acidic medium too, hence the product, after administration, undergoes a significant decomposition at gastric level with a consequent variable intestinal absorption and an uncertain therapeutical dosage. In this case, therefore, it becomes fundamental to protect the tablets with a gastro-resistant coating, further increasing the production costs and terms.

[0013]We have now surprisingly found that the water-soluble salts of SAMe can be granulated providing stable, non hygroscopic and, optionally, gastro-resistant granulates with a simple, cheap and industrially applicable process.

[0014]Those granulates are a very advantageous form for the storage and the administration of the hygroscopic salts of SAMe and can be conveniently used by direct compression, optionally with the addition of suitable excipients, for manufacturing simple or coated non hygroscopic tablets or directly used for filling capsules.

Problems solved by technology

The molecule is characterized by a significant intrinsic instability, mainly due to the intramolecular attack of the carboxylate ion onto the methylene in beta position, providing homoserine and methylthioadenosine.

This high instability, that appears both in the solid state and as an aqueous solution at room temperature already, makes the isolation, the storage and the formulation of the product particularly difficult.

Nevertheless the water-soluble salts of SAMe currently on the market, such as for example the disulfate tosylate or the 1,4-butandisulfonate, are extremely hygroscopic and / or sensitive to the moisture, therefore they must be storage and processed under strictly controlled environmental conditions, with all the consequent economical and technological disadvantageous implications.

On the contrary other pharmaceutical forms, such as for example capsules, more handy and cheaper, are not practicable because rapidly damaged by the dehydrating action of the salt itself.

In this case, therefore, it becomes fundamental to protect the tablets with a gastro-resistant coating, further increasing the production costs and terms.

Finally, if the gastro-resistant granulate is directly used during the preparation of tablets and capsules, it is possible to avoid the coating step or the use of special capsules, with significant saving of costs and time.

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