JPH0517204B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to a pharmaceutical formulation of sulfo-adenosyl-L-methionine (SAMe) that is particularly suitable for oral use and for suppositories due to its properties that allow a high degree of absorption into the gastrointestinal tract. Sulfo-adenosyl-L-methionine (SAMe) is the major biochemical donor of the methyl group. Because of this special property, it is a compound of considerable importance both from a biochemical point of view and for its therapeutic uses. The main problem with large-scale use of this compound is that it is thermally unstable even at fairly ambient temperatures and its preparation and purification are complex. SAMe is therefore the subject of a number of patents, both for the formulation of new stable salts and for the preparation of the process which can be carried out on an industrial scale. The applicant has filed several patents for both new stable salts and processes for sulfo-adenosyl-L-methionine (Italian patent
1043885, 1022016, 1022036 and 1054175; Italian patent applications 23603A/81 and 22622A/83). All SAMe known today are highly water-soluble, hygroscopic, highly acidic and particularly suitable for injectable formulations. However, it has important limitations, especially regarding the poor absorption of SAMe in the gastrointestinal tract, which strongly limits the possibility of reaching blood levels suitable for obtaining the required pharmacological effects. Considerable improvements in this sense have been achieved by using the already patented gastrotolerant formulation of the applicant (patent application 22621A/83). However, the situation is still far from perfect, with experimental data on animals showing oral bioavailability for these formulations in the range of 3% to 20%, depending on the experimental model used. . Surprisingly, we have now demonstrated that 20%
- on the order of 30% and 60-70 for enteral administration
new
I discovered the SAMe formula. Therefore, these formulations represent ideal solutions for SAMe-containing oral drug forms and for suppositories. The novel sulfo-adenosyl-L-methionine (SAMe) according to the invention, particularly suitable for oral use and suppositories, is a water-soluble SAMe salt and has the general formula R(O)m( _SO3Na ) () where m is 0 or 1, and R is selected from the group consisting of alkyls containing 8 to 18 carbon atoms, phenylalkyls and carboxyalkyls, in which the linear or branched alkyl group consists of an organic sodium salt of It is characterized by In particular, the formulation according to the invention comprises a water-soluble SAMe salt and a sulfonic acid falling within the general formula ().
or of the sulfuric acid ester, or of the sodium salt of dioctyl sulfosuccinic acid; the term "dioctyl sulfosuccinic acid" above refers to the free acid of the commercial product "dioctyl sulfosuccinate". These and further properties and advantages of the formulations according to the invention will become more apparent from the following description of preferred compositions of the formulations and absorption experiments carried out on them. Water-soluble SAMe that can be used in formulations according to the invention
Examples of salts are disulfate-p-toluenesulfonate, disulfate-di-toluenesulfonate, 2.5sulfate and 1.5(1,4-butanedisulfonate). These salts are commercially available or can alternatively be prepared by known methods. Examples of sulfonic acid sodium salts that can be used in the above formulations are decane sulfonate, undecane sulfonate, dodecane sulfonate, tetradecane sulfonate, hexadecane sulfonate, octadecane sulfonate, lauryl sulfate, dodecylbenzene sulfonate and dioctyl sulfosuccinate. These salts are also generally commercially available. In either case, they can be easily prepared from the corresponding bromides by treatment with sodium zincate by the reaction: RBr + Na ₂ SO ₃ → RSO ₃ Na + NaBr. The molar ratio of water-soluble SAMe salt to organic sodium salt as defined above is from 5:1 to 1:1, preferably 3:1. The formulations are mixed according to known formulation methods. They can be made with or without the addition of other pharmaceutically acceptable excipients and auxiliaries, such as microcrystalline cellulose, polyvinylpyrrolidone, mannitol, lactose, carboxymethyl cellulose, and the like. Oral forms, suppositories and other forms can be prepared using the formulations of SAMe salts and organic sodium salts according to the invention. Thus, the product typically contains
For example, it can be provided as a tablet, pill, capsule or other form for use. Furthermore, the above prescription
As a completely new formulation form for SAMe,
For example, it can be used as a suppository, cream, ointment, etc. As mentioned above, the main advantage of the SAMe formulation according to the invention is that, compared to hitherto known water-soluble SAMe salts, the formulation exhibits a high degree of absorption into the gastrointestinal tract. The above absorption is the weight of 110 animals that have been fasting since last night.
A 210 g Sprague Dawley male rat was studied. The product was administered as a solution or as a 2% aqueous gum arabic suspension. For each product, five rats were operated under anesthesia to introduce the test substance into the adjacent jejunum. The wall incision was closed with a ligature and the animal was sutured. The product was administered orally to an additional 5 animals via gastric probe. Blood samples were taken at the beginning and after administration, 10, 20, 40,
The tail vein was extracted at 60, 90, 120, 180 and 240 minutes. SAMe concentration in plasma was determined by Baldessarini and Kopin.
It was determined by the improved method of J. Neuochem 13:769, 1966. Plasma concentration values lower than the original values were plotted against the time under and area of the time to infinity curve calculated by trapezium and curve extrapolation. The results obtained are shown in Table 1 and are compared to the known
Significantly higher absorption is shown for the formulation according to the invention than for the SAMe salt.

【table】

TABLE The examples set forth below describe several formulations according to the invention for illustrative purposes only. Example 1 A 100 mg tablet contains: (a) SAMe disulfate-p-toluenesulfonate 200mg equivalent to SAMe ions 100mg lauryl sulfate USP 217mg (b) SAMe disulfate-p-toluenesulfonate 200mg SAMe ions Equivalent to 100mg Sodium hexadecane sulfonate 247mg (c) SAMe2.5 sulfate 162mg Equivalent to SAMe ion 100mg Sodium tetradecane sulfonate 226mg (d) SAMe2.5 sulfate 162mg Equivalent to SAMe ion 100mg Sodium otakudecane sulfonate 686mg (e) SAMe1. 5 (1,4-butandyl sulfonate
182mg SAMe ion content 100mg Sodium dodecane sulfonate 209mg (f) SAMe1.5 (1,4-butane disulfonate
182mg Equivalent to SAMe ion 100mg Sodium dodecylbenzenesulfonate 262mg (g) SAMe1.5 (1,4-butanedylsulfonate)
Equivalent to 182mg SAMe ion 100mg Sodium dioctyl sulfosuccinate 334mg.

Claims (1)

[Claims] 1 Water-soluble SAMe salt and the general formula R(O)m(SO ₃ Na) ( ) where m can be 0 or 1, and R is a linear or branched alkyl group of 8 selected from the group consisting of alkyls, phenylalkyls and carboxyalkyls containing from 1 to 18 carbon atoms; Molar ratio is 5:
A pharmaceutical composition of sulfo-adenosyl-L-methionine (SAMe) for oral use, characterized in that the ratio is 1 to 1:1. 2 The water-soluble SAMe salt is disulfate-p-
Toluenesulfonate, disulfate-di-toluenesulfonate, 2.5 sulfate or 1.5
(The composition according to claim 1, which is 1,4-butanedylsulfonate. 3. The organic sodium salt of the general formula () above is a sodium salt of sulfonic acid, a sulfuric acid ester, or a dioctylsulfosuccinic acid. 4. The composition of claim 1, wherein the organic sodium salt is decane sulfonate, undecane sulfonate, dodecane sulfonate, tetradecane sulfonate, hexadecane sulfonate, octadecane sulfonate, lauryl sulfate, dodecylbenzenesulfonate or dioctyl sulfosuccinate. Nate,
A composition according to claim 1. 5. The composition of claim 1, wherein the molar ratio of the water-soluble SAMe salt to the organic sodium salt of general formula () is 3:1. 6. The composition of claim 1 containing excipients and auxiliaries such as microcrystalline cellulose, carboxymethylcellulose, mannitol, polyvinylpyrrolidone, etc.