Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1999-11-08
2002-08-27
Rose, Shep K. (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
Reexamination Certificate
active
06441011
ABSTRACT:
This invention relates to a pharmaceutical that is characterized in that it contains a combination of 2-methyl-thiazolidine-2,4-dicarboxylic acid and paracetamol.
Long-term application and/or high doses of the widely used analgesic, paracetamol (acetaminophen), result in the destruction of hepatic and renal cells. The toxicity of paracetamol is caused by a chemically reactive metabolite, N-acetyl-p-benzochinonimine (NAPQI). This metabolite binds cell proteins such as enzymes that are thus deactivated. In addition, high doses of paracetamol increase the concentration of oxygen radicals, which results in the collapse of the cellular defense system against toxic influences. The degree to which cellular defense mechanisms are impaired, and cells destroyed, can be evaluated by measuring certain substances in the blood plasma as well as directly in the tissue. Examples of such indicator substances are lactate dehydrogenase (LDH), an enzyme, or the transaminases alanine-aminotransferase (AlAT), aspartate aminotransferase (AspT) in the blood serum as well as cysteine, cystine, malonyl dialdehyde, glutathione, accumulation of proteins containing sulfhydryl groups, and accumulation of smaller substances that also contain sulfhydryl groups.
The most widespread antidote to paracetamol poisoning is N-acetylcysteine. Compound preparations of paracetamol and N-acetylcysteine, however, are unknown. It is generally assumed that N-acetylcysteine is a low-toxic pharmaceutical. However, some barely known reports point to the fact that the toxicity risk N-acetylcysteine poses is underestimated (Estrela, J. M., Saez, G. T., Such, L. and Vina, J., Biochem. Pharmacol. 32:3483-3485 (1983), and Vina, J., Romero, F. J., Saez, G. T. and Pallardo, F. V., Experientia 39:164-165 (1983)). Researchers repeatedly tried to find alternatives because of the fact that N-acetyl cysteine can trigger toxic responses. It is absolutely improper to apply L-cysteine itself as this amino acid is highly toxic and causes the death of brain cells (Karlsen, R. L., Grofova, Y., Malthe-Sorensen, D. and Farnum, E., Exp. Brain. Res. 208:167-180 (1981)). This toxicity can be bypassed if a so-called prodrug is applied, i.e. a predecessor pharmaceutical from which the effective amino acid is released in a controlled way inside the body.
It is the problem of this invention to provide a compound preparation that is capable of reducing the cell toxicity of paracetamol, the proven analgesic and antipyretic.
This problem is solved according to the invention by providing a pharmaceutical that is characterized by containing a combination of 2-methyl thiazolidine-2,4-dicarboxylic acid and paracetamol as well as pharmaceutically harmless substrates, adjuvants and/or additives.
It was found, surprisingly, that 2-methyl-thiazolidine-2,4-dicarboxylic acid causes a reduction in the formation of free radicals and an increase in the concentration of sulfhydryl groups in the organism. Thus this compound has a cytoprotective and anti-inflammatory effect. This substance therefore is clearly superior to all compounds known as yet, e.g. N-acetylcysteine. Using 2-methyl thiazolidine-2,4-dicarboxylic acid can considerably reduce the toxic side-effects known from N-acetylcysteine.
Pyruvate, a completely harmless physiological substance, is formed as a by-product when L-cysteine is released from 2-methyl-thiazolidine-2,4-dicarboxylic acid. Unlike N-acetylcysteine, 2-methyl-thiazolidine-2,4-dicarboxylic acid is therefore very well tolerated. There are even indications that pyruvate has a protective effect (Rastellini, C., Cicalese, L., Zeevi, A., Mattes, C., Stauko, R. T., Starzl, T. E. and Rao, A. S., Transplant. Proceed. 27:3383-3384 (1995)). Pyruvate is physiologically formed from glucose and is needed in the tricarboxylic acid cycle for producing the cell's energy. It can therefore be expected that a slow enzymatic release of L-cysteine in the cells of the body has a retarding effect which would give rise to hope for a more lasting efficacy as compared to N-acetylcysteine.
Surprisingly, it was found that the treatment with a combination of 2-methyl-thiazolidine-2,4-dicarboxylic acid and paracetamol does not only prevent the destruction of the cellular defense system but also builds up a lasting efficacy of the mixture of 2-methyl thiazolidine-2,4-dicarboxylic acid and paracetamol. This points to an enzymatically controlled release of L-cysteine from 2-methyl-thiazolidine-2,4-dicarboxylic acid. Moreover, the findings after a monotherapy using a combination of 2-methyl-thiazolidine-2,4-dicarboxylic acid and paracetamol show that this substance is well tolerated by the liver.
The pharmaceuticals of the invention can be designed for oral, rectal, subcutaneous, intravenous or intramuscular administration.
The pharmaceuticals of the invent-ion are produced in a generally known way using the common solid or liquid substrates or diluents and the commonly used adjuvants of pharmaceutical engineering, their dosage depending on the intended application. Preferred preparations are forms of application suitable for oral administration. Such forms of application include tablets, film tablets, lozenges, capsules, pills, powder, solutions or suspensions, or depot systems.
Parenteral preparations such as injection solutions can also be taken into consideration, of course. Another example of suitable preparations is suppositories.
The respective tablets can be produced, for example, by intermixing the active ingredient with known adjuvants, e.g. inert diluents such as dextrose, sugar, sorbitol, mannite, polyvinylpyrrolidone, blasting agents such as corn starch or alginic acid, binding agents such as starch or gelatin, lubricants such as magnesium stearate or talc and/or agents for producing a depot effect such as carboxyl polymethylene, carboxylmethyl cellulose, cellulose acetate phthalate, or polyvinyl acetate. The tablets may also consist of multiple layers.
Accordingly, lozenges can be produced by coating the cores produced in a similar way as the tablets with agents that are typically used in lozenge coatings, e.g. polyvinylpyrrolidone or shellac, gum arabic, talc, titanium dioxide, or sugar. The lozenge coating may consist of multiple layers, and the adjuvants listed above for tablets can be used here as well.
Solutions or suspensions with the active agent of the invention may further contain sweetening agents such as saccharin, cyclamate or sugar as well as aromatizers such as vanillin or orange extract. They may further contain suspending agents such as sodium carboxymethyl cellulose or preservatives such as p-hydroxybenzoates. Capsules containing active ingredients can be produced, for example, by mixing the active agent with an inert carrier such as lactose or sorbitol and encapsulating it in gelatin capsules.
Suitable suppositories can be produced, for example, by intermixing with the respective substrates such as neutral fats or polyethylene glycol or their derivatives.
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Rommelspacher Hans
Susilo Rudy
Wlodek Lidia
Rose Shep K.
Susilo Rudy
Wood, Philips, Katz Clark & Mortimer
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