Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1998-02-02
2001-08-07
Travers, Russell (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
06271254
ABSTRACT:
BACKGROUND OF THE INVENTION
The present invention relates to pharmaceutical compositions containing R-&agr;-lipoic acid or S-&agr;-lipoic acid as an active ingredient. The compositions are useful because they inhibit, for example, acute inflammation as well as inflammatory pain and they possess a specific cytoprotective activity.
&agr;-lipoic acid is 1,2-dithiacyclopentane-3-valeric acid.
&agr;-lipoic acid is widely distributed in plants and animals in the form of the R-enantiomer; it acts as coenzyme in many enzymatic reactions, constitutes a growth factor for a number of bacteria and protozoa and is used in death-head fungus poisoning. In addition, the &agr;-lipoic acid racemate displays anti-inflammatory, antinociceptive (analgesic) and cytoprotective properties.
SUMMARY OF THE INVENTION
It has now surprisingly been found that, in the case of the purely optical isomers of &agr;-lipoic acid (R- and S-form, i.e. R-&agr;-lipoic acid and S-&agr;-lipoic acid), unlike the racemate, the R-enantiomer mainly has an anti-inflammatory activity and the S-enantiomer mainly has an antinociceptive activity, the anti-inflammatory activity of the R-enantiomer also, for example, being stronger by a factor of 10 than that of the racemate. The antinociceptive (analgesic) activity of the S-enantiomer is for example stronger by a factor of 5 to 6 than that of the racemate. The enantiomers therefore constitute very much more specific and stronger acting active substances than the racemate.
The following differences exist in particular in comparison to &agr;-lipoic acid, i.e. to the racemate:
The R-enantiomer acts mainly as an anti-inflammatory and the S-enantiomer mainly as an analgesic, the optical isomers of &agr;-lipoic acid being a number of times stronger (for example by at least a factor of 5) than the racemate of -lipoic acid.
It is therefore an object of the present invention to provide improved pharmaceutical compositions which have, in particular, analgesic and anti-inflammatory activity.
The invention relates to pharmaceutical compositions containing as active ingredient either R-&agr;-lipoic acid or S-&agr;-lipoic acid (i.e. the optical isomers of &agr;-lipoic acid) or a pharmaceutically acceptable salt of these optical isomers of &agr;-lipoic acid, the preparation thereof and the use of the optical isomers of &agr;-lipoic acid or salts thereof for the preparation of appropriate pharmaceutical compositions. These are particularly suitable for combatting pain and inflammation. A cytoprotective activity is also obtained.
The amounts by weight set out herein relate, in each case, to the purely optical isomers of &agr;-lipoic acid, i.e. not to the salts. When salts are used, the appropriate amounts must correspond in each case to the amounts of the free acid and be increased according to the gram-molecular weight of the salt.
The optical isomers of &agr;-lipoic acid, i.e. R-&agr;-lipoic acid and S-&agr;-lipoic acid are preferably used as free acids. In aqueous solutions the salts are preferably used with pharmaceutically acceptable salt formers.
The preparation of R-&agr;-lipoic acid and S-&agr;-lipoic acid and of salts thereof is effected in known manner-or in an analogous manner.
Salt formers that may be considered for R-&agr;-lipoic acid and S-&agr;-lipoic acid are, for example, conventional bases or cations which are physiologically acceptable in the salt form. Examples include: alkali metals or alkaline earth metals, ammonium hydroxide, basic amino acids such as arginine and lysine, amines having the formula NR
1
R
2
R
3
in which the radicals R
1
, R
2
and R
3
are the same or different and represent hydrogen, C
1
-C
4
-alkyl or C
1
-C
4
-oxyalkyl, such as mono- and diethanolamine, 1-amino-2-propanol, 3-amino-1-propanol; alkylene diamine with an alkylene chain consisting of 2 to 6 carbon atoms, such as ethylenediamine or hexamethylene tetramine, saturated cyclic amino compounds having 4-6 ring carbon atoms such as piperidine, piperazine, pyrrolidine, morpholine; N-methylglucamine, creatine, tromethamine.
In, for example, the acid writhing pain test in the mouse and in the Randall-Selitto inflammatory pain test in the rat, the S-enantiomer (S-&agr;-lipoic acid) displays an analgesic activity (peroral application) which is superior by at least a factor of 5 or 6 to that of &agr;-lipoic acid (i.e. the racemate).
Thus, for example, the above mentioned acid writhing test yielded an analgesically active ED
50
of the S-&agr;-lipoic acid of 10.2 mg/kg per os (ED
50
of the racemate 51.3 mg/kg per os). In the above mentioned Randall-Selitto test; the analgesically effective ED
50
of S-&agr;-lipoic acid is 7.5 mg/kg per os (ED
50
of the racemate 45.9 mg/kg).
In, for example, carragheen-induced oedema in the rat the R-enantiomer (R-&agr;-lipoic acid) shows an anti-inflammatory activity (peroral application) which is superior by at least a factor of 10 to that of racemic &agr;-lipoic acid.
For example, the above mentioned carragheen-induced oedema test yielded an anti-inflammatorily active ED
50
of the R-enantiomer of 4.9 mg/kg per os (ED
50
of the racemate 49.7 mg/kg).
The minimum analgesically effective dose of S-&agr;-lipoic acid in the Randall-Selitto pain test is, for example, 1 mg/kg per os.
The minimum anti-inflammatorily effective dose of R-&agr;-lipoic acid in the carragheen-induced oedema test is, for example, 1 mg/kg per os.
Similarly, both the R- and the S-form display cytoprotective activity in animal experiments with a dose of as little as 10 mg/kg per os.
In addition, R- and-S-&agr;-lipoic acid surprisingly possess a growth-inhibiting activity against retroviruses, in particular human immunodeficiency virus HIV (HIV-1, HIV-2) and are, therefore, also suitable for the treatment of disorders caused by viruses of this type.
They possess a good growth-inhibiting activity in HIV (Types 1 and 2) which may be demonstrated in vitro for example by means of the following virological and cell biological test procedures:
1. Plaque reduction test
2. CPE reduction test
3. Determination of reverse transcriptase in culture supernatant
4. Determination of p24 antigen in culture supernatant
Thus, for example, a single dose of 0.035 mg/ml reduces the number of infectious viruses (for example HIV-1) in cell culture supernatant from 100% in the positive control to 0%. A virus-inhibiting activity can be demonstrated in this test procedure even in very small doses, for example 0.001 mg/ml.
The general dosage range for the activity (experiment as above) may for example be: 0.0035-0.091 mg/ml, in particular 0.035-0.070 mg/ml.
In the case of the in vitro experiments the active ingredient is used, for example in benzyl alcohol as solvent.
The following substrates may, for example, be used for the in vitro investigations of the replication behavior of retroviruses, in particular HIV:
1. Virus-containing RPMI 1640 medium, for example 1X liquid 041-01875 (synthetic culture medium from Gibeo according to Moore, Gerner and Franklin, H. A. (1967), J.A.M.A. 199; 519) in a concentration of 2×10
3
-1×10
4
infectious units (PFU)/ml
2. The cell lines Jurkat Clone E6-1, Sup T1 and HeLa CT4.
The pharmaceutical formulations contain in general between 50 mg to 3 g as a single dose, preferably 100 mg to 1 g of R- or S-&agr;-lipoic acid. The dose per kg of body weight should be between 3.5 and 200 mg, preferably between 7 and 100 mg, in particular between 35 and 70 mg/kg body weight.
The active ingredient should be released slowly from the formulations.
Administration may for example be in the form of tablets, capsules, pills, coated tablets, aerosols or suppositories, or in liquid form.
Liquid forms of application that may, for example, be considered are: alcoholic or aqueous solutions as well as suspensions and emulsions.
Preferred dosage forms are, for example, tablets containing between 100 mg and 2 g or solutions containing between 10 mg to 2 g/ml of liquid of active ingredient.
The single dose of active ingredient of may for example be:
a) in the oral medicinal: form between 100 mg-3 g, preferably
Engel Jurgen
Hettche Helmut
Ulrich Heinz
Weischer Carl-Heinrich
Asta Pharma Aktiengesellschaft
Pillsbury Madison & Sutro LLP
Travers Russell
LandOfFree
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