Inclusion complexes of racemic ibuproxam and of optically active

Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Carbohydrate doai

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514532, 514777, 514965, 536 46, 536103, A61K 4740, C07H 2100

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active

058407146

DESCRIPTION:

BRIEF SUMMARY
TECHNICAL FIELD

The present invention belongs to the field of pharmaceutical industry and relates to novel inclusion complexes of racemic ibuproxam and optically active S-(+)-ibuproxam with cyclodextrin derivatives such as methyl-.beta.-cyclodextrin, dimethyl-.beta.-cyclodextrin, hydroxypropyl-.beta.cyclodextrin, hydroxyethyl-.beta.-cyclodextrin, triacetyl-.beta.-cyclodextrin and, in the case of optically active S-(+)-ibuproxam, also with .beta.-cyclodextrin. The invention also relates to a process for the preparation thereof, to pharmaceutical compositions containing these inclusion complexes or optically active S-(+)-ibuproxam, and to the use thereof in the treatment of inflammations and febrile conditions as well as in alleviating pain.


TECHNICAL PROBLEM

There exists a constant need for preparing novel galenic forms of ibuproxam, racemic as well as optically active one, having improved biopharmaceutical properties such as low toxicity, better antiinflammatory action and non-irritation of gastric mucous membrane.


PRIOR ART

Ibuproxam is a generic name for 2-(4-isobutylphenyl)-propiohydroxamic acid of the formula ##STR1##
The substance was described for the first time in U.S. Pat. No. 4,082,707 as a solid crystalline substance in the form of white shining thin platelets having analgetic, antipyretic and antiinflammatory properties. The substance is soluble in methanol, ethanol, acetone and ethyl ether and is insoluble in water and petroleum ether.
The substance is ibuprofen (2-(4-isobutylphenyl)-propionic acid) prodrug. It has been experimentally confirmed that, irrespective of the ibuproxam application route, there occurs a rapid and almost complete metabolic conversion into ibuprofen. In the article by Orzalesi G. et al., Arzneim.-Forsch./Drug Res. 30 (II), the determination of ibuproxam and ibuprofen in blood is disclosed. The presence of ibuproxam and ibuprofen in blood was measured 15 minutes after application. The value of ibuprofen was 2.5 times higher than the value of ibuproxam, thus indicating a high rate of the conversion of ibuproxam into ibuprofen. In the article by Orzalesi G. et al., Arzneim.-Forsch./Drug Res. 27 (I) there are disclosed comparisons between the properties of ibuprofen and ibuproxam evidencing the same analgetic, antipyretic and antiinflammatory action of both substances. The introduction of hydroxylamine radical into the ibuprofen molecule increases the tolerance of the molecule, which is especially the result of different pharmakinetics of ibuproxam. The latter is less toxic for the mucous membrane of the alimentary tract with the result that the by-effects and toxicity of the active substance are essentially reduced. Simultaneously, the chemical conversion of ibuprofen into ibuproxam makes possible an increase of the transfer rate and an increase of ibuprofen concentration in blood in comparison with ibuprofen. The better bioavailability of ibuproxam in comparison with ibuprofen is the result of different physicochemical properties of either substance. In the same article a comparison between parenteral and peroral application of ibuprofen and ibuproxam is also disclosed. At parenteral application LD.sub.50 is the same for both substances, whereas LD.sub.50 at peroral application of ibuproxam is twice to three times greater than that of ibuprofen.
It is well-known that several biologically active substances exist in the form of a stereoisomeric mixture whereas usually only one isomer is biologically active. It has been proven that only S-(+)-enantiomer of ibuprofen is pharmacologically active. In the body of mammals (in liver and kidneys) R-(-)-enantiomer is to a varying extent converted by means of metabolic steroisomeric inversion into the active form of S-(+)-ibuprofen (Ching-Shih C. et al., Biochimica et Biophysica Acta, 1078 (1991)). According to data from the article by Geisslinger G. et al., Agents and Actions, Vol. 27, 3/4 (1989), in humans only R-(-)-enantiomer, yet only one third thereof, is converted to S-(+)-enantiomer.
In the literature there are disclos

REFERENCES:
patent: 4082707 (1978-04-01), Orzalesi et al.
patent: 4727064 (1988-02-01), Pitha
patent: 4869904 (1989-09-01), Vekama et al.
patent: 4952565 (1990-08-01), Zmitek et al.
patent: 5100918 (1992-03-01), Sunshine et al.
patent: 5324718 (1994-06-01), Loftsson

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