Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Radical -xh acid – or anhydride – acid halide or salt thereof...
Patent
1994-06-15
1999-12-21
Henley, III, Raymond
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Radical -xh acid, or anhydride, acid halide or salt thereof...
514570, A61K 31195, A61K 3119
Patent
active
060050055
DESCRIPTION:
BRIEF SUMMARY
The present invention relates to a liquid pharmaceutical composition for oral administration containing 2-(4-isobutylphenyl) propionic acid as the active ingredient, and more particularly, it relate to a liquid pharmaceutical composition containing 2-(4-isobutylphenyl)propionic acid and arginine.
2-(4-isobutylphenyl)propionic acid, hereinafter designated as "Ibuprofen," is a known non-steroidal anti-inflammatory drug (Merck Index XI ed., n.4812, page 476) used in therapy for its analgesic, anti-pyretic and anti-inflammatory activity.
Notwithstanding Ibuprofen's use in therapy for years in its racemic form, (RS)-Ibuprofen, it has been known for some time that the enantiomer with the (S) configuration, (S)-lbuprofen, is the active eriantiomer.
Nevertheless, (R)-Ibuprofen aids in the pharmacological activity of the racemate since it is partially transformed into the (S) enantiomer by the organism. For a bibliographic reference on this subject, see, for example, S. S. Adams et al., J. Pharm. Pharmac., 28, 256-257, (1976).
For simplicity, hereinafter the term Ibuprofen will indicate the (S) form as well as the racemic form.
Liquid injectable formulations containing Ibuprofen and basic amino acids in equimolar amounts are known.
U.S. Pat. No. 4,279,926 (SPA - SocietaProdotti Antibiotici S.p.A.) describes injectable liquid formulations containing (RS)-Ibuprofen lysinate. U.S. Pat. No.4,877,620 (Medice Chem. Pharm. Fabrik Putter GmbH & Co. KG) describes injectable liquid formulations containing a mixture 1:1 of (S)-lbuprofen and lysine.
There are also known solid formulations containing Ibuprofen and a molar excess of basic amino acids which can be used to prepare extemporaneous aqueous solutions.
U.S. Pat. No. 4,689,218 (Zambon S.p.A.) describes an effervescent composition consisting of Ibuprofen 9-17% by weight, arginine 17-33% by weight, sodium or potassium bicarbonate 20-35% by weight, sodium bitartrate 25-40% by weight.
U.S. Pat. No. 4,834,966 (Zambon S.p.A.) describes a pharmaceutical composition consisting of Ibuprofen 33-46% by weight, arginine 34-51% by weight, sodium bicarbonate 9-29% by weight.
However, the formulations containing Ibuprofen and basic amino acids described in the literature are not suitable for the preparation of liquid pharmaceutical forms for oral use such as concentrated aqueous solutions diluted in water at the moment of the administration. In fact, liquid pharmaceutical forms for oral use such as, for example, oral drops, must be chemically and physically stable for a long time even after a first use.
We have now found a liquid pharmaceutical composition for oral use consisting of an aqueous solution of a mixture of arginine and Ibuprofen, in a molar ratio between 1.1 and 1.5, so that the weight/volume concentration of Ibuprofen is equal to or greater than 200 mg/ml, and of optional excipients.
Preferably, L-arginine is used in the compositions of the present invention. More preferably, arginine is used in a molar ratio 1.1 with respect to Ibuprofen.
The excipients optionally present in the pharmaceutical composition of the present invention are the usual excipients suitable for the preparation of liquid pharmaceutical forms for oral use to be diluted at the moment of use, such as sweetening agents, flavoring agents and preservatives.
The liquid pharmaceutical compositions of the present invention are characterized by a remarkable chemical and physical stability.
The stability tests show the absence of precipitation or degradation phenomena assuring a constant titer of the active ingredient for at least 3 years. In particular, the liquid compositions of the present invention have been shown to be stable (i.e., with a practically constant titer of the active ingredient) after 1 year at 50.degree. C., 40.degree. C., 30.degree. C. and room temperature. This is particularly worth noting in the case of highly concentrated aqueous solutions.
Furthermore, the pharmaceutical compositions of the present invention are characterized by a remarkable efficacy and by a rapid onset of the pharmaco
REFERENCES:
International Search Report, dated Jan. 12, 1996, for International Application No. PCT/EP.95/03676.
Journal of the American Chemical Society, vol. 79, No. 18, Sep. 24, 1957, Washington, D.C., pp. 5019,5023.
Journal of Organic Chemistry, vol. 41, No. 26, Dec.24, 1976, Washington, D.C. pages L. R. Subramanian, et al, "On attempts at solvolytic generation of aryl cations," compound 9, p. 4100.
T. H. Coffield et al, "Some reductions of 2,6-dialkylphenols," (1980) J. of Org. Chem. vol. 41, No. 26, p. 5023.
Bonadeo Daniele
Gazzaniga, deceased Annibale
Gazzaniga, legal representative by Paola Maria
Stroppolo Federico
Vigano Luigi
Henley III Raymond
Zambon Group S.p.A.
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