Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1996-07-03
1997-11-25
Reamer, James H.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
514970, A61K 31445
Patent
active
056913524
DESCRIPTION:
BRIEF SUMMARY
The present invention is directed to a chemically stable pharmaceutical composition containing ibuprofen in combination with terfenadine, wherein the oxidation of terfenadine to terfenadone is prevented by the presence in the composition of an .alpha.-hydroxy carboxylic acid.
BACKGROUND
As known to those skilled in the art, many of the products currently available for the treatment of the symptomatology associated with ailments such as the common cold, seasonal rhinitis, sinus headaches, sinusitis, etc., contain multiple therapeutic agents. Many of these products contain an antihistamine in combination with an analgesic. They can also contain a sympathomimetic decongestant. These combination products are convenient for the patient since they allow the patient to obtain relief from numerous symptoms without taking multiple medications.
A variety piperidinoalkanol derivatives possessing antihistaminic properties are disclosed in U.S. Pat. Nos. 3,878,217, 4,254,129 and 4,285,957. Specifically included within the scope of these patents is nebutanol, known by its generic name terfenadine. This agent is commercially available and has experienced widespread acceptance by consumers and can be used according to the present invention as the free compound or as a pharmaceutically acceptable salt thereof as described in the above patents.
Recently, attempts have been made to produce dosage forms which contain these piperidinoalkanol antihistamines in combination with other therapeutic agents.
The pharmaceutical literature contains numerous examples of compounds which interact in the solid state when mixed. This interaction often results in the degradation of one or more of the mixture's components. Terfenadine and ibuorofen are examples of compounds which undergo such an interaction. By itself, terfenadine is chemically and physically stable. When combined with the nonsteroidal anti-inflammatory agent ibuprofen, however, terfenadine exhibits both physical and chemical incompatibilities. Neither terfenadine nor ibuprofen is hygroscopic, yet mixtures begin to cake shortly after preparation when stored at room temperature. The primary manifestation is an increase in the rate at which terfenadine is oxidized to its major degradation product, terfenadone. Terfenadone production is inhibited when tartaric acid is added to the mixtures. Since tartaric acid possesses only mild reducing properties, it is likely that its ability to inhibit terfenadone production is due to something other than antioxidant action. Previously, we have shown that terfenadine forms acid-base salts with both ibuprofen and tartaric acid. Here we examine tartaric acid's ability and the ability of other carboxylic acids to inhibit the oxidation of terfenadine in the presence of ibuprofen.
SUMMARY OF THE INVENTION
The degradation of terfenadine to terfenadone in mixtures containing ibuprofen alone or ibuprofen and unsubstituted dicarboxylic acids follows a diffusion controlled model. Adding .alpha.-hydroxy carboxylic acids, however, inhibits terfenadone production in the mixtures and brings the topochemical degradation under kinetic control. These results, along with infared absorption data and physical considerations, suggest the formation of hydrogen bonded terfenadine-.alpha.-hydroxycarboxylic acid complexes. The inhibition of terfenadone production may be due to the involvement of terfenadine's secondary alcohol in the complex formation.
DETAILED DESCRIPTION OF THE INVENTION
A therapeutically effective antihistaminic amount of terfenadine is that amount which produces the desired antihistaminic response upon oral administration, and as known to those skilled in the art this amount can vary widely. Typically, the amount required to produce this result will vary from about 0.1 mg to about 140 mg. The preferred therapeutically effective antihistaminic amount will vary from about 20 mg to about 70 mg. The tablets will generally contain about 60 mg of terfenadine. In determining the therapeutically effective antihistaminic amount, a number of fac
REFERENCES:
patent: 4254129 (1981-03-01), Carr et al.
patent: 4285957 (1981-08-01), Carr et al.
patent: 4999226 (1991-03-01), Schock et al.
patent: 5512300 (1996-04-01), Weng et al.
Ertel Keith D.
Long David F.
Merrell Pharmaceuticals Inc.
Reamer James H.
Sayles Michael J.
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