Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
2000-01-27
2000-12-26
Krass, Frederick
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
514414, 514415, 514970, A61K 3140
Patent
active
061660256
DESCRIPTION:
BRIEF SUMMARY
The present invention relates to pharmaceutical compositions containing eletriptan hemisulphate. More particularly, it relates to aqueous pharmaceutical formulations containing eletriptan hemisulphate that are stabilised by caffeine.
Eletriptan (UK-116,044), 3-([1-methylpyrrolid in-2(R)-yl]methyl)-5-(2-phenylsulphonylethyl)-1H-indole, is a selective 5-HT.sub.1 -like agonist that is being developed for the treatment of migraine. ##STR1##
Eletriptan is described in WO-A-92/06973.
Eletriptan hemisulphate (molecular weight=431.6) has a higher aqueous solubility (>100 mg/ml @ 4.degree. C.) than eletriptan itself and alpha- and beta-polymorphic forms are specifically disclosed in WO-A-96/06842. However, eletriptan hemisulphate is hydrolytically unstable and it is degraded by hydrolysis and oxidation in aqueous solutions. Indeed, a solution of this salt in pH 8 aqueous buffer degrades to leave less than 85% (relative to the original weight) of eletriptan on standing for 12 weeks at 50.degree. C. At least five degradation products have been detected by H.P.L.C. techniques.
This level of stability is highly unsuitable for aqueous pharmaceutical formulations of eletriptan which must have a long shelf-life. Preferably, such formulations should not degrade to leave less than 95% (relative to the original weight) of eletriptan on standing in pH 8 aqueous buffer for 12 weeks at 50.degree. C., and, additionally, the total detectable impurities should not be above 2% by weight after this time.
The object of this invention is to provide a stable, aqueous pharmaceutical formulation containing eletriptan hemisulphate.
A further object of this invention is to provide a stable, aqueous pharmaceutical formulation containing eletriptan hemisulphate that is suitable for intra-nasal and subcutaneous administration and which allows the drug to have good bioavailability and rapid absorption and onset of action when so administered.
Higuchi e al, J. Am. Pharm. Association, XLIV (9), 521 (1955), have reported that caffeine substantially reduces the hydrolytic degradation of benzocaine in aqueous solution.
Samie et al, Pharm. Acta Helv., 58(1), 28 (1983), have shown that caffeine can improve the photochemical stability of certain phenothiazines. However, this is not a general effect for this class of compound. It was similarly found that caffeine also had a variable effect on the non-photochemical degradation of the phenothiazines examined.
It has now been surprisingly found that caffeine stabilises aqueous pharmaceutical formulations containing eletriptan hemisulphate and also improves the solubility thereof.
Further, eletriptan hemisulphate has good bioavailability and rapid absorption and onset of action when administered as caffeine-stabilised formulations by the intra-nasal and subcutaneous routes.
It has also been surprisingly found that the stability of such formulations is further increased by the additional presence of an anti-oxidant (preferably citric acid or ascorbic acid) and/or a co-solvent (preferably ethanol).
The present invention provides an aqueous pharmaceutical composition comprising from 5 to 200 mg/mi of eletriptan hemisulphate and from 0.5 to 2.0% weight/volume of caffeine.
Optionally, an anti-oxidant can be present. Suitable anti-oxidants include citric acid and ascorbic acid. Preferably, up to and including 1.0% weight/volume of citric acid or ascorbic acid can be present.
Optionally, a co-solvent such as ethanol can be present. Preferably, up to and including 20.0% weigh/volume of ethanol can be present.
Preferably, the composition is buffered to a pH of from 4.0 to 9.0.
Preferably, the composition is buffered to a pH of from 7.0 to 9.0.
Preferably, the composition is buffered to a pH of from 7.5 to 8.5.
Preferably, the composition is buffered to about pH 8.
Preferably, the composition is buffered to a pH of from 4.0 to 5.0.
Preferably, from 5 to 150 mg/ml of eletriptan hemisulphate is present.
Preferably, from 10 to 100 mg/ml of eletriptan hemisulphate is present.
Preferably, from 40 to 160 mg/ml of eletr
REFERENCES:
J. Am. Pharm. Association, XLIV (9), 521-527 1955.
Pharm. Acta Helv., 58(1), 28-32 1983.
Pharm. Acta Helv., 58(1), 23-27 1983.
Drug Development and Industrial Pharmacy, 17(11), 1419-36, 1991.
Billotte Anne
Harding Valerie Denise
Benson Gregg C.
Jones James T.
Krass Frederick
Pfizer Inc.
Richardson Peter C.
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