Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Carbohydrate doai
Patent
1995-12-04
1998-05-26
Reamer, James H.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Carbohydrate doai
514284, A61K 31435, A61K 918
Patent
active
057564833
DESCRIPTION:
BRIEF SUMMARY
This invention is related to pharmaceutical compositions for nasal administration of dihydroergotamine, apomorphine and morphine, and methods of administering such compositions.
Dihydroergotamine mesylate (DHE) has been used in migraine therapy already for a long time. In patients with migraine attacks, DHE is suitable for basic interval treatment using tablets or solution, both for oral application, as well as for acute treatment by intravenous or intramuscular injection. DHE has been introduced in a nasal spray to avoid the parenteral and the oral route of administration. The nasal spray seems a good alternative, because it is less painful, less expensive and less inconvenient than injection therapy. Secondly, nausea and vomiting are common in migraine patients, making a nasal spray much more efficient than oral treatment.
A nasal spray containing DHE 4 mg/ml in an aqueous solution has been studied extensively by a number of investigators. Some of these investigators report, that besides DHE the nasal spray also contains glucose 5% and caffeine 1%. It was found that 1 mg of DHE, nasally administered, had the equivalence of 10 mg orally, and almost 40% of the bioavailability of the i.m. administration (PG Andersson and LT Jespersen, Cephalalgia 1986; 6: 51-54).
The maximal venoconstrictor effect of 1 mg nasal DHE amounted to about 40%, of 0.5 mg i.m. DHE to about 50% of the initial venous diameter (W. H. Aellig and J. Rosenthaler, Eur. J. Clin. Pharmacol. 1986; 30: 581-584).
Nasal DHE appeared to be equally effective than a combination of oral ergotamine and caffeine in relieving migraine attacks (D. Hirt et al, Cephalalgia 1989; 9, suppl. 10: 410-411). Another study in 904 patients confirmed the efficacy of nasal DHE and reported side effects in 18.4% of patients: nasal irritation, nausea, vomiting, fatigue, vertigo, breathlessness, tachycardia and perspiration. Only 3.9% of the patients refused further treatment with nasal DHE (G. Jenzer and M. F. Bremgartner, Schweiz. Rundsch. Med. Prax. 1990: 79: 914-917). Lataste et al (Cephalalgia 1989; 9 suppl. 10: 342-343) and Di Serio et al (Cephalalgia 1989; 9 suppl. 10: 344-345), confirm the efficacy of nasal DHE in the acute management of migraine. In contrast, Tulunay et al (Cephalalgia 1987; 7: 131-133) found little difference in nasal DHE and placebo.
Most of these studies are very encouraging and therefore nasal DHE, in the pharmaceutical composition studied by the above mentioned authors, seems an interesting alternative for oral and parenteral DHE preparations. Nasal DHE in the composition of DHE mesylate 4 mg/ml in 5% glucose and 1% caffeine, is available on prescription in several countries (e.g. Switzerland, France, Belgium).
Nevertheless, there is an urgent need for another DHE nasal drug formulation, because the nasal preparation, presently on the market, is not stable. It is on the market as a separate glass ampoule (containing the DHE formulation) which has to be broken by the patient and sprayed in the nose using a separate spray device. After opening of the ampoule, the spray can be used no longer than 24 hours.
Accordingly, it is an object of the invention to provide a highly stable pharmaceutical composition, suitable for nasal administration, capable of introducing efficiently a therapeutical amount of DHE into the human body. It has surprisingly been found that a pharmaceutically acceptable DHE composition can be formulated, suitable for nasal administration, without the presence of a special caffeine-glucose vehicle and without the necessity of presenting the formulation in a separate glass ampoule.
According to the invention, the nasal pharmaceutical composition contains DHE and/or a salt of DHE (mesylate or tartrate) and a cyclodextrin and/or other saccharides and/or sugar alcohols. Such compositions appear to result in a surprisingly high bioavailability and a superior stability of DHE.
The term "cyclodextrins" refers to cyclic oligosaccharides, like .alpha.-, .beta.- and .gamma.-cyclodextrin and their derivatives, preferably .beta.-cycl
REFERENCES:
patent: 4727064 (1988-02-01), Pitha
patent: 5602112 (1997-02-01), Rubinfeld
Deutsche Apotheker Zeitung, vol. 130, No. 44, Nov. 1, 1990. pp. 2411-2415, Hermens and Merkus, Entitled "Nasale Arneimittel".
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