Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Cyclopentanohydrophenanthrene ring system doai
Reexamination Certificate
2000-03-15
2002-12-17
Criares, Theodore J. (Department: 1617)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Cyclopentanohydrophenanthrene ring system doai
C514S250000
Reexamination Certificate
active
06495535
ABSTRACT:
FIELD OF THE INVENTION
The present invention encompasses pharmaceutical compositions containing dihydroergotamine (DHE) and methods in which these pharmaceutical compositions are administered to patients, particularly for the treatment of migraine headaches. The invention also encompasses the packaging of injection syringes prefilled with DHE preparations.
BACKGROUND OF THE INVENTION
Dihydroergotamine (DHE) is an ergot alkaloid that was identified as an effective treatment for migraine nearly fifty years ago (Raskin,
Neurology
36:995-997 (1986); Silberstein, et al.,
Headache
30:334-339 (1990); Saadah,
Headache
32:18-20 (1992); and Winner,
Headache
33:471-475 (1993)). It is presently marketed both as an injectable product (DHE 45®) and as a nasal spray (Migranal®). DHE is typically administered by intramuscular or intravenous injection (Belgrade, et al.,
Neurology
39:590-592 (1989); Winner,
Headache
33:471-475 (1993)), but it is also effective when given subcutaneously (Klapper, et al.
Headache
32:21-23 (1992); Winner, et al.,
Arch. Neurol.
53:180-184 (1996); and Becker, et al.,
Headache
36:144-148 (1996)).
Although effective in the treatment of migraine, DHE administration is often accompanied by side effects such as nausea, vomiting and chest pain (Winner, et al.,
Arch. Neurol.
53:180-184 (1996)). At least one side effect, nausea, occurs more frequently after intravenous administration than after intramuscular or intranasal administration. When given subcutaneously at a concentration of only 1.5 mM, DHE has been reported to cause nausea in nearly 16% of treated patients (Winner, et al.,
Arch. Neurol.
53: 80-184 (1996)). New drug formulations and methods for administering DHE which reduce its adverse side effects would represent a significant advance in migraine therapy.
SUMMARY OF THE INVENTION
The present invention is based upon the discovery that the side effect profile of DHE can be unexpectedly improved when the drug is administered to patients in a novel, high-potency form. More particularly, it has been found that when the concentration of DHE in compositions is increased from 1.5 mM (the concentration in commercially available injectable preparations) to 2.9 mM or more, side effects, particularly nausea, are reduced even though the total quantity of DHE administered remains constant.
In its first aspect, the invention is directed to a pharmaceutical composition in unit dose form containing DHE dissolved in a pharmaceutically acceptable liquid vehicle. The concentration of DHE must be at least 2.9 mM and a “unit dose” should contain a sufficient amount to be effective in the symptomatic treatment of migraine headache when administered to a patient. This means that enough drug must be given to significantly reduce or eliminate migraine-related pain. In order to preserve drug activity, steps should be taken to inhibit the oxidation of DHE. Preferably, this can be accomplished by dissolving sufficient CO
2
and/or N
2
compositions to retard oxidative degradation and/or including one or more antioxidants. Although any salt form of DHE can be effectively used in compositions, dihydroergotamine mesylate at a concentration of 2 mg/ml or more is preferred. A typical example of a formulation might contain 2 mg/ml of DHE in a vehicle containing glycerin and anhydrous alcohol in sterile water for injection, pH adjusted to 3.6 with methanesulfonic acids/sodium hydroxide. If desired, other agents may also be included in pharmaceutical preparations. For example, the rate at which DHE enters the bloodstream of a patient may be adjusted by including vasodilators or uptake enhancers (e.g., caffeine) in compositions.
The invention also includes a method of treating a patient for the symptoms associated with migraine headache by administering one or more unit doses of the pharmaceutical composition described above. Preferably, compositions will contain dihydroergotamine mesylate and sufficient dissolved CO
2
and/or N
2
to retard its oxidative degradation. Subcutaneous injection is preferred in order to obtain the greatest improvement in the side effect profile, but other routes of delivery may also be used. The total dosage of DHE that will be administered to a patient per migraine attack should generally be between 0.5 mg and 5.0 mg. The term “per migraine attack” refers to the period immediately preceding a migraine headache and extending for about the next twenty-four hours. Since headache may recur, it may be necessary to administer a second therapeutic dose of the drug during this period.
In addition, the invention is directed to a process for preparing a therapeutic package in which the unit dose pharmaceutical composition described above is made and then used to prefill a syringe for injection. As used herein, a “prefilled” syringe is one that has been loaded with pharmaceutical composition for a period of at least twenty-four hours prior to the time that it is administered to a patient. In a preferred embodiment, the prefilled syringes are enclosed in an opaque, sealed package from which oxygen has been excluded. For example, oxygen may be displaced with CO
2
and/or N
2
. In addition to including these processes, the present invention also encompasses the therapeutic packages that are their end result.
A surprising discovery that has been made is that caffeine greatly increases the solubility of DHE in aqueous formulations. As a result, compositions having DHE at a concentration of greater than 4, 5 or 6 mM, can be obtained for administration to patients. Caffeine appears to be most effective when present in compositions roughly at a weight ratio of between 0.1:1 and 10:1 relative to DHE. In addition, there are some indications from animal studies that caffeine at high concentrations, e.g., at a 10:1 weight ratio relative to DHE improves drug absorption characteristics, e.g., by producing a more consistent time of absorption.
Based upon these findings, the invention is, in another aspect, directed to a pharmaceutical composition in unit dose form containing: a) DHE in an amount such that one or more unit doses are effective in the symptomatic treatment of migraine headache when administered to a patient; (b) a pharmaceutically acceptable liquid vehicle in which the DHE is dissolved at a concentration of at least 2.9 mM; and (c) caffeine at between a 0.1:1 and 10:1 weight ratio relative to DHE. The most preferred composition contains caffeine in a 1:1 weight ratio. In order to retard the rate of oxidative degradation of the composition, CO
2
and/or N
2
may be dissolved in preparations and one or more antioxidants may be added. Any salt of DHE may be used but the mesylate salt is generally preferred.
The compositions containing caffeine may be used in a method for the symptomatic treatment of patients suffering from migraine headache. Preferably, preparations are administered by subcutaneous injection and, in general, patients will receive a total dosage of between 0.5 and 5.0 mg per migraine attack. The compositions may also be used in a process for preparing a therapeutic package in which a unit dose is present in a prefilled injectable syringe. As part of the process, the prefilled syringes may be enclosed in an opaque, sealed package from which oxygen has been excluded. The invention includes not only these processes for making therapeutic packages but also the packages themselves.
Finally, the invention encompasses improved pharmaceutical compositions and treatment methods involving the combination of DHE at high concentration and caffeine. With respect to unit dose pharmaceutical compositions, the improvement comprises the presence of a concentration of DHE of at least 2 mg/ml; sufficient carbon dioxide and/or nitrogen to retard oxidative degradation; and caffeine at between a 0.1:1 and 10:1 weight ratio relative to DHE. The use of this composition results in an improved method for the symptomatic treatment of a patient suffering from or susceptible to the development of a migraine attack.
REFERENCES:
patent: 4138565 (1979-02-01), Ehrhardt et al.
Gilbert Donna
Plachetka John R.
Criares Theodore J.
Fitch Even Tabin & Flannery
Kim Jennifer
Pozen Inc.
Sanzo Michael A.
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