Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form
Reexamination Certificate
2002-04-26
2004-02-03
Page, Thurman K. (Department: 1615)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
C424S422000, C424S434000, C424S435000, C424S451000, C424S484000
Reexamination Certificate
active
06685951
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to the use of dihydroergotamine for the treatment of migraine headaches via sublingual administration.
BACKGROUND OF INVENTION
Migraine is the most common neurological condition in the developed world. It affects 10% of the U.S. population and is more prevalent than diabetes, epilepsy and asthma combined. Migraine is more than just a headache. It can be a debilitating condition which has a considerable impact on the quality of life of sufferers and their families. Attacks can be completely disabling, forcing the sufferer to abandon everyday activities for up to 3 days. Even in symptom-free periods, sufferers may live in fear of the next attack. Migraine attacks normally last between 4 and 72 hours and sufferers are usually symptom free between attacks.
Migraine is believed to be caused by the release of a chemical called serotonin or 5HT into the bloodstream from its storage sites in the body, resulting in changes in the neurotransmitters and blood vessels in the brain. This causes the pain neurons in the blood vessel wall to become irritated. Exactly what cause the release of serotonin is still a subject for research and debate. However, certain factors have been identified which can trigger attacks in susceptible people. Some of these are stress or sometimes the relief of stress, lack of food or infrequent meals, foods containing monosodium glutamate, caffeine and tyramine, certain specific foods like chocolate, citrus fruits or cheese, alcohol (especially red wine), overtiredness (physical or mental), changes in sleep patterns (e.g., late nights or a weekend lie-in), or hormonal factors (e.g., monthly periods, the contraceptive pill or hormonal changes in males and females as they age), etc.
Migraine triggers are numerous and varied and occur in combinations peculiar to each individual. It should be noted that not all migraineurs will be affected by all of the above triggers and possibly by none of them. Everyone has the capacity to suffer from migraine but in some people, most probably because of a genetic predisposition, the threshold at which attacks occur is lower. Migraineurs come from all walks of life, all areas of the world and ethnic groups, and all social classes.
Migraine is a complex condition and a treatment which is successful for one patient may have no effect on another. It is therefore important to continue to develop new methods of treatment and new modes of administration of compounds that show therapeutic potential in mitigating migraines.
What is needed are compounds and drugs that are effective for the treatment of migraines in a formulation that allows for better drug delivery and ease of use by the patient.
SUMMARY OF INVENTION
The present invention relates to the use of dihydroergotamine via sublingual administration for the treatment of migraine headaches. The present invention contemplates both prophylactic and acute treatment of migraine.
Current methods of administering DHE to migraine sufferers have major efficacy limitations. For example, due to degradation in the gastrointestinal track and low adsorption of the drug, oral forms of DHE have to be administered in large doses of about 20-30 mg. These high doses may causes nausea, vomiting and other unwanted adverse side effects. Much of the DHE is subject to pre-systemic and first pass metabolism. Because of this, is it estimated that as little as 2-10% of the active unchanged drug actually reaches the blood stream. Likewise, intranasal administration of DHE is hampered with significant limitations. A 2 mg intranasal dose of a pharmaceutical salt of DHE is required and must be administered as 4 intranasal sprays with subsequent reduced systemic absorption by the unintended oral ingestion of DHE intranasal solution.
Injectable forms of DHE are also available for the treatment of migraines. Although parenteral administration of DHE into the blood stream allows for a lower dose as compared to other non-injectable methods of administration, the inconvenience of an office visit for an injection or problems with the self-administration of injectables are self evident.
Although not limited to any particular mechanism, the present invention contemplates the sublingual administration of DHE in a drug delivery system that adjusts the pH of the local environment thereby allowing for the ready absorption of DHE into the blood stream. This is because the adjustment of the pH permits the conversion of DHE to the more permeable base form. Additionally, the quick-dissolve nature of the formulation of the present invention also aids in the rapid absorption of DHE into the blood stream.
The following description does not limited the present invention to any particular mechanism and is only for illustrative purposes. 5HT agonists (sometimes known as triptans) act directly to correct the serotonin imbalance in the brain during a migraine attack. Dihydroergotamine (DHE), however, belongs to the group of medicines known as ergot alkaloids. DHE is involved in vasoconstriction (narrowing of arteries and veins that supply blood to the head). Dihydroergotamine is also involved in altering blood flow patterns that are associated with vascular headaches.
Migraine drugs are often not suitable for many patients for a variety of reasons. One of the common reasons is that the drugs are given in inconvenient or ineffective modes of administration. Often times the mode of administration may limit the effectiveness of the drug. Furthermore, some patients may have difficulty in self-administering these drugs due to the limited formulations in which they are made available.
The oral modes of administration of DHE for migraine necessitate large doses of DHE to be used, e.g., 20-30 mg for oral administration and 2 mg for nasal administration, respectively. Large doses may cause adverse side effects in the patient. For example, nausea and vomiting are common side effects. One way to reduce the severity of side effects would be to lower the dose of DHE administered to the patient while still maintaining a therapeutic level of DHE at the target site. A sublingual formulation of DHE would permit the use of lower doses of DHE since a greater portion of the medication would be absorbed directly into the blood stream thereby allowing a direct route to the afflicted target area. For example, although the present invention is not limited to any particular dose or dose range, as compared to the current marketed nasal spray formulation, the present invention contemplates about a 25% reduction in dose, giving a preferred dose in of about 1.5 mg. In another embodiment, as compared to the current marketed nasal spray formulation, the present invention contemplates about a 50% reduction in dose, giving a preferred dose of about 1.0 mg, which is the same dose as the parenteral administration. In yet another embodiment, the present invention contemplates a sublingual dose that delivers efficacy about equivalent to intranasal administration. Sublingual formulations of DHE will also allow for ease of administration by the patient. Of course, it will be clear to one practiced in the art that the dosages of DHE administered by the methods contemplated by the present invention may need to be adjusted depending on the weight, age and physical condition of the patient and use of other medications by the patient, etc.
The present invention comprises treating a patient suffering from a migraine headache with a therapeutic dose of dihydroergotamine, or a pharmacologically acceptable salt thereof, in a sublingual formulation. It is contemplated that the DHE may be in the form of dihydroergotamine mesylate or any pharmaceutically acceptable salt. It is contemplated that the sublingual administration of DHE may be made with a fast dissolve formulation.
Although the present invention is not limited to any particular mechanism, it is believed that the adjustment of the pH of the environment of the sublingual area will convert the administered DHE to the more readily absorbable DHE base. The pH of DHE in solution
Joynes Robert M.
Medlen & Carroll LLP
Page Thurman K.
R. T. Alamo Ventures I, Inc.
LandOfFree
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