Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Implant or insert
Reexamination Certificate
2001-11-01
2003-11-18
Page, Thurman K. (Department: 1615)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Implant or insert
C424S434000, C424S451000, C424S456000, C424S464000, C424S045000, C514S327000
Reexamination Certificate
active
06649183
ABSTRACT:
1. FIELD OF THE INVENTION
The invention relates to methods of treatment, management, or prevention of apnea, apnea disorders, or symptoms thereof.
2. BACKGROUND OF THE INVENTION
Apnea is defined in
Stedman's Medical Dictionary,
26
th
Edition, Williams and Wilkins (1995), as the absence of breathing. There are a number of disorders associated with apnea, which are characterized by interrupted breathing in which a person stops breathing long enough to decrease the amount of oxygen and increase the amount of carbon dioxide in the blood and brain. Each type of apnea involves the absence of airflow at the nose or the mouth, typically for at least 10 seconds.
Various apnea disorders exist, including: central apnea, which results from medullary depression and inhibits respiratory movement; deglutition apnea, which is the inhibition of breathing during swallowing; obstructive or peripheral apnea, which is either a result of obstruction of air passages or inadequate respiratory muscle activity; sleep apnea, which is central and/or obstructive apnea during sleep; and sleep induced apnea, which results from failure of the respiratory center to stimulate adequate respiration during sleep.
Obstructive apneas usually occur in obese men and are much less common in women. The obesity, perhaps in combination with aging body tissues and other factors, leads to narrowing of the upper airways. Tobacco smoking, excessive alcohol use, and lung diseases, such as emphysema, increase the risk of developing obstructive apneas.
For those suffering from sleep apnea, quitting smoking, avoiding excessive use of alcohol, and losing weight are commonly the first behavioral steps for treating the disorder. In order to inhibit or avoid apnea, heavy snorers and people who often choke in their sleep should not take tranquilizers, sleep aids, and other sedating drugs.
Sleep apnea is one of the most common forms of apnea. Rarely, a person who has severe sleep apnea needs a tracheostomy, as surgical procedure that creates a permanent opening into the windpipe through the neck. Sometimes other surgical procedures are performed to widen the upper airway and alleviate the problem. However, such extreme measures are seldom needed and never desired.
Apnea can also be treated by non-invasive means, such as therapeutic drugs, by administering to a patient a therapeutic agent. U.S. Pat. No. 5,075,290 discloses the medical treatment of obstructive sleep apnea and associated symptoms, such as snoring, by the administration of the nucleoside uptake blocker, dipyridamole, during sleep. U.S. Pat. Nos. 5,502,067 and 5,407,953 disclose a method of treating sleep apnea, hyponea and snoring in a human patient by administering a pilocarpine compound. U.S. Pat. No. 5,422,374 discloses a method of treating sleep apnea by the administration of ubidecarenone to a patient. U.S. Pat. No. 5,356,934 discloses a method of employing (R)-fluoxetine to treat sleep apnea.
Ondansetron, which is available commercially only as a 1:1 racemic mixture of its R and S enantiomers, is a well known anti-emetic agent. Commonly administered as a hydrochloride salt, it is an antagonist of the 5-hydroxytryptamine (5-HT or serotonin) receptor, subtype 5-HT
3
. The role of serotonin has been broadly implicated in a variety of conditions for many years. See, e.g., Phillis, J. W.,
The Pharmacology of Synapses,
Pergamon Press, Monograph, 43 (1970); Frazer, A. et al.,
Annual Rev. of Pharmacology and Therapeutics,
30:307-348 (1990). Research has focused on locating the production and storage sites of serotonin, as well as on the location of serotonin receptors in the human body, to determine the connection between these sites and various disease states or conditions.
Most research regarding the compound ondansetron has been directed to understanding its ability to reduce chemotherapy- and radiotherapy-induced emesis. See, e.g., Naylor, R. J. et al.,
Euro. J. Anaesth.,
9:3-10 (1992). The usefulness of racemic ondansetron in this regard is quite clear. For example, its use as an antiemetic by either intravenous or oral routes is disclosed in U.S. Pat. Nos. 4,753,789 and 4,929,632. Recently, it has been reported that the optically pure R(+) stereoisomer of ondansetron is also useful for treating emesis. Specifically, U.S. Pat. No. 5,712,302 discloses methods and compositions utilizing R(+) ondansetron for the treatment of nausea and vomiting associated with chemotherapy and radiation therapy.
Although the ability of both racemic and optically pure ondansetron to antagonize retching and vomiting has encouraged research, many questions concerning the pharmacology of the compound remain unanswered. Kesai, K. M.,
Br. J. Pharmacol.,
111:346-350 (1994). Current understanding is based upon the fact that racemic ondansetron is an antagonist of serotonin 5-HT
3
receptors. Serotonin is a neurotransmitter that has powerful vasoconstrictor properties, and is capable of depolarizing the sympathetic nerve fibers to the heart. Fozard, J. H. et al.,
Br. J. Pharmacol.,
57:115-125 (1976). Along with other types of 5-HT receptors found in mammals, 5-HT
3
receptors have been located in the mammalian hind-brain, peripherally on the vagal nerve, and on neuronal elements in the gastrointestinal tract. It has been theorized that physical disruptions of the gastrointestinal tract can somehow cause the release of humoral substances including serotonin, which stimulate receptors on the vagal nerves and which in turn trigger the emetic reflex. Naylor, R. J. et al.,
Euro. J. Anaesth.,
9:3-10 (1992).
It is desirable to provide methods of treating, preventing, or managing apnea and apnea disorders, including sleep apnea, or symptoms thereof.
3. SUMMARY OF THE INVENTION
The present invention encompasses the use of optically pure R(+) ondansetron, or a pharmaceutically acceptable salt thereof, substantially free of its S(−) stereoisomer, in preventing, treating or managing apnea or apnea disorders, or symptoms thereof in a patient. The invention also encompasses the use of optically pure R(+) ondansetron, or a pharmaceutically acceptable salt thereof, substantially free of its S(−) stereoisomer, in treating these disorders while avoiding or decreasing adverse effects including, but not limited to, headache, constipation and increases in transaminase levels which are associated with the racemic mixture of ondansetron. It should be understood that the invention encompasses any combination of preventing, treating, or managing apnea or apnea disorders.
This invention also encompasses compositions adapted for the treatment of a patient suffering from apnea or related diseases, or symptoms thereof, which comprises a therapeutically effective amount of R(+) ondansetron, or a pharmaceutically acceptable salt thereof, substantially free of its S(−) stereoisomer; and a pharmaceutically acceptable carrier. The invention encompasses single unit dosage forms that comprise from about 0.001 mg to about 35 mg of optically pure R(+) ondansetron, or a pharmaceutically acceptable salt thereof, substantially free of its S(−) stereoisomer, i.e., an amount particularly suitable for the prevention, treatment, or management of apnea and apnea disorders. In one embodiment, the pharmaceutical compositions of the present invention encompass a solid unit dosage form comprising from about 10 mg to about 35 mg of optically pure R(+) ondansetron, or a pharmaceutically acceptable salt thereof, substantially free of its S(−) stereoisomer; and a pharmaceutically acceptable carrier.
4. DETAILED DESCRIPTION OF THE INVENTION
The present invention encompasses the use of optically pure R(+) ondansetron, or a pharmaceutically acceptable salt thereof, substantially free of its S(−) stereoisomer, in preventing, treating or managing apnea or apnea disorders, or symptoms thereof in a patient. Apnea or apnea disorders treated include, but are not limited to, central apnea, deglutition apnea, obstructive or peripheral apnea, sleep apnea, and sleep i
Barberich Timothy J.
Rubin Paul D.
Page Thurman K.
Pennie & Edmonds LLP
Sepracor Inc.
Sheikh Humera N.
LandOfFree
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