Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – C-o-group doai
Reexamination Certificate
2000-08-15
2002-03-26
Fay, Zohreh (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
C-o-group doai
C514S415000, C514S569000, C514S570000, C514S629000
Reexamination Certificate
active
06362234
ABSTRACT:
BACKGROUND OF THE INVENTION
This invention relates to the field of pharmaceuticals. More specifically, this invention relates to prodrugs of propofol that are water soluble and non-toxic.
Propofol (2,6-diisopropylphenol) is a low molecular weight phenol that is widely used as an intravenous sedative-hypnotic agent in the induction and maintenance of anesthesia or sedation in humans and animals. Among its advantages as an anesthetic are rapid onset of anesthesia, rapid clearance, and minimal side effects.
Propofol has a broad range of biological and medical applications. For example, it has been reported to be an anti-emetic (Castano et al.,
Rev. Esp. Anestesiol. Reanim.
42(7):257-60 (1995)), an anti-epileptic (Kuisma M. et al.
Epilepsia
36(12):1241-1243 (1995)) and an anti-pruritic. (Borgeat, A. et al.,
Anesthesiology
80:642-56 (1994); Lawson, S. et al.,
Brit. J. Anesthesia
64:59-63 (1990).)
Migraine has been a well known medical problem for many years and represents one of the most investigated types of head pain. Epidemiological research has shown that in the United States, 18% of women and 6% of men suffer from migraine headaches. This extrapolates to approximately 18 million females and 5.6 million males over the age of 12 with this disorder. The prevalence of migraine, according to the Center for Disease Control, has increased 60% from 1981 to 1989. While migraine can occur at any age, 30% of migraine sufferers report their first attack before the age of ten, and the condition is most common in adolescents and young adults. The economic impact of migraine is staggering, with annual cost of the disease estimated at 18 billion dollars.
In 1938, Graham and Wolff developed the vascular hypothesis of migraine. They suggested that contraction of the intracranial arteries caused a reduction in blood flow to the visual cortex in the occipital lobe, resulting in the focal neurological symptoms (“aura”) that accompany a migraine episode. As a consequence, the head pain that followed was the result of extra-cranial vasodilatation of the external carotid system, along with nerve compression in the carotid artery wall. These conclusions were based on the observation that the vasoconstricting drug ergotamine tartrate dampened pulsation of the superficial temporal artery (an end branch of the external carotid artery), resulting in migraine pain relief.
Despite the fact that the vascular model has been a dominant concept in migraine pathophysiology, several difficulties arising from this theory have been noted. These include the fact that during a common migraine attack, only minor changes in cerebral blood flow have been noted. Furthermore, oligemia, a phase of reduced blood flow, lasts for several hours longer than the aura. Lastly, the reduced blood flow is not sufficient to induce ischemia, alter neuronal function, and produce the aura phase. As a consequence of these criticisms, the central theory of migraine has been proposed.
The central theory suggests that spreading oligemia is the consequence of spreading neuronal depression, which begins as a result of decreased neuronal function in the occipital poles of the brain and progresses forward at a rate of two to three millimeters per minute. The spreading depression involves the depolarization of neurons and has associated with it marked cellular ionic abnormalities. The resulting lowered levels of cellular magnesium increase the likelihood of this type of spreading neuronal depression occurring. This repression of neural function results in a spreading oligemia that can last up to four to six hours. It progresses anteriorly, in a wave-like fashion, over the areas perfused by the middle and posterior cerebral arteries, temporarily impairing cortical vascular functioning. As a result, the aura of migraine may be the result of spreading depression, “a phenomenon originating within brain neurons and involving cerebral blood vessels only secondarily.”
Many researchers have felt that serotonin (i.e., 5-hydroxytryptamine, “5HT”) is the specific neurochemical cause of migraine. Platelets contain all of the 5HT normally present in blood, and after they aggregate, 5HT is released, resulting in a potent vasoconstricting effect. During a migraine attack, platelet 5HT increases in the aura phase and diminishes in the headache phase. Following a migraine attack, there is an increase in urinary 5-hydroxyindolacetic acid (5-HIAA), the main metabolite of serotonin.
While the concept of spreading neuronal depression and oligemia may explain the migraine aura, it does not account for the ensuing headache. Migraine head pain may be the result of inflammation in the trigeminovascular system (TVS). This theory suggests that the trigeminal nerve fibers innervating cranial vessels are an important component of an elaborate defense network protecting the brain from an actual or perceived insult. Inflammatory neurotransmitters such as substance P, calcitonin gene-related peptide and neurokinin A are released by the fifth cranial nerve. This release signals adjacent meningeal blood vessels to dilate. The resulting neurogenic inflammation sensitizes the neurons and this induces head pain.
A recent report has disclosed that propofol is highly effective at alleviating migraine symptoms (Krusz et al.
Headache
40: 224-230 (2000)). A limiting disadvantage of propofol is that it is almost completely insoluble in water. Therefore, before it can be used for intravenous applications, such as treating migraine, it must be specially formulated in aqueous media using solubilizers or emulsifiers. The early developmental studies with intravenous propofol were performed with clear formulations containing the solubilizer Cremophor EL®. Later developmental studies and the current commercial products use an oil-in-water emulsion in which the emulsifier is the lecithin mixture Intralipid®. The commercial products are sold under various names including Diprivan®, Disoprofol®, Disoprivan®, and Rapinovet®.
Formulations that contain solubilizers or emulsifiers have been fraught with problems. Formulations containing the solubilizer Cremophor EL® have been reported to cause allergic complications (Briggs et al.,
Anesthesis
37:1099 (1982)). Stable emulsions are technically difficult to prepare and are consequently more expensive. Microbial growth has sometimes been observed in such emulsions and is believed to be supported by the emulsifier components (McHugh et al.,
Can. J. Anaesth.
42(9):801-4 (1995)). Moreover, currently available commercial formulations contain approximately 1% propofol, necessitating a large volume of administration.
Other investigators have sought to overcome the problem of water insolubility by incorporating the propofol within a water-soluble carrier such as a cyclodextrin. Such a molecular complex allows delivery of propofol in a clear water solution and the eventual release of propofol in vivo. Unfortunately, the cyclodextrin complex produced cardiovascular complications in vivo, discouraging further study (Bielen et al.,
Anesth. Analg.
82(5):920-4 (1996)).
Patients undergoing surgery who are anesthetized using presently available propofol formulations will likely be treated with these formulations very rarely, and most likely only once or twice during their lifetime. Thus, although current propofol preparations used for anesthesia are associated with measurable risk and other undesirable characteristics, the rarity of their repeated administration to a particular individual ameliorates, to a degree, the undesirability of these formulations. The presently used formulations are, however, inappropriate for the continued, intermittent administration necessary for the treatment and prophylaxis of migraine headaches. Thus, in view of the efficacy of propofol in the treatment of migraine, it would be highly desirable to provide to migraine sufferers a treatment method utilizing a water-soluble formulation, which is free from the difficulties associated with present oil and water emulsions of propofol.
A published PCT application naming the prese
Fay Zohreh
Kwon Brian-Yong
Townsend and Townsend / and Crew LLP
Vyrex Corporation
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