Title:  Compositions including modafinil for treatment of eating disorders and for appetite stimulation

United States Patent:  6,455,588

Issued:  September 24, 2002

Inventors:  Scammell; Thomas E. (Wellesley, MA); Miller; Matthew S. (Newtown, PA)

Assignee:  Cephalon, Inc. (West Chester, PA)

Appl. No.:  640824

Filed:  August 17, 2000

Modafinil is effective in improving symptoms of eating disorders or in stimulating appetite.

DETAILED DESCRIPTION OF THE INVENTION

Modafinil is an agent with activity in the central nervous system, and has been developed as a treatment for excessive daytime sleepiness associated with narcolepsy. The primary pharmacological activity of modafinil, like amphetamine-like agents, is to promote wakefulness. Modafinil promotes wakefulness in rats (Touret, et al., Neuroscience Letters, 189:43-46 (1995); Edgar and Seidel, J. Pharmacol. Exp. Ther., 283:757-69 (1997)), cats (Lin et al., Brain Research, 591:3 19-326 (1992)), canines (Shelton et al., Sleep 18(10):817-826, (1995)) and non-human primates (DS-93-023, pp 180-181; Hernant et al., Psychopharmacology, 103:28-32 (1991)), as well as in models mimicking clinical situations, such as sleep apnea (English bulldog sleep disordered breathing model) (Panckeri et al, 1996) and narcolepsy (narcoleptic canine) (Shelton et al., Sleep 18(10):817-826, (1995)). Modafinil has also been demonstrated to be a useful agent in the treatment of Parkinson's disease (U.S. Pat. No. 5,180,745); in the protection of cerebral tissue from ischemia (U.S. Pat. No. 5,391,576); in the treatment of urinary and fecal incontinence (U.S. Pat. No. 5,401,776); and in the treatment of sleep apneas of central origin (U.S. Pat. No. 5,612,378). U.S. Pat. No. 5,618,845 describes modafinil preparations of a defined particle size less than about 200 microns that is more potent and safer than preparations containing a substantial proportion of larger particles.

Various neuroanatomical pathways have been investigated for their role in inducing and maintaining wakefulness, and some of the work has pointed to the potential role of the tuberomamillary nucleus (TMN) (Sherrin et al., Science 271:216-219, 1996). A study by Lin et al., (Proceedings of the National Academy of Science, USA 93:14128-14133, 1996) demonstrated selective activation of the anterior hypothalamus by modafinil, and the authors of that study also demonstrated that administration of modafinil to cats at a wake-promoting dose failed to cause activation of the TMN of the posterior hypothalamus. A similar study of wake-promoting doses of modafinil administered to rats (Engber et al., Neuroscience, 87:905-911 (1998)) also demonstrated that modafinil-induced wakefulness was not associated with activation of the TMN. Thus, while activation of the TMN has been implicated in normal wakefulness, the studies of these researchers has clearly taught that TMN activation was not involved in modafinil-induced wakefulness.

The present invention arises in part from the discovery that modafinil, when administered at wakefulness-promoting doses, does result in a stimulation of activity in the TMN of the posterior hypothalamus. Modafinil administration in rats reduced the activity of the neurons in the ventrolateropreoptic area (VLPO) of the hypothalamus, which are known to inhibit the activity of wake-promoting histaminergic neurons in the TMN during sleep. Activation of this histaminergic pathway by modafinil results in cortical activation and wakefulness. Thus, it appears that the physiologic basis for the wake-promoting actions of modafinil involves disinhibition of histaminergic neurons of the TMN by inhibitory actions on the VLPO. This represents the first pharmacologic agent known to produce wakefulness by activation of the TMN.

Furthermore, because the lateral hypothalamus is classically implicated in eating behavior, activation of this area by modafinil indicates that administration of modafinil will also be useful in control of eating disorders or for appetite enhancement. Because the present inventors also discovered that this area is innervated by orexin neurons, they were led to the discovery that modafinil is able to stimulate orexin activity in the hypothalamus and is thus useful as an agent in the treatment of eating disorders.

The present invention arose from studies in which double-immunostainini, techniques were used determine that orexin neurons projected directly onto the central nervous system nuclei known to be important in sleep-wakefulness regulation. The distribution of orexin-immunoreactive terminals was similar to that previously reported, including particularly dense innervation of the locus coeruleus, dorsal and median raphe nuclei, and tuberomammillary nucleus (Peyron et al., Neurosci. 18:9996-10015, 1998, Elias et al., J. Comp. Neurol. 402:442-459, 1998; Date et al., Proc. Natl. Acad. Sci. USA, 96:748-753, 1999). Innervation was also observed in the pedunculopontine nucleus, the lateral dorsal tegmental nucleus, the horizontal and vertical limbs of the diagonal band of Broca, and the medial septal nucleus, as previously reported (Peyron et al., Neurosci. 18:9996-10015, 1998; Nambu et al., Brain Res. 827:243-260, 1999). Double-label immunohistochemistry was performed in these sites in both rat and mouse brains. Histaminergic neurons in the tuberomammillary nucleus (adenosine deaminaseimmunoreactive) received very dense orexin innervation on cell bodies and on proximal dendrites. Noradrenergic neurons in the locus coeruleus received a similar dense innervation by orexin immunoreactive fibers. Somatic and dendritic appositions on tyrosine hydroxylase-immunoreactive cells were best observed on solitary neurons on the edges of the locus coeruleus. Serotonergic neurons in the dorsal and median raphe nucleus also were densely innervated. It was also observed that serotonergic neurons in the dorsal raphe are specifically targeted by orexin terminals. In the mouse brain, cholinergic neurons in the pedunculopontine nuclei, lateral dorsal tegmental nucleus, diagonal band, and medial septal nuclei, received orexin innervation. The innervation of cholinergic cells was particularly dense in the rat brain. In all sites, apparent somatic and dendritic appositions were observed in the chemically characterized neurons.

To determine that modafinil might act through orexin neurons, wild-type mice were injected at noon with modafinil (150 mg/kg i.p.), or vehicle, and sacrificed 2 hours later. Brains were removed, double immunostained for orexin and Fos (an indicator of neuronal activity), and cells were counted in the periforllical region. The number of orexin-immunoreactive neurons was the same in both groups (44-47 cells/section), but the modafinil-treated group had over three times as many Fos-immunoreactive neuronal nuclei (38 in the modafinil-treated mice vs. 11 in the vehicle controls; p=0.01). Within the population of orexin-immunoreactive neurons, modafinil induced a 9-fold increase in the number of Fos-immunoreactive cells (64% double labeled neurons in the modafinil group vs. 7% in the vehicle group, p=0.01) (FIG. 1). Thus, in the lateral hypothalamus, modafinil treatment is associated with activation of orexin neurons, and is thus useful as a treatment for eating disorders or for increasing appetite.

Modafinil also strongly activates orexin neurons in the lateral hypothalamus. However, it is difficult to conclude that modafinil promotes wakefulness solely through orexin neurons because it also induces neuronal activation in other brain regions implicated in sleep-wakefulness regulation, such as the suprachiasmatic nucleus, anterior hypothalamic area (Lin et al., Proc. Natl. Acad. Sci. USA, 93:14128-14133, 1996), tuberomammillary nucleus, and locus coeruleus. Since orexin neurons heavily innervate the tuberomammillary nucleus and locus coeruleus (Peyron et al., Neurosci. 18:9996-10015, 1998), it is possible that modafinil may activate the orexin system which then recruits other arousal regions.

Prior to any invention disclosed or claimed herein, modafinil was known in the art in the form of a therapeutic package, marketed under the name Provigil.RTM.. Provigil.RTM. is a pharmaceutical product manufactured by Cephalon, Inc. of West Chester. Pa. and is also marketed by Cephalon, Inc. Provigil.RTM. is supplied as tablets containing 100 mg or 200 mg modafinil. In commercial use, modafinil-containing therapeutic packages in the prior art were labeled and otherwise indicated for use in narcolepsy patients.

Accordingly, known in the prior art were therapeutic packages providing one or more unit doses of modafinil as an active ingredient thereof, supplied in a finished pharmaceutical container that contain said unit doses, and further contained or comprised labeling directing the use of said package in the treatment of a human disease or condition as described above. n the provided literature accompanying a pharmaceutical container are instructions that the daily dosage of modafinil is 200 mg/day given as a single dose in the morning. Although 400 mg/day was well tolerated in clinical trials, 200 mg/day is the optimum wakefulness promoting dose in adult humans.

All of the compositions and methods disclosed and claimed herein can be made and executed without undue experimentation in light of the present disclosure. While the compositions and methods of this invention have been described in terms of preferred embodiments, it will be apparent to those of skill in the art that variations may be applied to the compositions and/or methods and in the steps or in the sequence of steps of the methods described herein without departing from the concept, spirit and scope of the invention. More specifically, it will be apparent that certain agents which are both chemically and physiologically related may be substituted for the agents described herein while the same or similar results would be achieved. All such similar substitutes and modifications apparent to those skilled in the art are deemed to be within the spirit, scope and concept of the invention as defined by the appended claims.

Claim 1 of 30 Claims

What is claimed is:

1. A method of treating an eating disorder requiring appetite stimulation in a mammal comprising administering to a mammal in need thereof an amount of a modafinil compound effective to stimulate the appetite of said mammal.

 

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