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Title:  Compositions including modafinil for treatment of attention deficit hyperactivity disorder and multiple sclerosis fatigue

United States Patent:  6,346,548

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

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

Appl. No.:  638353

Filed:  August 15, 2000

Abstract

Modafinil is effective in improving symptoms of attention deficit hyperactivity disorder and symptoms of multiple sclerosis fatigue. The administration of modafinil is also shown to activate the tuberomamillary neurons of the posterior hypothalamus, and thus exhibits activity in an area of the brain associated with normal wakefulness functions.

SUMMARY OF THE INVENTION

The present disclosure provides a novel use for modafinil in treatment of attention deficit hyperactivity disorder (ADHD) and in ameliorating the symptoms of fatigue due to multiple sclerosis (MS).

Studies forming the basis of the present disclosure demonstrate that, unexpectedly, administration of wake-promoting doses of modafinil to rats results in selective increases in activity of the tuberomamillary nucleus (TMN) of the posterior hypothalamus. Modafinil administration reduced the activity of the neurons in the ventrolateropreoptic area (VLPO) of the hypothalamus which are known to inhibit the activity during sleep of wake-promoting histaminergic neurons in the TMN. 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 selective activation of the TMN and was unexpected based on the previous publications in the field.

Based on these mechanistic studies, modafinil has a significantly different activity than the stimulants in common use for ADHD and MS fatigue. These are quite different drugs, as it is herein disclosed that modafinil promotes wakefulness by selective activation of hypothalamic nuclei involved in normal wakefulness, and in contrast, commonly used psychostimulants, such as amphetamines, act largely by enhancing dopaminergic input to the cortex and other brain regions by facilitating neurotransmission of dopaminergic neurons in the mesolimbic, tuberoinfundibular and nigrostriatal systems. Of these major dopaminergic pathways, the mesolimbic system originating in the ventral tegmentum may be most directly involved in cortical activation while the tuberoinfundibular and nigrostriatal systems are involved in pituitary and motor function, respectively. Simultaneous facilitation of these pathways by amphetamines results in the well-characterized cortical stimulation and hyperactivity associated with amphetamine administration. In contrast to the hypothalamic systems involved in normal wakefulness, facilitation of dopaminergic neurotransmission appears to induce a state of wakefulness that is abnormal in that it is associated with alterations in mood and perceptions of well-being as well as increases in motor activity.

Because of the surprising discovery of activation of the tuberomamillary neurons of the posterior hypothalamus by modafinil, as disclosed herein, novel uses for modafinil are revealed and such uses are an aspect of the present invention. For example, it is an aspect of the present invention that modafinil is a novel therapeutic agent that would provide important benefits for patients suffering from ADHD. Because modafinil activates the hypothalamus, and further because an inhibitory histaminergic neural pathway from the hypothalamus synapses on inhibitory gamma-aminobutyric acid (GABA) frontal lobe interneurons, the activation of the hypothalamus may contribute to subsequent pyramidal cell activation and provides a mechanism for the usefulness of modafinil in ADHD. In addition, activation of the TMN can also result in enhanced cortical action by direct histerminergic excitation. In other words, activation of the TMN neurons is excitory either directly or indirectly to the cortex. Insufficient activity at the frontal cortex has been implicated in the etiology of ADHD (Castellanos, F. X., Clinical Pediatrics, 381-393 (1997); Swanson, J., et al., Current Opinion in Neurobiology, 8:263-271 (1998); Barkley, R. A., Scientific American, 66-71 (1998)).

An aspect of the present disclosure may be described therefore as a method of treating attention deficit hyperactivity disorder, where the treatment includes administering to a subject suffering from or susceptible to the development of attention deficit hyperactivity disorder a composition that includes a modafinil compound in an amount effective to improve or prevent symptoms of attention deficit hyperactivity isorder in said subject.

An additional aspect of the present disclosure is a method of treating fatigue associated with multiple sclerosis including administering to a subject suffering from multiple sclerosis fatigue a composition that contains a modafinil compound in an amount effective to improve or prevent symptoms of multiple sclerosis fatigue in the subject. As used herein "fatigue" includes loss of power, or capacity to respond to stimulation. As such, modafinil is shown herein to be effective as a treatment for alleviating tiredness, or sleepiness associated with multiple sclerosis and also as a method of promoting wakefulness in multiple sclerosis patients.

A further aspect of the disclosure is a method of treating a subject suffering from the symptoms of attention deficit hyperactivity disorder or multiple sclerosis fatigue that includes administering to the subject a pharmaceutical composition that includes a modafinil compound in an amount effective to stimulate activity in the tuberomamillary neurons of the brain of the subject.

Yet a further aspect of the disclosure is a pharmaceutical composition in unit dose form, for use in treating attention deficit hyperactivity disorder in a subject susceptible to the development of or suffering from attention deficit hyperactivity disorder, which includes an amount of a modafinil compound such that one or more unit doses thereof are effective to stabilize or improve the symptoms of attention deficit hyperactivity disorder in the subject upon periodic administration.

An aspect of the present disclosure is also a pharmaceutical composition in unit dose form, for use in treating fatigue in a multiple sclerosis patient, where the composition includes an amount of a modafinil compound such that one or more unit doses thereof are effective to stabilize or improve the symptoms of multiple sclerosis fatigue in the patient upon periodic administration.

As disclosed herein and as used in the compositions and methods of the present invention, a modafinil compound may include a racemic mixture, and may be in an acid form, such as a metabolic acid of modafinil or a benzhydrylsulfinylacetic acid, a sulfone form, a hydroxylated form, a conjugated form such as a modafinil compound conjugated to a protein, a polysaccharide, a glucuronide or a sulfate, or a polymorphic form, it may include compounds containing isosteric replacements of the phenyl groups of modafinil, and polymorphic species or analogs of modafinil, or derivatives of cogeners and prodrugs, particularly those preparations that stimulate activity in the TMN when administered to a mammal. In preferred embodiments, the modafinil compound is modafinil. Prodrugs are known in the art as compounds that are converted to the active agent (modafinil) in the body of a subject.

Compositions and methods as disclosed herein are preferably useful in the treatment of mammalian subjects, and more particularly in humans. Because MS and ADHD are known to afflict both adults and juveniles or children, the methods and compositions disclosed herein are directed to those population groups. While effective doses may be given in mg/day for human oral administration, it is understood that the dose, unless otherwise stated, may be directed to the treatment of a human adult and that a dose for a child is adjusted appropriately.

It is an object of the present invention to provide methods of treatment that include effective doses of a modafinil compound for the treatment of ADHD and MS fatigue, and that an effective amount is preferably from about 1 to about 400 mg per daily dose. It is known in the art, for example, that a dose of from about 200 mg/day to about 400 mg/day is an effective wake-promoting dose, and that such a dose is contemplated to be useful in treatment of ADHD and MS fatigue. It is also known that a dose of about 100 mg/day is at the lower threshold of wake-promoting doses, but that such a dose is contemplated to be useful for the treating ADHD and MS fatigue. Studies reported elsewhere have also shown beneficial activity of modafinil at sub-wakefulness-promoting doses, particularly in the improvement of cognitive function. As such, it is an aspect of the present disclosure that an effective amount of a modafinil compound for use in the methods disclosed herein may include from about 1 mg/day to about 400 mg/day, or from about 100 to about 400 mg per daily dose, or from about 200 to about 400 mg per daily dose, or even 200 mg per daily dose. It is also understood that doses within those ranges, but not explicitly stated, such as 30 mg, 50 mg, 75 mg, etc. are encompassed by the stated ranges, as are amounts slightly outside the stated range limits.

In the preferred embodiments, a composition including a modafinil compound is formulated for oral administration, and is more preferred to be formulated as a tablet for oral administration. The formulation of modafinil containing tablets is known in the art as described below, and such tablets may preferably contain various inert ingredients such as lactose, corn starch, magnesium silicate, croscarmellose sodium, povidone, magnesium stearate, or talc in any combination thereof.

An aspect of the present disclosure may also be described as a therapeutic package for dispensing to, or for use in dispensing to, a mammal being treated for attention deficit hyperactivity disorder or multiple sclerosis fatigue, where the package includes (1) one or more unit doses, each such unit dose containing an amount of a modafinil compound such that said one or more unit doses thereof are effective to stabilize or improve a symptom of attention deficit hyperactivity disorder or multiple sclerosis fatigue in the mammal upon periodic administration and the unit doses being administered periodically, and (2) a finished pharmaceutical container therefor, said container containing (a) said unit dose or unit doses and (b) labeling directing the use of the package in the treatment of said mammal. In preferred embodiments the package is adapted for oral administration.

Although the compositions and methods disclosed herein have been described in light of certain preferred embodiments, it is understood that the modafinil compounds described herein may be orally administered with an inert diluent or an assimilable edible carrier, for example. The compositions may also be enclosed in hard or soft shell gelatin capsule, compressed into tablets, or incorporated directly with the food of the diet. For oral therapeutic administration, the active compounds such as modafinil may be incorporated with excipients and used in the form of ingestible tablets, buccal tablets, troches, capsules, elixirs, suspensions, syrups, wafers, and the like, although tablets are the generally preferred method of administering modafinil. Such compositions and preparations should contain at least 0.1% of active compound. The percentage of the compositions and preparations may, of course, be varied and may conveniently be between about 2 to about 60% of the weight of the unit.

The tablets, troches, pills, capsules and the like may also contain any of the following: a binder, as gum tragacanth, acacia, cornstarch, or gelatin; excipients, such as dicalcium phosphate; a disintegrating agent, such as corn starch, potato starch, alginic acid and the like; a lubricant, such as magnesium stearate; and a sweetening agent, such as sucrose, lactose or saccharin may be added or a flavoring agent, such as peppermint, oil of wintergreen, or cherry flavoring, for example. When the dosage unit form is a capsule, it may contain, in addition to materials of the above type, a liquid carrier. Various other materials may be present as coatings or to otherwise modify the physical form of the dosage unit. For instance, tablets, pills, or capsules may be coated with shellac, sugar or both. A syrup or elixir may contain the active compounds sucrose as a sweetening agent methyl and propylparabens as preservatives, a dye and flavoring, such as cherry or orange flavor. Of course, any material used in preparing any dosage unit form should be pharmaceutically pure and substantially non-toxic in the amounts employed. In addition, the active compounds may be incorporated into sustained-release preparation and formulations.

In certain embodiments, the disclosed compositions may be formulated to be administered by use of a skin patch, or transdermal delivery system. The administration of the modafinil compositions described herein transdermally may be accomplished by any of a number of systems known in the art. Examples of systems that may be adapted for use with the compositions described herein include those systems of transdermal administration described in U.S. Pat. No. 4,816,252; U.S. Pat. No. 5,122,382; U.S. Pat. No. 5,198,223; U.S. Pat. No. 5,023,084; U.S. Pat. No. 4,906,169; U.S. Pat. No. 5,145,682; U.S. Pat. No. 4,624,665; U.S. Pat. No. 4,687,481; U.S. Pat. No. 4,834,978; and U.S. Pat. No. 4,810,499 (all incorporated herein by reference.

These methods typically include an adhesive matrix or drug reservoir system and may include a skin permeation enhancement agent such as ethanol, polyethylene glycol 200 dilaurate, isopropyl myristate, glycerol trioleate, linolenic acid saturated ethanol, glycerol monooleate, glycerol monolaurate, n-decyl alcohol, capric acid, and certain saturated and unsaturated fatty acids, and their esters, alcohols, monoglycerides, acetate, diethanolamides and N,N-dimethylamides (See for examples, U.S. Pat. No. 4,906,169).

The present invention further relates to a method for identifying a compound that stimulates activity in the TMN of the posterior hypothalamus. This method involves the use of standard screening techniques applied to the novel discovery as set out hereinabove. Accordingly, there is provided by the present invention compounds identified by this method and uses therefor as drugs wherein stimulation in the TMN of the posterior hypothalamus will have a salutary effect on the wellbeing of the animal or patient being treated.

Claim 1 of 12 Claims

What is claimed is:

1. A method of treating attention deficit hyperactivity disorder comprising administering to a subject suffering from or susceptible to the development of attention deficit hyperactivity disorder a composition comprising a modafinil compound in an amount effective to improve or prevent symptoms of attention deficit hyperactivity disorder in said subject.


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