METHODS AND COMPOSITIONS FOR TREATING FATIGUE ASSOCIATED WITH DISORDERED SLEEP USING VERY LOW DOSE CYCLOBENZAPRINE

Abstract

The present invention relates to methods tor the treatment or prevention of fatigue associated with disordered sleep, for example, in multiple sclerosis, fibromyalgia, Fabry's disease, Parkinson's disease, or traumatic brain injury, using cyclobenzaprine. The present invention further relates to a biomarker for the therapeutic effects of a cyclobenzaprine treatment.

Claims

1-7. (canceled)

8. A method for treating muscle spasticity associated with multiple sclerosis or traumatic brain injury, comprising administering to a human in need of such treatment a pharmaceutical composition comprising cyclobenzaprine in a therapeutically effective amount and a therapeutically effective carrier, wherein such treatment ameliorates or eliminates the muscle spasticity.

9-10. (canceled)

11. The method of claim 8, wherein the pharmaceutical composition is administered as an orally dissolving tablet, as a thin film formulation, or as a promicellar formulation.

12-19. (canceled)

20. The method of claim 8, wherein the amount of cyclobenzaprine administered is between 5 mg/day and 12 mg/day.

21. The method of claim 8, wherein the amount of cyclobenzaprine administered is less than 5 mg/day.

22. The method of claim 8, wherein the amount of cyclobenzaprine administered is less than 2.5 mg/day.

Description

EXAMPLES

Example 1

Tablet Formulation

[0027] A typical oral formulation for coated tablets consists of the following: Formula quantity per tablet (mg.) cyclobenzaprine 1.0, lactose 74.0, corn starch 35.0, water (per thousand tablets) 30.0 ml, magnesium stearate 1.0, corn starch 25.0. The active ingredient (cyclobenzaprine) is blended with the lactose until a uniform blend is formed. The smaller quantity of corn starch is blended with a suitable quantity of water to form a corn starch paste. This is then mixed with the uniform blend until a uniform wet mass is formed. The remaining corn starch is added to the resulting wet mass and mixed until uniform granules are obtained. The granules are then screened through a suitable milling machine, using a ¼ inch stainless steel screen. The milled granules are then dried in a suitable drying oven until the desired moisture content is obtained. The dried granules are then milled through a suitable milling machine using ¼ mesh stainless steel screen. The magnesium stearate is then blended and the resulting mixture is compressed into tablets of desired shape, thickness, hardness and disintegration.

[0028] Tablets are coated by standard aqueous or nonaqueous techniques. For example, 2.5 mg of hydroxypropymethylcellulose can be dissolved in 25 mg of deionized water. An aqueous (10 mg) suspension of 1.88 mg talc, 0.5 mg of titanium dioxide, 0.1 mg of yellow iron oxide, and 0.02 mg of red iron oxide is stirred into this solution. The coating suspension is sprayed on the tablets and the coated tablets are dried overnight at 45° C.

Example 2

Development of an Optimized Gelcap Formulation of VLD Cyclo for Fatigue

[0029] We are developing a novel gelcap that employs a specific mixture of lipids to form micelles containing cyclobenzaprine that is expected to speed upper GI absorption, increase efficiency of absorption (in stomach and proximal small intestine); decrease or eliminate food effect (which is 20% for the Amrix formulation of cyclobenzaprine; and speed elimination (since lower GI absorption may prolong the terminal elimination phase in existing formulations). The gelcap formulation is expected to result in increased dosage precision; decreased potential for morning “hangover”; and potentially more rapid induction of sleep.

[0030] The lipid formulation is designed to form micelles in gastric-intestinal fluids, to solubilize cyclobenzaprine in the stomach and small intestine and to increase the rate, efficiency and predictability of absorption of cyclobenzaprine in the bloodstream. Cyclobenzaprine assumes a positive charge in the acidic gastric fluid. Micelles and charged cyclobenzaprine are highly soluble in gastric fluid. In the small intestine, the pH increases and cyclobenzaprine starts to lose its charge. Uncharged cyclobenzaprine molecules have poor solubility without micelles. The micelles prevent precipitation of the uncharged cyclobenzaprine by solubilizing it in their cores and to deliver the cyclobenzaprine to the wall of the small intestine where the cyclobenzaprine can be absorbed into the bloodstream. The lipid formulation is referred to as pro-micellar because prior to interacting with aqueous fluid, the lipids do not form micelles. The pro-micellar mixtures are typically encased in a gelatin capsule (gelcap).

Example 3

Cyclic Alternating Pattern Analysis VID CBP Effects on CAP A2+CAP A3

[0031] Subsequent to enrollment and completion, EEG sleep studies in FM patients were reported that identified increases in the periodic sleep EEG arousal disorder known as the cyclic alternating pattern (CAP) in non-REM sleep, (Rizzi et al. J. Rheumatol. 2004, 31(6); 1193-1199, Rosa et al. 1999, 110(4);585-592). Therefore, an analysts of sleep EEG CAP was performed that measured subtypes CAP A1, CAP A2, and CAP A3 and Total CAP (or CAP A1+A2+A3). Subtype CAP A1 is associated with sleep maintenance or least sleep instability, and subtypes CAP A2 and A3 are associated with moderate to prominent increases in sleep instability.

[0032] Because CAP A2 and A3 are most closely associated with sleep instability.sup.26,27, the sum of CAP.sub.A2+CAP.sub.A3 rates (CAP.sub.A2+A3) was used as an indicator of disordered sleep. CAP.sub.A2+A3 was normalized (CAP.sub.A2+A3(Norm)) by dividing CAP.sub.A2+A3 by the total CAP rate (CAP.sub.total=CAP.sub.A1+CAP.sub.A2+CAP.sub.A3 rates=CAP.sub.A1+A2+A3) and expressed as a percentage. Therefore, CAP.sub.A2+A3(Norm)=100*CAP.sub.A2+A3/CAP.sub.A1+A2+A3 and this reflects the percentage of total CAP that is associated with sleep instability.

[0033] To determine whether patients experienced nights with a potential CAP response to treatment, it was necessary to determine an empirical threshold below which CAP.sub.A2+A3(Norm) values reflect a night of relatively stable sleep for this population. To determine a threshold for CAP.sub.A2+A3(Norm) that could be informative for a potential treatment response, the study CAP data were then evaluated by considering a range of cutoff values for CAP.sub.A2+A3(Norm) from ≤10% to ≤50%. Testing various nCAP.sub.A2+A3 values revealed that defining a threshold for response CAP.sub.A2+A3(Norm)≤33% distinguished VLD CBP-treated subjects from placebo-treated subjects at which threshold, the percentage of patients with increased nights of CAP response while on treatment (ITT, LOCF) was 72% with VLD CBP vs. 33% with placebo (p=0.019).

[0034] Correlation of CAP.sub.A2+A3(Norm) with FM Symptoms. To evaluate whether increased nights with CAP.sub.A2+A3(Norm)≤33% was correlated with clinical improvement measures in pain, fatigue, tenderness, HAD, and HAD depression, over the course of the study (LOCF week 8), Spearman's rank correlation was then investigated separately for each treatment. Data were coded such that improvements were positive. Within the VLD CBP treated patients, increased nights with CAP.sub.A2+A3(Norm)≤33% was correlated positively to decreases in fatigue (rho=0.62, p=0.006), HAD total score (rho=0.505, p=0.033), HAD depression subscale (rho=0.556, p=0.017), patient rated fatigue (rho=0.614, p=0.007) and clinician-rated fatigue (rho=0.582, p=0.0112). In contrast, improved CAP response was not correlated with either musculoskeletal pain or dolorimetry. Within the Placebo-treated subjects, none of these FM symptoms or Sleep EEC parameters was significantly correlated to increased number of nights with CAP.sub.A2+A3(Norm)=33%. In the placebo group, increased nights of CAP response correlated with measures of improved sleep: a positive correlation with sleep efficiency and a negative correlation with total time awake. Together, these findings show that nights with CAP.sub.A2+A3(Norm)≤33% reflect relatively healthy or restorative sleep for FM patients as symptoms vary naturally over the course of the condition, as well as providing a potential biomarker for treatment effects of low dose cyclobenzaprine for disordered sleep.

Example 4

Treatment of Multiple Sclerosis

[0035] A 46 year old woman was diagnosed with multiple sclerosis three years ago. Her last flare-up was treated with a short course of steroids, and she has been symptom free for two months. However, she has noted that throughout the day she has very low energy levels. Her capacity for physical and mental work has declined to the point where she is unable to function at work. She reports getting 6 to 8 hours of sleep each night but feels unrefreshed in the morning. Taking naps or getting more sleep does nothing to improve her energy level. She began taking cyclobenzaprine initially at a dose of 2 mg at bedtime. Her doctor increased the dose to 4 mg at bedtime. With each does she felt that the quality of her sleep improved and her level of energy increased during the day. Within three weeks, her physical stamina as well as her ability to concentrate and focus increased to the extent that she was able to resume occupational functioning. Her doctor asks her to assess her level of fatigue on a scale of 1 to 10 before and after cyclobenzaprine treatment. Before treatment she assessed herself as having 9/10 fatigue. After treatment her level of fatigue decreased to 3/10.

Example 5

Treatment of Traumatic Brain Injury

[0036] A 27-year-old male survived a serious motor vehicle accident with closed head trauma. He underwent six months of physical rehabilitation. However, he was left with mild spasticity and hyper-reflexia of the upper extremities, general cognitive slowing, and mild language difficulties. Other symptoms including pronounced emotional lability often manifested as outbursts of anger or uncontrollable crying spells. These symptoms were felt by his neurologist to be consistent with traumatic brain injury. Because of the spasticity, the neurologist recommended six months of additional physical rehabilitation. However, the patient was unable to make progress with his physical rehabilitation because his physical energy level and motivation would drop very rapidly during the course of his rehabilitation sessions. He was unable to complete many of the exercises or follow complex instructions. If sleep is poor or, characterized by both difficulty falling asleep and early-morning awakening. His neurologist prescribed cyclobenzaprine at a dose of 5 mg at bedtime. Within three weeks, the patient's sleep improved substantially and his level of energy and concentration were markedly better. He was able to complete rehabilitation and make significant gains in physical capacity.

[0037] All references cited herein are incorporated by reference. The present invention may be embodied in other specific forms without departing from the spirit or essential attributes thereof and, accordingly, reference should be made to the appended claims, rather than to the foregoing specification, as indication the scope of the invention.