Title:  Method for increasing the bioavailability of metaxalone

United States Patent:  6,407,128

Assignee:  Elan Pharmaceuticals, Inc. (South San Francisco, CA)

Filed:  December 3, 2001

A method of increasing the bioavailability of metaxalone by administration of an oral dosage form with food is provided, as well as an article of manufacture comprising an oral dosage form of metaxalone in a suitable container and associated with printed labeling which describes the increased bioavailability of the medication in the container when taken with food.

SUMMARY OF THE INVENTION

The subject of this invention is the unexpected finding that administration of metaxalone with food increases both the rate and extent of absorption via the oral dosage form in human subjects.

One aspect of this invention is a method of increasing the bioavailability of metaxalone in a human patient receiving metaxalone therapy wherein the metaxalone is contained in a pharmaceutical composition, which method comprises administering a therapeutically effective amount of metaxalone to the patient with food.

Another aspect of the invention is providing a method of increasing rate and extent of metaxalone absorption as measured by the drug concentration attained in the blood stream over time of a patient receiving, the drug in an oral dosage form which method comprises administering a therapeutically effective amount of metaxalone to the patient with food.

Preferably the therapeutic amount is between about 200 mg to about 900 mg, and more preferably between about 400 mg to about 800 mg. Unit dosage forms are preferred.

Preferably the food is a solid food with sufficient bulk and fat content that it is not rapidly dissolved and absorbed in the stomach. More preferably the food is a meal, such as breakfast, lunch or dinner. Advantageously the dosage is administered to the patient between about 30 minutes prior to about 2 hours after eating a meal, most advantageously the dosage is administered within 15 minutes of eating a meal. The terms "without food", "fasted" and "an empty stomach" are defined to mean the condition of not having consumed solid food for about 1 hour prior to until about 2 hours after such consumption.

Yet another aspect of this invention is providing information to prescribing physicians and patients receiving metaxalone therapy useful in maximizing the therapeutic effect of the oral dosage form, by recommending that metaxalone be taken within about half an hour of consuming food.

Another aspect of this invention is an article of manufacture that comprises a container containing a pharmaceutical composition comprising metaxalone wherein the container holds preferably the metaxalone composition in unit dosage form and is associated with printed labeling instructions advising of the differing absorption when the pharmaceutical composition is taken with and without food.

The effect of food on metaxalone absortpion was identified in a study designed to compare the bioavailability of 400 mg of metaxalone in the formulation the drug product Skelaxin.RTM. administered to healthy volunteers with and without food.

An objective was to evaluate the bioavailability of metaxalone when administered to subjects with and without food. A single center, single dose, open-label, two-period, randomized, crossover trial in healthy subjects was conducted over a period of approximately 32 days.

The two study drug treatments were as follows:

Treatment A: metaxalone tablet (400 mg) administered with food

Treatment B: metaxalone tablet (400 mg) administered without food

In fed treatment condition A, study drug was taken 15 minutes after th e test meal. The test meal was consumed over a 15 minute time period. There was a 6-day washout period between study drug administrations. Seventeen blood samples were collected, starting with baseline (0 hour) and at the following time points: 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 8, 12, 16, 24, and 36 hours.

A total of 44 subjects (31 males/13 females) were enrolled and dosed. Only the plasma of subjects who completed the study were assayed and used for the pharmacokinetic analysis.

A single center, single dose, open label, two-period crossover trial was devised for study in healthy subjects. Each administration was a single oral dose of one Skelaxin.RTM. 400 mg tablet with or without food. The study drug was administered as follows:

Treatment A: One (1) 400 mg tablet of metaxalone with 240 mL of room temperature water with food: Breakfast was given to the subjects 30 minutes prior to dosing and eaten within a 15 minute period. The dose of study drug was administered to the subjects 15 minutes after the breakfast was finished.

The breakfast consisted of the following:

2 eggs (fried in butter);

2 strips of bacon;

2 slices of toast with butter;

4 ounces of hash brown potatoes;

1 glass whole milk (8 ounces).

Treatment B: 1 tablet of metaxalone) with 240 mL of room temperature water without food. The study drug was administered with 240 mL room temperature water. A mouth check was performed to verify that the subjects swallowed the dose. Subjects were sequentially dosed at 1 minute intervals. The actual time of dosing was recorded on the Master Flow Sheet (refer to the Appendix 16.3.2 Clinical Study Data). Drug administration (1.times.400 mg capsule) was assisted with 240 mL of room temperature water consumed under direct observation. Immediately after administration of product, the subject's oral cavity was checked to confirm complete medication and fluid consumption. Dosing was completed as scheduled in 42 of 44 subjects.

The drug substance, metaxalone; was dosed in tablet form. Content: 400 mg; Route: Oral, Batch/Lot No.: SKLWW263F; Expiration Date: FEB03; Manufacturer: West-Ward Pharmaceutical Corp

All pharmacokinetic parameters were analyzed by noncompartmental methods. The following PK parameters were calculated for the two PK profiles and are defined as follows:

Tmax: Time to maximum concentration;

Cmax: Observed maximum concentration;

kel: Slope of terminal linear portion of concentration/time curve;

T1/2: Half-life of metaxalone calculated as: 0.693/Kel;

AUC(last): Area under the curve to last quantifiable concentration as measured by the trapezoidal rule;

AUC(inf): The AUC value extrapolated to infinity calculated as: AUC(inf)=AUC(last)+C(t)last/Kel where C(t)last is the last measurable concentration.

Statistical Analysis

All statistical analyses were performed using SAS.RTM. software version 6.08 or higher. The PK parameters between the two treatments were compared using an appropriate ANOVA model (analysis of variance) that includes term for treatment, sequence, and period effect. Ninety percent confidence interval was computed for the Cmax and AUC values of the fed treatment with fasting as the reference treatment. During the study there were no protocol deviations to confound the pharmacokinetic and bioavailability analyses. Study results were not corrected for drug potency. The individual test results are summarized in table I

Claim 1 of 22 Claims

We claim:

1. A method of increasing the oral bioavailability of metaxalone to a patient receiving metaxalone therapy comprising administering to the patient a therapeutically effective amount of metaxalone in a pharmaceutical composition with food.

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