Gastric retentive gabapentin dosage forms and methods for using same

Abstract

Provided is a method of treating a patient suffering from a pain state by administering to the patient a gastric retentive dosage form of gabapentin that is capable of administration in once-daily or twice daily dosing regimens. By reducing the need to administer gabapentin from the thrice-daily administrations characteristic of immediate release gabapentin, the gastric retentive gabapentin dosage forms provided herein have the advantages of improving patient compliance for gabapentin treatment. In addition to the foregoing, the gastric retentive gabapentin dosages forms also exhibit decreased blood plasma concentrations and increased bioavailability throughout the dosing regimen.

Description

RELATED APPLICATIONS[0001]This application claims priority to pending U.S. Ser. No. 11 / 348,134, filed Dec. 29, 2006, which claims priority to U.S. Provisional Application Ser. No. 60 / 852,534 filed Oct. 17, 2006, the disclosures of which are incorporated herein by reference.FIELD OF THE INVENTION[0002]The invention relates to gastric retentive gabapentin dosage forms and methods of using them to reduce or eliminate gabapentin-induced side effects. For example, the dosage forms of the invention can be used to reduce or eliminate the side effects associated with treatment of non-nociceptive pain states.BACKGROUND OF THE INVENTION[0003]Gabapentin (1-(aminomethyl)cyclohexane acetic acid) is a 3-substituted γ-aminobutyric acid (“GABA”) analog that was approved in the United States on Dec. 30, 1993 as NEURONTIN® (Pfizer Inc., New York, N.Y.), an immediate release dosage form of gabapentin for use as adjunctive therapy in the treatment of partial seizures in children and adults, and was sub...

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Benefits of technology

[0146]Another advantage of the present invention is that it may allow patients who are unable to reach an effective therapeutic dose of gabapentin to be effectively treated with gabapentin. For those patients who are unable to reach an effective dose of gabapentin due to inability to tolerate side effects, the combination of extended release with a lower maximum concentration (Cmax) compared to the equivalent IR dose if both are administered as single doses, as well as the dosing regimen in which all or a larger fraction of the dose, is administered after the evening meal, may lower the incidence of side effects sufficiently to allow the patient to reach a therapeutically effective dose. Moreover, some patients may not be effectively treated with gabapentin because they experience no increase in efficacy with increased dose. The present invention will allow for a larger percentage of the administered dose to be absorbed at higher doses when compared to immediate release gabapentin, and thus may allow some patients to obtain efficacious treatment who found immediate release gabapentin insufficient. Thus, the combination of dosing regimen, increased bioavailability (when compared to immediate release gabapentin) and the extended release of gabapentin over time may allow for reduced incidence of side effects and as a result, improved efficacy as more patients may be able to reach an efficacious dose.

[0147]As previously noted, the patient may be titrated up to the maintenance dose (i.e., the highest maximum dose allowable or preferred for a patient). Titration may occur over a period of days or weeks, depending on the patient's therapeutic needs, the magnitude of the maintenance dose, and the patient's apparent tolerance for gabapentin. Titration will generally be determined by the administrating practitioner.

[0148]Likewise the patient may be weaned from the high maintenance dose down to a zero dose in a gradual process that allows the patient's body to adjust to reduced medication and to determine whether the gabapentin therapy is sufficient at the lower dose.

[0149]When the administration of an additional therapeutic agent in addition to the gabapentin is desired, the additional active agent may be administered at the same time or at a different time than gabapentin. For purposes of facilitating patient compliance, administration of any of the aforementioned additional agents at the same time is preferred.Dosage Forms

[0150]There are several drug delivery systems that are suitable for use in delivering gabapentin in the method of the invention as they are particularly tailored to be gastric-retentive dosages, such as the swellable bilayer described in U.S. Pat. No. 5,232,704 to Franz et al.; the multilayer tablet with a band described in U.S. Pat. No. 6,120,803 to Wong et al.; the membrane sac and gas generating agent described in U.S. Pat. No. 4,996,058 to Sinnreich; the swellable, hydrophilic polymer system described in U.S. Pat. No. 5,972,389 to Shell et al. and WO 98 / 55107 to Shell et al.; all of which are incorporated herein by reference.

[0151]Of particular interest are gastric retentive dosage forms that contain hydrophilic polymers that swell to a size such that the dosage form is retained in the fed mode. For example, the gastric retentive dosage form can contain polymers with a high swelling capacity such as polyethylene oxide, hydroxyethylcellulose, and hydroxypropylmethylcellulose. The polymers are preferably of a moderate to high molecular weight (4×103 to greater that 107) to enhance swelling and provide control of the release of gabapentin. In one embodiment of the invention, a hydroxypropylmethylcellulose polymer of such molecular weight is utilized so that the viscosity of a 1% aqueous solution is about 4000 cps to greater than 100,000 cps. An example of suitable polyethylene oxide polymers are those having molecular weights (viscosity average) on the order of 2-7 million. A typical dosage form should swell to approximately 115% of its original volume within one hour after administration, and at a later time should swell to a volume that is 130% or more of the original volume. Fillers, binders, lubricants and other additives may also be included in the gastric retentive dosage form, such as are well known to those of skill in the art.

Problems solved by technology

Furthermore, the slower release rate allows for a slower rise in peak plasma levels, which may be associated with side effects.

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