WO2005009432A1

WO2005009432A1 - New dosage regimen in case of concurrent intake of gabapentin with food and an increased oral bioavailability therewith

Info

Publication number: WO2005009432A1
Application number: PCT/IB2004/051334
Authority: WO
Inventors: Manish Chawla; Rajeev Singh Raghuvanshi; Ashok Rampal
Original assignee: Ranbaxy Laboratories Limited
Priority date: 2003-07-29
Filing date: 2004-07-29
Publication date: 2005-02-03
Also published as: CN1832735A

Abstract

The present invention relates to the use of a gabapentin containing controlled-release oral dosage form for the manufacture of a medicament for once-dailly administration and consuming food within one hour after gabapentin intake for treating conditions for which gabapentin is indicated.

Description

Description NEW DOSAGE REGIMEN IN CASE OF CONCURRENT INTAKE OF GABAPENTIN WITH FOOD AND AN INCREASED ORAL BIOAVAILABILITY THEREWITH Technical Field

[1] The present invention relates to methods of increasing the oral bioavailability of gabapentin. Background Art

[2] Gabapentin (l-(aminomethyl)cyclohexaneacetic acid) is a #-amino acid analogue effective in the treatment of epilepsy. Gabapentin is indicated as an adjunctive therapy in the treatment of partial seizures with and without secondary generalization in adults with epilepsy. Gabapentin has also been approved for neuropathic pain in some countries.

[3] Gabapentin has shown to exert its anti-seizure activity in mice and rats in both maximal electroshock and pentylenetetrazole seizures, but the mechanism of action of gabapentin against seizures is unknown. What is known is that Gabapentin is structurally related to the neurotransmitter GABA (gamma-aminobutyric acid) but does not interact with GABA receptor. It is not converted to GABA or a GABA agonist and is not an inhibitor of GABA uptake or degradation.

[4] Common side effects associated with gabapentin therapy include somnolence, dizziness, ataxia, fatigue and nystagmus. Of these, somnolence and ataxia have been found to be dose related, i.e., a patient taking a higher dose may have higher incidence of these side effects. Therefore, it would be desirable to have a method of decreasing the dose of gabapentin without compromising the therapeutic effectiveness.

[5] Gabapentin has a relatively short half-life (5-7 hours), which leads to substantial fluctuations in the plasma concentration of the drug. Frequent dosing is necessary to maintain reasonably stable plasma concentrations. The effective dose of gabapentin is 900 to 1800 mg/day and is given three times a day. Gabapentin is typically absorbed from the upper intestine, i.e., it has a narrow absorption window and is absorbed by active transport through a large neutral amino acid (LNAA) transporter. This transporter is located in upper small intestine and has limited transport capacity and becomes saturated when exposed to high drug concentrations. Consequently, the plasma levels of gabapentin are not dose proportional and, therefore, higher doses do not give proportionately higher plasma levels. This fact also explains the poor oral bioavailability of gabapentin even when the dose is increased.

[6] Since the LNAA transporter responsible for gabapentin absorption is present specifically in the upper region of the intestine, any means that can slow the passage of gabapentin from the stomach to the upper intestine will lead to more efficient absorption of gabapentin. When a drug is administered in fasting conditions, it is likely that a large percentage of the dose passes on to the intestine from the stomach within a short period permitting only a small amount of the drug to be absorbed at the specific absorption site. In contrast, in fed conditions, the pyloric sphincters in the stomach constrict to control the passage of gastric contents to the intestine. Generally the food from the stomach is emptied into the upper intestinal regions in about 2 to 4 hours. Accordingly, a drug, when given with food, will also remain in stomach for a longer duration than when given in fasting conditions. As a result, a drug given in fed conditions will bereleased from the stomach at a slower rate leading to better absorption.

[7] As per the Physicians' Desk Reference and the labeling for the currently marketed, immediate release gabapentin drug product, food has no effect on oral bioavailability of gabapentin although the labeling notes that the gabapentin immediate release product can be taken with or without food. Contrary to this observation, we have surprisingly found that bioavailability of gabapentin is considerably improved when the gabapentm dosage form is administered with food. This improvement in bioavailability helps reduce the effective daily dose, and consequently the side effects. The frequency of dosing can also be reduced. These factors will also contribute to improved patient compliance. Disclosure

[8] In one general aspect there is provided a method of treating a patient for a condition for which gabapentin is indicated. The method includes administering a controlled release oral dosage form comprising a therapeutically effective amount of gabapentin, the gabapentin dosage form being indicated for once daily administration; and consuming food within one hour of administering the oral dosage form.

[9] Embodiments of the method may include one or more of the following features. For example, administering the dosage form within one hour of consuming food may increase the extent of absorption of gabapentin in the patient. Administering the dosage form within one hour of consuming food may increase the oral bioavailability of gabapentin in the patient. Administering the dosage form within one hour of consuming food may reduces the per day dosing frequency of the gabapentin by increasing the oral bioavailability of gabapentin in the patient, and the dosing frequency may be reduced from twice daily to once daily. Administering the dosage form within one hour of consuming food may reduce the daily dose of gabapentin to the patient.

[10] The oral dosage form may be one or more of tablets, capsules, granules, solid dosage form, or oral liquid dosage form. The oral dosage form may be a sustained release dosage form.

[11] The oral dosage form may be administered within 20 minutes to one hour of the consumption of food. The oral dosage form may be administered at the same time as the consumption of food. The oral dosage form may be administered at a time ranging between immediately after consumption of food and up to one hour after the consumption of food.

[12] The details of one or more embodiments of the inventions are set forth in the description below. Other features, objects and advantages of the inventions will be apparent from the description and claims. Detailed Decription of the Invention

[13] The invention relates to a method of increasing the oral bioavailability of gabapentin by administering a therapeutically effective amount of gabapentin or a pharmaceutically acceptable salt or hydrates thereof in an oral dosage form with food. A dosage form of gabapentin, when taken with food, allows for the increased absorption of gabapentin at the specific absorption site. Our studies have revealed that an improvement in oral bioavailability is observed when an oral gabapentin dosage form is administered with food as indicated by the various pharmacokinetic parameters such as C max and AUG.

[14] The term 'therapeutically effective amount' refers to an amount which is sufficient to treat a mammal in need of the treatment. Generally, the therapeutically effective amount varies depending upon the subject being treated and upon the medical condition for which the treatment is being given. The method of the present invention involves administering gabapentin with food to a subject as long as the medical condition exists.

[15] The term 'gabapentin' as used herein includes gabapentin or a pharmaceutically acceptable salt of hydrates thereof. Non-limiting example include gabapentin hy- drochloride, gabapentin monohydrate or any other pharmaceutically acceptable form known to the skilled in the art. The dose of gabapentin is determined by the medical condition for which the treatment is sought. One aspect of the method of the present invention includes increasing the oral bioavailability of gabapentin for treating the medical condition which is responsive to gabapentin therapy. For example, when the medical condition is epilepsy, the dose can be from about 300 - 3600 mg per day, particularly about 900 -2400 mg per day, more particularly about 900 - 1800 mg per day. Similarly, for treating neuropathic pain, the dose can be from about 100 - 4800 mg per day, particularly from about 300 - 3600 mg per day, and more particularly from about 900 - 2400 mg per day.

[16] The dosage form for delivering gabapentin to a subject is oral. The oral dosage form can be a tablet, capsule or granule or any other solid oral dosage from or an oral liquid dosage form, in which the intended dose may be conveniently delivered to the subject being treated. Further, the dosage form also includes the conventional dosage forms meant for immediate release and sustained release dosage form meant for controlled release of gabapentin. Commercially available dosage forms of gabapentin are also included in the method of the invention.

[17] The oral administration of gabapentin with food means that the gabapentin is ingested anywhere within the time period from one hour before the consumption of food to one hour after the consumption of food, as well as at the same time as the consumption of food. Although not bound by theory, it is believed gabapentin absorption is more efficient, for a given amount of dose, when administered with food because the chance that the specific LNAA transporter becoming saturated are reduced as a result of the slow feeding of gabapentin from the stomach to the upper regions of intestine over a prolonged period.

[18] The following example illustrates an aspect of the invention and does not limit the scope of the invention.

[19] EXAMPLE 1 [20] An open label, randomized, two-treatment, two period, two sequence, crossover, single dose pharmacokinetic study under fasting (Test A) and fed (Test B) conditions was conducted in 12 healthy human male volunteers with a washout period of 3 days to compare the effect of food on the bioavailability of gabapentin. Fasting state was achieved by overnight fast of at least 10 hours and continued until 4 hours post dose. For fed state the subject was given breakfast and the gabapentin was administered 20 minutes after the breakfast. Each subject was administered gabapentin as a 900 mg sustained release tablet with 240 L of water under both fasting and fed states. Plasma sample were taken from pre-dose to up to 24 hours. The resulting pharmacokinetic data is given in Tables 1-5.

[21] Table 1 Comparative C of gabapentin in individual subjects under fasting and fed conditions. [22]

[23] Table 2 Comparative AUC of gabapentin in individual subjects under fasting and fed conditions. [24]

[25] Table 3 Comparative AUC o-# of gabapentin in individual subjects under fasting and fed conditions. [26]

[27] Table 4 Comparative mean pharmacokinetic parameters of gabapentin in human subjects following administration under fasting and fed states. [28]

[29] Table 5 Summary Statistics of Pharmacokinetic parameters for gabapentin in 12 healthy human subjects. [30]

[31] The above studies indicate that the oral bioavailability of gabapentin is considerably improved over the fasting mode when the gabapentin dosage form is administered with food. As shown, ' an increase in values of AUC 0-r , AUC 0-¥ and C max is realized in those subjects in the fed state.

[32] The linear plot of mean plasma gabapentin concentrations against time for the above study is given in Figure 1. Figure 1 is a plot of mean plasma concentration of gabapentin in nanograms per miUiliters versus the time elapsed from administration of the dosage form. Two plots are shown for a 900 mg dosage form administered with and without food.

[33] The data shows that the oral administration of gabapentm with food increases the extent of absorption, and hence the enhancement in oral bioavailability of gabapentin is realized. The enhancement of oral bioavailability of gabapentin when given with food presents the opportunity to reduce the frequency of administration of gabapentin. Oral gabapentin, typically ingested thrice a day, may be reduced to twice a day and/or once a day. An additional benefit is that the amount of daily dose can be reduced without compromising the therapeutic effectiveness of gabapentin. For a treatment responsive to gabapentin, the daily dose may be reduced.

[34] In separate pharmacokinetic studies, it was observed that immediate release tablets demonstrate comparable bioavailability to sustained release tablets under both fasting and fed conditions. This further indicates that there is marked increase in bioavailability when gabapentin is administered with food.

[35] While several particular forms of the invention have been described, it will be apparent that various modifications and combinations of the invention detailed in the text can be made without departing from the spirit and scope of the invention. For example, the methods described herein can be implemented in the form of written labeling or promotional lableing for gabapentin. Accordingly, it is not intended that the invention be limited, except as by the appended claims. Description Of Drawings [36] FIG. 1 shows a plot of the mean plasma concentration of gabapentin in nanograms per miUiliters versus the time elapsed administered with and without food.

Claims

[I] A method of treating a patient for a condition for which gabapentin is indicated, the method comprising: administering a controlled release oral dosage form comprising a therapeutically effective amount of gabapentin, the gabapentin dosage form being indicated for once daily administration; and consuming food within one hour of administering the oral dosage form. [2] The method according to claim 1 wherein the oral dosage form comprises tablets, capsules, granules, solid dosage form, or oral liquid dosage form. [3] The method according to claim 1 wherein the oral dosage form is a sustained release dosage form. [4] The method according to claim 1 wherein the oral dosage form is administered within 20 minutes to one hour of the consumption of food. [5] The method according to claim 1 wherein the oral dosage form is admimstered at the same time as consumption of food. [6] The method according to claim 1 wherein the oral dosage form is administered at a time ranging between immediately after consumption of food and up to one hour after the consumption of food. [7] The method according to claim 1 wherein administering the dosage form within one hour of consuming food increases the extent of absorption of gabapentin in the patient. [8] The method according to claim 1 wherein administering the dosage form within one hour of consuming food increases the oral bioavailability of gabapentin in the patient. [9] The method according to claim 1 wherein administering the dosage form within one hour of consuming food reduces the per day dosing frequency of the gabapentin by increases the oral bioavailability of gabapentin in the patient. [10] The method according to claim 1 wherein dosing frequency is reduced from twice daily to once daily.

[II] The method according to claim 1 wherein administering the dosage form within one hour of consuming food reduces the daily dose of gabapentin to the patient.