Controlled release pharmaceutical compositions containing...

Details Controlled release pharmaceutical compositions containing... Controlled release pharmaceutical compositions containing...

1998-07-31

2002-06-04

Spear, James M. (Department: 1615)

Drug, bio-affecting and body treating compositions

Preparations characterized by special physical form

Tablets, lozenges, or pills

C424S469000, C424S474000, C424S475000, C424S486000, C424S488000, C424S489000, C424S490000, C514S772300, C514S781000

Reexamination Certificate

active

06399100

ABSTRACT:

FIELD OF THE INVENTION
This invention relates to controlled release tiagabine formulations and in particular to matrix delivery systems for providing oral controlled release tiagabine formulations, including once or twice daily formulations.
BACKGROUND OF THE INVENTION
The anti-epileptic drug tiagabine hydrochloride, a nipecotic acid derivative linked to a lipophilic anchor which enables it to cross the blood-brain barrier, potently and specifically inhibits uptake of the inhibitory neurotransmitter &ggr;-aminobutyric acid (GABA) into astrocytes and neurons. Tiagabine is primarily under investigation as an anticonvulsant agent, but the compound is also reported to possess anxiolytic activity and may be beneficial in the treatment and prevention of tardive dyskinesia. Tiagabine has shown broad activity against a range of seizure types, including drug-induced, electroshock-induced, light-induced, amygdala-kindled, and audiogenic and has been approved in a number of countries for add-on treatment of adult epileptic patients with complex partial seizures. It is well tolerated and does not cause withdrawal effects or displace other drugs. In humans, tiagabine absorption is rapid and complete. It is metabolized in the liver with a linear process of elimination and a half-life of 5-8 hours. Although tiagabine does not induce or inhibit metabolic processes, it can provide a target for enzyme inducers that can lower its elimination half-life to 2-3 hours. Conventional formulations of tiagabine, such as 10 mg formulations, are dosed t.i.d. or q.i.d.
Published information regarding therapeutic plasma levels for tiagabine include Leach et al. (
Seizure
4(2):155-7, 1995), which reports an experience with a deliberate overdose of tiagabine. Plasma levels were 3.1 &mgr;g/ml four hours after ingestion which is 30 times higher than typical steady state therapeutic dosing levels. Sachdeo et al. (
Archives of Neurology
54(5):595-601, 1997) evaluated 2 regimens for tiagabine dosing, 16 mg b.i.d. or 8 mg q.i.d. (34 mg/day), as add-on therapy for patients with complex partial seizures. Schacter (
Epilepsia
36 Suppl 6:S2-26, 1995) assessed tiagabine monotherapy in patients with partial seizures. In a dose-ranging study, the mean final dose was 38.4 mg/day (range: 24-54 mg/day) for patients who converted to tiagabine monotherapy. In a low (6 mg/day) versus high (36 mg/day) dose study, median 4-week complex partial seizure rates decreased significantly in patients from both dose groups but significantly more patients in the high-dose group experienced a reduction in seizures of at least 50% compared with the low-dose group.
U.S. Pat. No. 5,010,090 discloses a class of novel compounds, including tiagabine, and their pharmaceutically acceptable salts that exhibit GABA-uptake inhibitory properties useful for the treatment of epilepsy and other CNS related diseases. U.S. Pat. No. 5,354,760 discloses crystalline tiagabine hydrochloride monohydrate and a process for preparing the same. WO 96/34606 discloses tiagabine hydrochloride compositions which include an antioxidant such as &agr;-tocopherol to stabilize the tiagabine. Despite the relatively short elimination half-life for tiagabine in humans and the concomitant need to administer the drug several times per day, none of these patents address the additional benefits possible from a controlled-release formulation for tiagabine such as enhanced patient compliance or improved therapeutic results.
WO 95/29665 discloses a slow-release extended antiepileptic drug dosage form that has an exit in the dosage form for releasing the antiepileptic drug and a lamina between the dosage form wall and the antiepileptic drug formulation to maintain the integrity of the dosage form during the delivery of the antiepileptic drug to the patient. Additionally, this application discloses a diffusion-dosage form that releases a drug by membrane-controlled diffusion, a bioerodible dosage form and a ion-exchange dosage form for administration of antiepileptic drugs selected from the group consisting of hydantoins, barbiturates, deoxybarbiturates, iminostilbenes, succinimides, oxazolidinediones and benzodiazepines. Examples for the antiepileptic drugs phenytoin, carbamazepine, and ethotoin are provided.
Controlled-release therapeutic dosage forms for tiagabine in which the medicinal substance is incorporated into a matrix would be desirable per se on account of the ease of their manufacture, the low degree of variation between different manufacturing processes and because of the relatively low costs. Ideally, not only should the dosage form control release of the tiagabine in such a manner that an effective concentration in the blood can be maintained over an extended period of time, but also the drug release should be such that the drug concentration in the blood remains relatively constant over the extended period of time to improve therapeutic results and/or minimize side effects. Thus, there exists a need for a controlled-release tiagabine formulation having these properties, especially one having minimal C
max
to C
min
peak to trough variations over a period of at least either 12 or 24 hours.
SUMMARY OF THE INVENTION
It is an object of the present invention to provide controlled release oral dosage forms for tiagabine which provide therapeutic levels of tiagabine for a period of at least 12 hours, preferably 24 hours or longer.
It is a further object of the present invention to provide controlled release oral dosage forms for tiagabine which provide a tiagabine plasma concentration equal to or greater than 50% of the maximum plasma concentration (C
max
) for at least 10 hours, preferably 15 hours, most preferably 20 hours or more. Preferably, the maximum plasma concentration minus the minimum plasma concentration divided by the average plasma concentration [(C
max
−C
min
)/C
av
] taken over a period of at least 12 hours, preferably 24 hours, is less that 0.80, more preferably less than 0.60.
It is yet a further object of the present invention to provide controlled release oral dosage forms for tiagabine which provide therapeutic levels of tiagabine for a period of at least 12 hours, preferably 24 hours, having a mean in vitro dissolution profile in aqueous media at 37° C. such that about 5
5
to 40% of the tiagabine is released after 1 hour; about 25-65% is released after 4 hours; about 55-95% is released after 10 hours and about 80-100% is released after 22 hours when measured according to the USP Apparatus II (paddles) method. More preferably, the in vitro dissolution profile shows release of about 10 to 30% tiagabine after 1 hour; 30 to 60% release after 4 hours; 60 to 90% release after 10 hours and 85 to 100% release after 22 hours.
The above-mentioned objects and others are achieved by virtue of the present invention, which provides a controlled release preparation comprising a therapeutically effective amount of tiagabine dispersed in a rate controlling polymeric matrix comprising at least one rate controlling polymer. It is found that incorporation of tiagabine in the polymeric matrixes according to this invention allows for effective control over the release of tiagabine over time such that administration of the preparation achieves therapeutic levels of tiagabine over extended periods of time in humans, such as for at least 12 hours, and in certain preferred embodiments, for 24 hours or longer.
The applicants have found in the case of the formulations of the present invention that therapeutically effective blood levels of tiagabine can be maintained substantially over 24 hours with peak plasma levels occurring between 2 and 18 hours, preferably between 4 and 16 hours, most preferably between 6 and 14 hours.
The rate controlling polymer preferably includes a hydroxypropyl-methylcellulose (HPMC), a hydroxypropylcellulose (HPC), a poly(ethylene oxide), an ethylcellulose or a combination thereof present in an amount of 5 to 75% by weight, more preferably 20 to 50% by weight, most preferably 30 to 45% by weight in the preparation.
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