Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Capsules
Reexamination Certificate
2001-08-14
2003-11-11
Page, Thurman K. (Department: 1615)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Capsules
C424S451000, C424S464000, C424S490000, C424S496000, C424S497000, C424S474000, C424S465000
Reexamination Certificate
active
06645524
ABSTRACT:
TECHNICAL FIELD
The present invention relates generally to drug delivery, and more specifically relates to novel pharmaceutical dosage forms that provide pulsatile delivery of an antiarrhythmic agent for optimal therapeutic response. The invention additionally relates to methods for administering an antiarrhythmic agent using the novel dosage forms.
BACKGROUND
Antiarrhythmic agents are employed to treat patients suffering from, inter alia, cardiac contractions that are too rapid, too slow or asynchronous. Generally, antiarrhythmic agents are classified according to the Vaughan Williams' classification. For example, beta adrenoreceptor-blocking agents are classified as “Class II” antiarrhythmic agents and potassium channel blocking agents are classified as “Class III” antiarrhythmic agents.
Sotalol, N-[4-[1-hydroxy-2-[(1-methylethyl)amino]ethylphenyl]methane-sulfonamide, is a nonselective beta-adrenoreceptor blocking (Vaughan Williams Class II) agent with additional Class III antiarrhythmic properties, i.e., the ability to prolong the duration of the action potential. Both of these pharmacological properties contribute to the antiarrhythmic efficacy of sotalol. These same properties, however, may also cause cardiac toxicity with bradyarrhythmias, hypotension and torsade de pointes episodes, particularly with excessive doses of sotalol. Both isomers, i.e., d- and l-sotalol, have similar Class III antiarrhythmic effects, while the 1-isomer is responsible for virtually all beta-blocking activity. The racemic form, i.e., dl-sotalol, has both Class III antiarrhythmic and beta-blocking activities and has been marketed as a treatment of documented ventricular arrhythmias, atrial fibrillation and atrial flutter.
Sotalol hydrochloride is currently marketed in the United States by Berlex Laboratories in 80, 120, 160 and 240 mg tablets. To reduce the risks associated with sotalol therapy, the labeling recommends that treatment should be initiated with low doses (80 mg twice daily) administered in a monitored setting followed by a gradual dose increase to 120 to 160 mg twice daily. The drug can be given parenterally and is marketed for intravenous administration in several countries outside the United States.
The clinical pharmacokinetics of sotalol have been extensively studied. The drug is completely absorbed after oral ingestion on an empty stomach with time to maximum concentration occurring between about two to four hours following ingestion. When given with food, absorption is approximately 80%. After absorption, there is no significant presystemic metabolism, and the drug is completely bioavailable. Sotalol is not subject to many drug/drug interactions since sotalol exhibits negligible protein binding. The apparent volume of distribution of sotalol is two liters per kilogram of body weight. There is no major biotransformation of the drug after its absorption in the liver or other organs, and it is eliminated almost entirely (80-90%) by renal excretion as unchanged sotalol. Sotalol has a terminal elimination half-life of about 10 to 20 hours, and the drug's pharmacokinetics are unchanged with long-term administration. The usual antiarrhythmic dose of sotalol hydrochloride is 160 to 320 mg daily given in two or three doses. The clearance of sotalol is decreased in renal insufficiency and adjustment in the dosing interval or doses becomes necessary in kidney-compromised situations. The elderly may also experience decreased elimination of sotalol due to an age-related reduction in renal clearance.
To minimize the risks associated with sotalol therapy, patients are initiated on the drug at low doses, under close supervision, while monitoring both the degree of beta-blockade as well as electrocardiac activity. This approach generally requires patients to stay in the hospital for four days during which the pharmacodynamic response is closely supervised. In this way, the physician is assured that the patient is suitably stabilized with respect to ventricular arrhythmias or supraventricular arrhythmias such as arterial fibrillation and arterial flutter. After normal rhythm has been achieved, patients are discharged with a view to continuing treatment with twice or three times daily administration of sotalol. In order to overcome compliance problems and assist caregivers, there is a need in the art for a dosage regimen wherein the drug is administered in a convenient dosage form, e.g., a dosage form administered once daily, to these critical patients. The present invention is addressed to this need in the art by providing a means for administering an antiarrhythmic drug, e.g., sotalol or dofetilide, in a convenient, once-a-day, dosage form for optimal response.
It has been reported that possible loss of clinical efficacy occurs as a result of pharmacological tolerance after twice or three times daily dosing (80 mg each administration) in four out of ten patients after six days of dosing. Padrini et al. (1997)
Br. J. Clin. Pharmacol.
44:463-470; Le Coz (1992)
Clin. Pharmacol. Ther.
52:417-426. Therefore, for optimal response and maintenance of efficacy in a majority of patients, it is important for patients to have a drug release-free or nearly drug release-free period in order to allow receptors to return to their basal state. Thus, in order to minimize the development of tolerance, there is a need for a delivery system to deliver sotalol in a pulsatile manner having the appropriate drug release profile.
Clearly, the development of such a pulsatile delivery release system would be more desirable than a sustained release dosage form which generally delivers an active agent in a zero order release or at a constant rate. It is important to understand that if constant plasma levels (i.e., as provided by dosage forms having a zero order release or constant rate release) are delivered (or maintained) in these patients, there is the potentially serious problem of lost clinical efficacy as a result of supra sensitization, i.e., loss of repolarization of the cardioreceptors associated with beta-blockade and potassium channel blockade. In effect, these receptors get “tired” due to constant presence of the drug. Preferably, the cardioreceptors are given a period of time free from the presence of the drug so that the cardioreceptors may return to their normal state.
By providing a pulsatile delivery dosage form for administering sotalol, the invention mimics twice or three times daily dosing of sotalol. That is, the invention provides an immediate dose followed by one or more pulsatile doses several hours after ingestion of the dosage form. The pulsatile delivery dosage form of the invention improves compliance in critically ill patients and minimizes the development of tolerance relative to a sustained release dosage form. In addition, the pulsatile delivery dosage forms are ideal for controlling life-threatening arrhythmias in patients who have been discharged from clinical/hospital care.
A four-year Electrophysiologic Study vs. Electrocardiographic Monitoring (ESVEM) investigators' trial with sotalol has demonstrated that sotalol reduces the probability of recurrent ventricular tachycardia compared with Class I agents examined in the study. Lazzara et al. (1994)
Pacing Clin. Electrophysiol.
17:473-477. This trial assessed the long-term efficacy of racemic sotalol, imipramine, mexiletine, pirmenol, procainamide, propafenone and quinidine in 496 patients with histories of sustained ventricular tachyarrhythmias who were identified as responders based upon electrophysiologic testing or Holter monitoring. In the ESVEM trial, sotalol was more effective than the other agents in preventing death from arrhythmias or any other cardiac cause.
Sotalol is associated with side effects of beta-adrenergic blocking agents with a 4 to 6% incidence of proarrhythmias and a general incidence of torsade de pointes episodes. The incidence of torsade de pointes episodes associated with sotalol administration is greatest in patients with a history of sustained ventricular tachyca
Hirsh Mark
Lo Whe-Yong
Midha Kamal K.
Eberle Shelley P.
Page Thurman K.
Pierce Management LLC
Pulliam Amy E
Reed Dianne E.
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