Drug – bio-affecting and body treating compositions – Inorganic active ingredient containing – Elemental iodine or iodine compound
Reexamination Certificate
2000-05-24
2002-04-23
Jones, Dwayne C. (Department: 1614)
Drug, bio-affecting and body treating compositions
Inorganic active ingredient containing
Elemental iodine or iodine compound
Reexamination Certificate
active
06375990
ABSTRACT:
BACKGROUND OF THE INVENTION
As a mood stabilizing agent, lithium has a long history of documented efficacy as well as risk associated with its use. Lithium has the narrowest gap between therapeutic and toxic concentrations of any drug routinely prescribed in psychiatric medicine, and is poorly tolerated in one-third or more of treated patients. The incidence and severity of toxicity associated with its use is related to the plasma concentration of Li
+
and its rate of rise following conventional oral routes of dosing. Lithium can be lethal in overdose and there is no specific antidote for Li
+
intoxication. The safety and tolerability of Li
+
could be dramatically improved by the use of a sustained, controlled Li
+
delivery system.
Applicants have discovered a transdermal route of delivery as a suitable means of avoiding oral dosing “peaks” and symptomatic “troughs”, of minimizing the need for routine blood concentration monitoring, and of decreasing total daily doses, drug interactions, and dosing frequency. These advantages allow improved patient compliance and quality of life for patients treated with Li
+
. The well-recognized medical-legal liabilities associated with Li
+
treatment are substantially changed, and allow an expanded use of Li
+
as an effective drug in the treatment of disabling mood disorders and other psychiatric illnesses.
Lithium is a fixed monovalent cation and the lightest of the alkali metals (group la of the Periodic Table of the elements). Of relevance to the design of this device, Li
+
has the highest energy of hydration of the alkali metals and, as such, can substitute for Na
+
(and to a lesser extent K
+
) for ion transport by biological systems. Lithium is both electroactive and hydrophilic. Lithium is abundant in some alkali metal-spring waters and has numerous industrial applications. Trace amounts of Li
+
are found in human tissues; typical human blood plasma concentrations of Li
+
are 17 &mgr;g/L.
Lithium has no known physiological effects in man. Unlike other psychotropic drugs, Li
+
has no discernible psychotropic effects in normal man. The therapeutic efficacy of lithium in the treatment of acute mania and the prophylactic management of bipolar (manic/depressive) disorder has been consistently demonstrated. Lithium, along with the recent addition of valproic acid (Depakote ®, Trademark of Abbot Laboratories, Inc.), are the only drugs currently approved by the US Food and Drug Administration for the treatment of acute mania. Manic-depressive disorder (bipolar disorder) is a chronic, cycling disease that afflicts approximately 1-1.8% of the population. Manic symptoms include hyperactivity, impaired judgment, insomnia, grandiosity and other delusions. Affected individuals exhibit severe functional impairments evidenced by alienation from family, friends, and coworkers; indebtedness; job loss; divorce; and other problems of living. Lithium salts were introduced into psychiatry in 1949 for the treatment of mania and were accepted for this use in the United States in 1970. Evidence for the efficacy of lithium salts in the treatment of mania and the prevention of recurrent symptoms of manic-depressive illness is now highly impressive. The additional use of lithium coadministration in augmentation strategies has been used as a means of enhancing treatment response to a wide range of psychiatric drugs. Both lithium carbonate and lithium citrate are currently in therapeutic use in the US.
In the nearly 50 years of accumulated clinical experience with Li
+
no distinctly improved agent has emerged for the treatment of the morbidity and mortality of bipolar disorder. While it remains the first-line therapy for bipolar disorder, the oral administration of Li
+
is predictably associated with a large and diverse array of adverse effects that impact negatively on patient compliance and safety. These events are in turn well related to the pharmacokinetics of orally administered formulations. Symptomatic states related to interdose concentration “troughs” or inadvertent noncompliance further exacerbates noncompliance. Only one-third of patients in a recent community sample were estimated to be compliant. The development of sustained or slow release Li
+
preparations represents a direct response to the limitations of oral routes of lithium salt administration. However, the performance of these preparations vary between manufacturers and between batches and they are often used in divided daily dosing strategies similar to nonsustained release preparations. Extremely slow release preparations are furthermore associated with pronounced GI irritation. Available sustained release formulations represent an imperfect solution to the limitations of oral lithium dosing. There is thus a clinical need for an alternative dosing strategy for Li
+
that is not met by currently available preparations. The device and methods of the present invention offer a novel strategy of transdermal Li
+
delivery to enhance the safety and efficacy of a drug of documented effectiveness and value in psychiatric practice.
The device of the present invention was developed to meet pharmacokinetic inadequacies of the use of conventional oral dosing strategies that limit therapeutic applications of lithium in clinical medicine. Such limitations include acute and long term toxic reactions, the emergence of breakthrough symptoms, poor patient compliance, the necessity of therapeutic drug monitoring and a lack of safety in overdose situations. A transdermal delivery system for lithium according to the present invention is suitable for these purposes.
BRIEF DESCRIPTION OF THE INVENTION
A method of administering Li
+
to a patient at substantially constant rate without causing significant pain or tissue damage is disclosed. The method involves the attachment of a dermal patch to the patient, wherein the patch delivers Li
+
in response to a current, desirably a direct current, even more desirably a pulsed direct current, presumably by iontophoresis. Also disclosed is a dermal patch for use in the method of the present invention. The method and the patch are suitable for the treatment of acute mania, bipolar (manic/depressive) disorder, and other psychiatric illnesses susceptible to treatment with lithium, and is particularly adaptable to long-term administration and treatment.
The transdermal delivery of lithium to the systemic circulation is based on the application of patch technology incorporating an iontophoretic form of electrically assisted drug delivery. In a particular embodiment of the invention, the device uses direct current (dc), desirably pulsed, anodal iontophoretic lithium delivery, with patch placement typically at a site rich in sweat glands, such as at an axillary site. Controlled lithium delivery is dose adjustable and programmable as a function of the applied current density.
The device and method of the present invention allow the administration of lithium ion to the bloodstream within the therapeutic window without peaks (creating damage of toxicity) and troughs (creating the danger of breakthrough symptoms and decreased patient compliance) experienced with conventional methods of lithium administration. Lithium is controllably delivered across at least the stratum corneum, and possibly other layers of the epidermis, using an unobtrusive device that requires minimal compliance activity on the part of the patient.
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Kilts Clinton D.
Nemeroff Charles B.
Emory University
Gray Bruce D.
Jones Dwayne C.
Kilpatrick & Stockton LLP
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