Surgery – Means for introducing or removing material from body for... – Treating material introduced into or removed from body...
Reexamination Certificate
1999-05-24
2004-04-27
Casler, Brian L. (Department: 3763)
Surgery
Means for introducing or removing material from body for...
Treating material introduced into or removed from body...
C604S020000, C604S291000, C424S447000, C424S449000
Reexamination Certificate
active
06726673
ABSTRACT:
BACKGROUND
1. Field of the Invention
The present invention relates to methods and apparatus for the administration of testosterone and other androgens. More particularly, the present invention relates to using controlled heat to improve administration of testosterone pharmaceuticals.
2. Description of the Prior Art
The dermal administration of pharmaceutically active compounds involves the direct application of pharmaceutically active formulation(s) to the skin, wherein the skin absorbs a portion of the pharmaceutically active compound which is then taken up by the blood stream. Such administration has long been known in the practice of medicine and continues to be an important technique in the delivery of pharmaceutically active compounds. For example, U.S. Pat. No. 4,286,592, issued Sep. 1, 1981, to Chandrasekaran shows a bandage for administering drugs to a user's skin consisting of an impermeable backing layer, a drug reservoir layer composed of a drug and a carrier, and a contact adhesive layer by which the bandage is affixed to the skin.
For some drugs, such dermal administration offers many important advantages over other delivery techniques, such as injection, oral tablets, and capsules. These advantages include being noninvasive (thus, less risk of infection), avoiding first pass metabolism of the drug in the liver when the drug is taken orally and absorbed through the gastrointestinal tract, and improved control of the concentration of pharmaceutically active compounds in a patient's bloodstream. In particular, uncontrolled and unwanted variance in concentrations over time are typical in injection and oral administrations and are often associated with undesirable side effects and/or less than satisfactory intended effects.
In recent years there has been an increased interest in noninvasive drug delivery systems such as androgen transdermal therapeutic systems (ATTS). ATTSs offer the advantages of providing controlled release of a drug for a specified period, in contrast to the uncontrolled peaks and troughs produced by oral or parenteral application. Other advantages of these systems include: elimination of gastrointestinal absorption, reduced total dosage, less expensive than intramuscular or intravenous administration where applicable, avoidance of “first pass” inactivation by the liver, use of agents with a narrow therapeutic index, and improved compliance with decreased administration cycle.
The major goals of testosterone replacement therapy are to restore serum testosterone concentrations to within the normal range for healthy men and, if possible, in a way that mimics the normal circadian pattern of endogenous secretion. More specifically it is desirable for the therapy to mimic the natural rise of testosterone level which peaks in the morning followed by gradual decrease, reaching a valley in the evening. Use of a androgen transdermal delivery system to deliver testosterone as disclosed in the present invention in hypogonadal men can achieve this goal. Other therapeutic uses of androgen(s) with the present invention include but are not limited to treatment of hypopituitarism, osteoporosis, menstrual disorders, refractory anemia, promotion of anabolism, and influencing conditions related to puberty.
Male hypogonadism is a disorder whereby testosterone production is reduced below the normal range of 3 to 10 mg/day. Symptoms of this disorder include impairment in:libido, sexual function, energy, mood, as well as regression of secondary sex characteristics and decreases in lean body mass and bone density. Available androgen replacement modalities include intramuscular injection of long-acting testosterone esters and oral administration of alkylated and esterified testosterone. However, neither of these treatments delivers testosterone in a manner which produces plasma levels mimicking normal circadian profiles of the endogenous hormone. Recently several transdermal testosterone systems have been developed. These systems have normalized serum testosterone concentrations over a period of 24 hours and allowed some approximation of the circadian pattern seen in healthy young men. Although these systems have proven useful, they are not without side effects. For example approximately 53 percent of men experience local skin reactions (contact dermatitis) at the application sites after using Androderm®, a testosterone patch, which in some instances necessitates discontinuing use of the patch.
The term “androgen transdermal therapeutic system” or “ATTS,” as used herein, is defined as an article, apparatus or method for delivery of androgen into the human body via skin permeation. An ATTS is designed for therapeutic and other uses of androgens. The term “ATTS” in this application, unless otherwise specified, only refers to those systems in which the main driving force for drug permeation is the drug concentration gradient.
The term “androgen,” as used herein, is broadly defined to include any pharmaceutically active compound which is capable of regulating masculine secondary sexual characteristics, including but not limited to esters of testosterone such as propionate, phenylacetate, enanthate, cypionate, methyl testosterone, fluoxymesterone, methandrostenolone, 17 alpha-methylnortestosterone, norethandrolone, stanolone, oxymetholone, stanozolol, ethylestrenol.
Additionally, androgens include pharmaceutically active agents which promote growth, such as an increase in height and development of skeletal musculature, thickening of the skin, proliferation of sebaceous glands, as well as loss of subcutaneous fat, growth of axillary and body hair, growth of the larynx, growth of beard and initiating the onset of male pattern baldness. Androgens may also be generally described as pharmaceutical agents acting on the pituitary, testes and sebaceous glands or an agent which has nitrogen retaining anabolic effects.
The term “skin,” as used herein, is defined to include stratum corneum covered skin and mucosal membranes.
In an ATTS, an androgen is usually contained in a formulation, such as a hydro-alcohol gel, and may include a rate limiting membrane between the formulation and skin for minimizing the variation in the permeation of the androgen. When an ATTS is applied to skin, the androgen begins to transport out of the formulation, and transport across the rate limiting membrane (if present). The androgen then enters the skin, enters the blood vessels and tissues under the skin, and is taken into the systemic circulation of the body by the blood. An ATTS may have certain amounts of androgen in or on the skin side (the bottom side) of the rate limiting membrane (if present) prior to use. For example, some of the drug may be present in an adhesive on the bottom side of the rate limiting membrane. In those ATTS's, that portion of the androgen on the skin side of the rate limiting membrane will enter the skin without passing through the rate limiting membrane.
After placing an ATTS on the skin, the androgen concentration in the blood typically remains unchanged from the natural levels for a period of time, before starting to gradually increase and reach a concentration deemed to be medicinally significantly beneficial, called the “therapeutic level” (the time it takes to reach the therapeutic level is referred to hereinafter as the “onset time.”). The onset time and the delivery rate of the androgen into the targeted area(s) of the body for a typical ATTS are usually determined by several factors, including: the rate of release of the androgen from the formulation, the permeability of the androgen across the rate limiting membrane (if a rate limiting membrane is utilized), the permeability of the androgen across the skin (especially the stratum corneum layer), androgen storage in and release from the depot sites, the permeability of the walls of the blood vessels, and the circulation of blood and other body fluid in the tissues (including the skin) under and around the ATTS.
While an ATTS works well in many aspects, current dermal androgen delivery technology has some s
Hull Wade A.
Rigby Larry
Zhang Hao
Zhang Jie
Casler Brian L.
Kirton & McConkie
Krieger Michael F.
Williams Catherine S.
Zars, Inc.
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