Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Web – sheet or filament bases; compositions of bandages; or...
Reexamination Certificate
1998-09-29
2001-09-04
Williamson, Michael A. (Department: 1616)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Web, sheet or filament bases; compositions of bandages; or...
C424S448000, C424S447000, C424S443000, C424S402000, C602S041000, C602S046000
Reexamination Certificate
active
06284266
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to methods and apparatus for administration of fentanyl and sufentanil. More particularly, the present invention relates to using controlled heat to improve administration of fentanyl and sufentanil.
2. State of the Art
The dermal administration of pharmaceutically active compounds involves the direct application of a 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.
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 (metabolism of the drug in the liver when the drug is taken orally and absorbed through the gastrointestinal tract), and avoiding of high peaks and low valleys of concentration of pharmaceutically active compounds in a patient's bloodstream. In particular, high peaks and low valleys of concentration are typical in injection and oral administrations and are often associated with undesirable side effects and/or less than satisfactory intended effects.
The term “transdermal analgesic delivery system” or “TADS”, as used herein, is defined as an article or apparatus containing analgesic(s) for delivery into the skin, the regional tissues under the skin, the systemic circulation, or other targeting site(s) in a human body via skin permeation. The term “TADS” in this application, unless otherwise specified, only refer to those systems in which the main driving force for drug permeation is the drug concentration gradient.
The term “analgesic”, as used herein, is defined to include any pharmaceutically active compound which renders a human body or portion of a human body insensible to pain without loss of consciousness.
The term “skin”, as used herein, is defined to include stratum corneum covered skin and mucosal membranes.
The term “clinical effect”, as used herein, is defined to include at least a diminishing of pain in an individual patient. The amount of analgesic necessary for a clinical effect will, of course, vary from patient to patient.
In TADSs, an analgesic(s) 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 analgesic. When a TADS is applied to skin, the analgesic begins to transport out of the formulation, and transport across the rate limiting membrane (if present). The analgesic then enters the skin, enters blood vessels and tissues under the skin, and is taken into the systemic circulation of the body by the blood. At least some TADSs have certain amount of analgesic in or on the skin side of the rate limiting membrane (if present) prior to use. In those TADSs, that portion of the analgesic on the skin side of the rate limiting membrane will enter the skin without passing through the rate limiting membrane. A significant portion of the dermally absorbed analgesic may be stored in the skin and/or tissues under the skin (hereinafter referred as “depot sites”) before being gradually taken into the systemic circulation (hereinafter referred as “depot effect”). For example, this depot effect is believed to be at least partially responsible for the delayed appearance of the fentanyl in the systemic circulation after the application of a fentanyl dermal delivery system, such as Duragesic® dermal fentanyl patch (distributed by Janssen Pharmaceutica, Inc. of Piscataway, N.J., USA), and for continued delivery of the fentanyl into the systemic circulation after the removal of the fentanyl dermal delivery system from the skin.
After placing a TADS on the skin, the analgesic concentration in the blood typically remains at or near zero for a period of time, before starting to gradually increase and reach a concentration deemed to be medicinally beneficial, called the “therapeutic level”(the time it takes to reach the therapeutic level is referred to hereinafter as the “onset time”). Ideally, the concentration of the analgesic in the bloodstream should plateau (i.e., reach a substantially steady state) at a level slightly higher than the therapeutic level and should remain there for extended period of time. For a given person and a given TADS, the “concentration of the analgesic in the bloodstream vs. time” relationship usually cannot be altered under normal application conditions.
The onset time and the delivery rate of the analgesic into the targeted area(s) of the body for a TADS are usually determined by several factors, including: the rate of release of the analgesic from the formulation, the permeability of the analgesic across the rate limiting membrane (if a rate limiting membrane is utilized), the permeability of the analgesic across the skin (especially the stratum corneum layer), analgesic 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 TADS. Although these primary factors affecting onset time and delivery rate are known, no existing TADS is designed to have alterable delivery rate in the course of the application of the analgesic.
While a TADS works well in many aspects, current dermal analgesic delivery technology has some serious limitations, including: 1) the onset time being undesirably long for many situations; 2) the rate that the analgesic is taken into the systemic circulation or the targeted area(s) of the body cannot be easily varied once the TADS is applied onto the skin and, when the steady state delivery rate is achieved, it cannot be easily changed; and 3) the skin permeability being so low that many analgesics are excluded from dermal delivery because the amount of analgesic delivered is not high enough to reach a therapeutic level. In addition, temperature variations in the skin and the TADS are believed contribute to the variation of dermal absorption of analgesics.
It is known that elevated temperature can increase the absorption of drugs through the skin. U.S. Pat. No. 4,898,592, issued Feb. 6, 1990 to Latzke et al., relates to a device for the application of heated transdermally absorbable active substances which includes a carrier impregnated with a transdermally absorbable active substance and a support. The support is a laminate made up of one or more polymeric layers and optionally includes a heat conductive element. This heat conductive element is used for distribution of the patient's body heat such that absorption of the active substance is enhanced. U.S. Pat. No. 4,230,105, issued Oct. 28, 1980 to Harwood, discloses a bandage with a drug and a heat-generating substance, preferably intermixed, to enhance the rate of absorption of the drug by a user's skin. Separate drug and heat-generating substance layers are also disclosed. U.S. Pat. No. 4,685,911, issued Aug. 11, 1987 to Konno et al., discloses a skin patch including a drug component, and an optional heating element for melting the drug-containing formulation if body temperature is inadequate to do so.
However, it would be advantageous to develop methods and apparatus to improve the analgesic administration of TADSs, and, more specifically, to make the use of TADSs more flexible, controllable, and titratable (varying the analgesic delivery rate, amount, or period according to the biological effect of the analg
Zhang Hao
Zhang Jie
Kirton & McConkie
Krieger Michael F.
Williamson Michael A.
Zars, Inc.
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