1. Field of Invention
This invention relates generally to transdermal and transmucosal drug delivery (DD) devices. More particularly, the present invention relates to dual drug loaded adhesive laminated TDD devices for delivering drugs at different rates, e.g., the delivery of fentanyl and its analgetically effective derivatives for the relief of postoperative and terminal cancer pains.
2. Description of the Prior Art
The efficacy of some systemically acting drugs may be optimized by administering them in a manner that rapidly produces therapeutically effective blood levels. The most common method to achieve such a goal is by bolus injection. Oral administration, depending upon the ability of the drug to be absorbed into the circulation via the gastrointestinal tract, may also afford a rapid onset of therapeutically effective blood levels. Transdermal drug delivery while often viewed is an advantageous mode of administration over injection or oral dosing, especially for establishing constant long term drug delivery, is not normally considered to be a practical means for rapidly achieving high blood levels of drugs. This is because most transdermal drug delivery devices operate in a manner that results in a significant lag time (the time needed for a given therapeutic agent to reach an effective blood concentration following administration) between placing the device on the skin and realizing the required or desired blood levels.
Representatives of drugs where a rapid onset of activity is desired are analagesics used to control or treat postoperative and terminal cancer pains. Fentanyl and its analgetically effective derivatives (hereafter referred to as xe2x80x9cderivativesxe2x80x9d such as sufentanyl, carfentanyl, lofentanyl and alfentanyl and analogous bases and salts thereof, have long been known as extremely potent and effective anesthetics and analgesics. The chemical nomenclature for fentanyl is N-phenyl-N-[1-2-phenylethyl)-4-piperidinyl]propanamide. Fentanyl has been used as a synthetic opioid to alleviate postoperative or terminal cancer pains due to the fact that its analgesic effects are 50-100 times more potent than morphine. The effective analgesic plasma concentration of fentanyl varies from subject to subject, however, the mean concentration of fentanyl is about 1 ng/mL and 3 ng/mL for postoperative administration and intraoperative administration, respectively. Plasma concentrations of fentanyl up to 10 ng/mL have been shown to be effective in treating pain experienced in the terminal stages of a cancer and similar situations.
Fentanyl has been traditionally administered via intravenous or intramuscular injection as a way to relieve pain. It is normally administered either as a bolus injection, infusion or continuous infusion. These conventional methods, although providing an analgesic effect, have been known to have some drawbacks. For example, fentanyl has to be administered in multiple doses and in an excessive amount because fentanyl has a relatively short biological activity half-life (3.7 hrs in plasma concentration and 0.78L/hr/kg in systemic clearance). Further, repeated administration of excessive amounts of fentanyl can lead to development of tolerance and physical dependence to fentanyl, as is often the case with other opioid drugs. In addition, intravenous injection of fentanyl may result in hypopnea.
The application of transdermal drug delivery technology to the administration of a wide variety of drugs has been proposed and various systems for accomplishing this have been disclosed. Recently, transdermal delivery systems for fentanyl were developed to remedy the above-mentioned drawbacks of traditional methods. Transdermal delivery systems can minimize the usual rejection of fentanyl administration by a patient due to side effects such as tolerance and physical dependence, which result from the pulsed nature of an oral or an injectable agent during delivery into the body and can maintain fentanyl concentrations at a constant level during administration thus eliminating the peak-and-valley phenomenon of blood levels often seen during drug injection. Furthermore, the fact that the drastic increase in blood concentration of fentanyl immediately after an injection may be too toxic, supports the idea that transdermal delivery systems will be more advantageous both in terms of safety and efficacy.
U.S. Pat. No. 4 ,626,539 discloses the transdermal delivery of an opioid and the use of various vehicles to enhance the penetration through skin of an opioid. U.S. Pat. No. 4.583,580 discloses a reservoir type transdermal delivery system of fentanyl that is already commercialized. The device disclosed uses ethanol as A permeation enhancer and the mixture of fentanylthanol is contained in the reservoir in a fluid form. However, a significant amount of fentanyl still remains unused even after completion of administration and this raises a safety problem in that leftover fentanyl can be recovered and misused for purposes other than the intended therapeutic use. Moreover, this system requires a multi-step manufacturing process and also requires a lag time of up to ten hours following administration for optimal analgesic effect to be realized thus necessitating the initial administration to be conducted in combination with an injection for more effective treatment of pain.
A common problem encountered with use of transdermal delivery systems is the presence of lag time. U.S. Pat. No. 5,352,456 discloses a transdermal drug delivery system that enables higher amounts of the therapeutic agent to be delivered systemically upon application by establishing a volatile penetration-enhancing layer within a laminated layer.
U.S. Pat. No. 5,820,875 discloses a reservoir drug delivery system combining a non- volatile permeation enhancer and a volatile penetration enhancer which provides an initial burst of a given therapeutic agent to the dermis. However, the extent of volatilization of a given therapeutic agent differs depending on the environment of the system being used, and it is difficult to maintain the skin flux of a given therapeutic agent at a constant level thus making the manufacturing process more complicated and consistent drug delivery somewhat variable.
U.S. Pat. No. 5,186,939 discloses a laminated transdermal system for administration of fentanyl which is characterized by using propylene glycol monolaurate as a penetration enhancer and a silicone adhesive as a reservoir for the therapeutic agent. However, this system cannot contain more than 2 wt % of a therapeutic agent due to the relatively low solubility of fentanyl in the silicone adhesive. There is a shorter duration of delivery of the therapeutic agent as compared to that in the abovementioned U.S. Pat. No. 4,588,580 because the reservoired therapeutic agent is rapidly released, e.g., within 24 hrs. This system is therefore unable to maintain a constant and sustained blood concentration of the therapeutic agent.
U.S. Pat. No. 5,843,472 discloses a drug delivery system for the transdermal administration of tramsulosin. The system is a laminated composite comprising a backing layer, a drug reservoir, and adhesive means for affixing the composite to the skin. The reservoir is comprised of a polymeric matrix material containing tamsulosin and a permeation enhancer. In a preferred embodiment, the system contains two drug reservoirs comprised of polymeric adhesive material, one overlays to another and they are separated by an absorbent source layer of a nonwoven fabric.
U.S. Pat. No. 5,626,866 discloses a method for making a transdermal drug deliver) device for heat sensitive and volatile drugs. The device for administering a drug to the skin consists of a drug-containing adhesive composite layer having an impermeable backing material laminated to the distal surface thereof and a proximal peelable impermeable backing material so adapted. The drug, in gelled form is extruded onto at least one exposed surface of the first or second adhesive laminate followed by laminating together the exposed surfaces of the first and second adhesive laminate such that the adhesive layers and gelled drug are combined to form the drug containing adhesive composite.
Some drugs, such as fentanyl and its derivatives, are highly potent, rapidly metabolized drugs having a relatively narrow therapeutic index, which produce extremely undesirable side effects when overdosed, most notably respiratory depression which if left unchecked could cause death. These drugs are also relatively expensive and have a high potential for abuse. Therefore, it would be desirable that the device deliver the drug at a substantially constant rate for a sustained period of time, e.g. aleast 24 hours, while at the same time not having a long lag time. This device would also keep the amount of drug within the depleted system to a minimum. It is also desirable that the device have a controlled delivery rate so that excessive amounts of drugs are not delivered.
Accordingly, the present invention provides a drug-containing laminated transdermal delivery system wherein the drug can be rapidly released during the early stages of administration and rapidly reach a therapeutic level systemically, and then maintain a persistent long-term therapeutic effect.
One embodiment of the present invention is a fentanyl-containing laminated transdermal delivery system which is useful for treating the acute pains that accompany any surgery or chronically experienced during terminal illness such as cancer.
The drug-containing laminated transdermal delivery system of the present invention comprises at least two adjacent drug containing pressure-sensitive adhesive(PSA) layers having different solubilities for the drug. One surface of each layer is laminated to an impermeable backing support and the opposing surface is adapted to be applied to and adhere to the skin of a wearer. For manufacturing and storage purposes, the surface to be attached to the skin is covered with a peelable backing layer which is stripped off prior to use. Each adhesive layer has a certain surface area or ratio of one layer to the other contingent upon factors affecting the delivery of drug therefrom such as the solubility of the drug in each adhesive. Therefore, in the device of the present invention, a certain amount of the drug can be rapidly released in the early stage of administration from the adhesive polymer layer which has a relatively low solubility of the drug, thus triggering earlier onset of the therapeutic effect of the by reducing the time needed to reach a therapeutic blood level. After a certain duration of time of administration, the drug can be released at a constant rate from the adhesive polymer layer which has a relatively high solubility of the drug and so maintains a persistent long-term analgesic effect
The present invention is particularly useful for the transdermal delivery of highly potent rapidly metabolized drugs having relatively narrow therapeutic indexes which may produce extremely undesirable side effects when overdosed, such as fentanyl and its derivatives, which are excellent therapeutic agents for treating acute postoperative or terminal cancer pains.
The present invention also provides methods of making and using a transdermal drug delivered device wherein the drug can be rapidly released during the early stages of administration to reach a therapeutic level systemically and maintain a persistent long-term analgesic effect.
USPTO Backgrounds
USPTO Backgrounds