Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Web – sheet or filament bases; compositions of bandages; or...
Reexamination Certificate
2002-03-01
2003-10-28
Page, Thurman K. (Department: 1615)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Web, sheet or filament bases; compositions of bandages; or...
C424S448000, C424S443000, C424S484000
Reexamination Certificate
active
06638528
ABSTRACT:
FIELD OF THE INVENTION
This invention relates generally to transdermal drug delivery systems, and more particularly to pharmaceutically acceptable adhesive matrix compositions, that use polymeric plastic materials, in particular insoluble cellulose derivatives such as ethyl celluloses, to regulate the drug release profile. The invention additionally relates to transdermal drug delivery systems providing substantially zero order drug release profiles for an extended period of time of up to seven days or longer.
BACKGROUND OF THE INVENTION
The use of transdermal drug delivery systems as a means to topically administer an active agent is well known. Such systems incorporate the active agent into a carrier composition, such as a polymeric and/or pressure-sensitive adhesive composition, from which the active agent is delivered through the skin or mucosa of the user.
In general, transdermal drug delivery systems are either reservoir-type or matrix-type devices. Both types of devices employ a backing layer that forms the protective outer surface of the finished transdermal system and which is exposed to the environment during use, and a release liner or protective layer that forms the inner surface and which covers whatever adhesive means is employed for affixing the system to the skin or mucosa of a user. The release liner or protective layer is removed prior to application, exposing the adhesive means, which is typically a pressure-sensitive adhesive.
In the “classic” reservoir-type device, the active agent is usually dissolved or dispersed in a carrier that typically yields a non-finite carrier form, like a fluid or gel, and which is kept separate from the adhesive means used to affix the device to the user. The device has a pocket or “reservoir” which physically serves to hold the active agent and carrier, and which is formed in or by the backing layer itself. A peripheral adhesive layer is then used to affix the device to the user. The early reservoir-type devices incorporated drugs which were readily absorbed through the skin like nitroglycerin and nicotine.
Such devices have a number of disadvantages including a non-uniform drug release profile wherein a high dose of drug is released initially upon application to the user, often described as a “burst effect.” This burst or high initial release of drug then drops off after a period of time to a rate that is less than is able to achieve a therapeutically effective amount. Drug delivery according to this profile is described as first order release.
While such classic devices are still in use today, the term reservoir is being used interchangeably with matrix-type devices which still rely upon a separate adhesive means used to affix the device to the user.
In a matrix-type device, the active agent is dissolved or dispersed in a carrier that typically yields a finite carrier form, which can be self-adhesive or non-adhesive. Non-adhesive matrix-type devices, that is, those which still rely upon a separate adhesive means to affix the device to the user, employ a drug permeable adhesive layer (often referred to as an “in-line adhesive” since the drug must pass through), applied over the drug matrix carrier layer. In an attempt to better control the release rate of the drug, such devices often employ one or more additional drug permeable layers such as rate controlling membranes, or containing excipients, such as drug delivery enhancers. Hence, such devices are also commonly referred to as multilayer or multilaminate.
In a “monolithic or monolayer” matrix-type device, the active agent is typically solubilized or homogenously blended in an adhesive carrier composition, typically a pressure-sensitive adhesive or bioadhesive, which functions as both the drug carrier and the means of affixing the system to the skin or mucosa. Such devices, commonly referred to as drug-in-adhesive devices, are described, for example, in U.S. Pat. Nos. 4,994,267, 5,446,070, 5,474,783 and 5,656,286, all of which are assigned to Noven Pharmaceuticals, Inc., Miami, Fla.
While matrix-type devices, especially drug-in-adhesive devices, have achieved more uniform and controlled drug deliver rates, and for longer periods of time, most transdermal systems remain subject to a higher initial drug release than is required to achieve therapeutic efficacy. For many drugs and/or therapeutic situations, it would be advantageous to eliminate or suppress this higher initial release and achieve a “steady state” (zero order) release profile which uniformly delivers a therapeutically effective amount of drug over the extended duration of device's desired use.
For example, the high initial release of certain drugs may cause adverse or undesired effects, or create toxicity concerns, thereby foreclosing the use of transdermal administration. In other instances, the higher initial release may reduce the amount of drug required for treatment to the point of risking underdosing, or may make it impractical to try and increase the duration of the device's application while retaining therapeutic effectiveness. The ability to reduce the frequency of replacing the transdermal drug delivery system would concomitantly increase user compliance, reduce any lag or drop off in efficacious. blood levels, and reduce the amount of drug required for treatment (also provided by reducing the higher initial blood level associated with the higher release rate).
Therefore, despite the existence of many different types of transdermal delivery systems in the art, there remains a continuing need for improving the release profile of drugs to achieve substantially zero order, as well as extending the duration of use of each transdermal system.
U.S. Pat. Ser. No. 07/897,269 discloses the use of glycerin to counteract the burst effect of drugs in transdermal formulations.
It has now been found that the addition of certain polymeric plastic polymers, in particular insoluble cellulose derivatives such as ethyl celluloses, into a pressure-sensitive adhesive matrix composition, eliminates or suppresses the initial high release rate of a drug subject to a first order release rate profile such that the system achieves substantially zero order release, and is able to maintain a substantially zero order release profile for an extended period of time up to seven days or longer.
Although not wishing to be bound by theory, particularly in this case where the structure of the composition has not been analyzed, it is postulated that the insoluble polymeric plastic material affects the uptake/absorption of water or moisture from the application site into the matrix composition which would otherwise create some of the kinetic driving force for release of the drug. This appears especially significant in the presence of hydrophobic drugs and/or in conjunction with the use of hydrophilic crystallization inhibitors, such as polyvinylpyrrolidones.
Ethyl celluloses have been extensively used in industrial applications since their commercial introduction in the mid-1930s. They are recognized and widely used as well for many different purposes in pharmaceutical applications, especially in conjunction with water-sensitive ingredients. Ethyl celluloses are most frequently used as binders, fillers, flavor fixatives, controlled release coatings/barriers in microencapsulation and other solid dosage forms, particularly multiparticulate systems, granulation aids, tablet film formers and taste maskers.
The prior art generally discloses the use of insoluble polymers such as ethyl cellulose as optional components in transdermal systems as thickening agents and as cohesiveness strengthening agents which effect the carrier's adhesive properties. For example, U.S. Pat. No. 5,232,702 discloses the use of a variety of substances that include ethyl cellulose and polyvinyl alcohol as cohesive strengthening agents (reducing flow properties of silicone adhesives) in a transdermal delivery system.
The present invention is able to regulate the release profile of the drug in a transdermal system without modifying the adhesive properties of
Joynes Robert M.
Kolman, Esq. Jay G.
Noven Pharmaceuticals Inc.,
Page Thurman K.
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