Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Web – sheet or filament bases; compositions of bandages; or...
Reexamination Certificate
2002-06-19
2004-01-06
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...
C424S443000, C424S445000, C424S447000, C424S448000, C514S946000, C514S947000, C514S944000
Reexamination Certificate
active
06673363
ABSTRACT:
FIELD OF THE INVENTION
This invention relates generally to the topical and transdermal administration of local anesthetic agents, and more particularly relates to methods and compositions for enhancing the flux of local anesthetic agents through a body surface utilizing a basic permeation enhancer.
BACKGROUND OF THE INVENTION
The delivery of drugs through the skin provides many advantages; primarily, such a means of delivery is a comfortable, convenient and noninvasive way of administering drugs. The variable rates of absorption and metabolism encountered in oral treatment are avoided, and other inherent inconveniences, e.g., gastrointestinal irritation and the like, are eliminated as well. Transdermal drug delivery also makes possible a high degree of control over blood concentrations of any particular drug.
Skin is a structurally complex, relatively thick membrane. Molecules moving from the environment into and through intact skin must first penetrate the stratum corneum and any material on its surface. They must then penetrate the viable epidermis, the papillary dermis, and the capillary walls into the blood stream or lymph channels. To be so absorbed, molecules must overcome a different resistance to penetration in each type of tissue. Transport across the skin membrane is thus a complex phenomenon. However, it is the cells of the stratum corneum, which present the primary barrier to absorption of topical compositions or transdermally administered drugs. The stratum corneum is a thin layer of dense, highly keratinized cells approximately 10-15 microns thick over most of the body. It is believed to be the high degree of keratinization within these cells as well as their dense packing which creates in most cases a substantially impermeable barrier to drug penetration. With many drugs, the rate of permeation through the skin is extremely low without the use of some means to enhance the permeability of the skin.
Numerous chemical agents have been studied as a means of increasing the rate at which a drug penetrates through the skin. As will be appreciated by those in the field, chemical enhancers are compounds that are administered along with the drug (or in some cases the skin may be pretreated with a chemical enhancer) in order to increase the permeability of the stratum corneum, and thereby provide for enhanced penetration of the drug through the skin. Ideally, such chemical penetration enhancers or “permeation enhancers,” as the compounds are referred to herein, are compounds that are innocuous and serve merely to facilitate diffusion of the drug through the stratum corneum. The permeability of many therapeutic agents with diverse physicochemical characteristics may be enhanced using these chemical enhancement means. However, there are skin irritation and sensitization problems associated with high levels of certain enhancers.
There are many potential uses for topical and transdermal delivery of local anesthetic agents. Such uses include the treatment of burns, contact dermatitis, insect bites, pain, pruritus, skin rash, wounds and other dermal injuries; use as part of or in preparation for a surgical procedure; use as a pretreatment prior to needle injection, such as for subcutaneous injections, venipucture, and in particular for intramuscular or intrajoint injections such as for the administration of corticosteroids and other steroids, and so forth.
Accordingly, there is a need for a method that is highly effective in increasing the rate at which local anesthetic agents permeate the skin, does not result in skin damage, irritation, sensitization, or the like, and can be used to effect transdermal delivery of a wide range of compounds within the class of local anesthetic agents. It has now been discovered that basic permeation enhancers as described herein are highly effective permeation enhancers, and provide all of the aforementioned advantages relative to known permeation enhancers. Furthermore, in contrast to many conventional enhancers, transdermal administration of local anesthetic agents with basic permeation enhancers, employed at the appropriate levels, does not result in systemic toxicity.
SUMMARY OF THE INVENTION
One aspect of the invention pertains to a method for enhancing the flux of a local anesthetic agent through a body surface, comprising: (a) administering the local anesthetic agent to a localized region of a human patient's body surface; and (b) administering a basic permeation enhancer to the localized region, the enhancer comprising a pharmaceutically acceptable base and being present in an amount effective to provide a pH within the range of about 8.0-13.0 at the localized region of the body surface during administration of the agent and to enhance the flux of the agent through the body surface without causing damage thereto. The pharmaceutically acceptable base can be an inorganic or an organic base.
Another aspect of the invention relates to a composition for the enhanced delivery of a local anesthetic agent through a body surface, comprising a formulation of: (a) a therapeutically effective amount of the local anesthetic agent; (b) a pharmaceutically acceptable base in an amount effective to provide a pH within the range of about 8.0-13.0 at the body surface during administration of the agent and to enhance the flux of the agent through the body surface without causing damage thereto; and (c) a pharmaceutically acceptable carrier suitable for topical or transdermal drug administration. In one aspect of the invention the pH is about 8.0-11.5 and in another aspect, the pH is about 8.5-10.5. The formulation is typically aqueous. The pharmaceutically acceptable base can be an inorganic or an organic base.
Yet another aspect of the invention pertains to a system for the enhanced topical or transdermal administration of a local anesthetic agent, comprising: (a) at least one drug reservoir containing the local anesthetic agent and a pharmaceutically acceptable base, in an amount effective to enhance the flux of the local anesthetic agent through the body surface without causing damage thereto; (b) a means for maintaining the system in agent and base transmitting relationship to the body surface and forming a body surface-system interface; and (c) a backing layer that serves as the outer surface of the device during use, wherein the base is effective to provide a pH within the range of about 8.0-13.0 at the body surface-system interface during administration of the local anesthetic agent. In one aspect of the invention the pH is about 8.0-11.5 and in another aspect, the pH is about 8.5-10.5. The pharmaceutically acceptable base can be an inorganic or an organic base.
DETAILED DESCRIPTION OF THE INVENTION
The present invention provides a method for enhancing the flux of local anesthetic agents through a body surface. A local anesthetic agent and a basic permeation enhancer are administered to a localized region of a human patient's body surface. The permeation enhancer is a pharmaceutically acceptable base and is present in an amount effective to: a) provide a pH within the range of about 8.0-13.0 at the localized region of the body surface during administration of the drug and b) enhance the flux of the local anesthetic agent through the body surface without causing damage thereto. Examples of suitable permeation enhancers are described below. The local anesthetic agent and the permeation enhancer may be present in a single pharmaceutical formulation, or they may be in separate pharmaceutical formulations.
The steps of (a) administering the local anesthetic agent and (b) administering the basic permeation enhancer can be done in any order. For example, step (a) can be done prior to step (b); step (b) can be done prior to step (a); and steps (a) and (b) can be done simultaneously. Certain methods may be preferred depending upon the selection of the local anesthetic agent and basic permeation enhancer, as well as taking into consideration ease of patient compliance and so forth. For example, performing steps (a) and (b) simultaneously, is one pre
Gricenko Nicole T.
Hsu Tsung-Min
Luo Eric C.
Dermatrends, Inc.
Eberle Shelley P.
Ghali Isis
Page Thurman K.
Reed Dianne E.
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