Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Web – sheet or filament bases; compositions of bandages; or...
Reexamination Certificate
2003-03-13
2004-12-28
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...
C424S443000, C424S445000, C424S447000, C424S448000, C514S946000, C514S944000
Reexamination Certificate
active
06835392
ABSTRACT:
TECHNICAL FIELD
This invention relates generally to the topical and transdermal administration of pharmacologically active agents, and more particularly relates to permeation enhancer compositions for enhancing the permeability of skin or mucosal tissue to topically applied pharmacologically active agents.
BACKGROUND ART
Skin is a structurally complex, relatively thick membrane. In order to deliver a drug into and through the skin, i.e., “transdermally,” drug molecules 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 that 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.
In order to increase the rate at which a drug penetrates through the skin, various approaches have been followed, each of which-involves the use of either a chemical penetration enhancer or a physical penetration enhancer. Methods for physically enhancing skin permeation include, for example, electrophoretic techniques such as iontophoresis. The use of ultrasound (or “phonophoresis”) as a physical penetration enhancer has also been researched. Chemical enhancers are compounds that are administered along with the drug (or in some cases used to pretreat the skin, prior to drug administration) 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.
Various compounds for enhancing the permeability of skin are known in the art and described in the pertinent texts and literature. Compounds that have been used to enhance skin permeability include: sulfoxides such as dimethylsulfoxide (DMSO) and decylmethylsulfoxide (C
10
MSO); ethers such as diethylene glycol monoethyl ether (available commercially as Transcutol®) and diethylene glycol monomethyl ether; surfactants such as sodium laurate, sodium lauryl sulfate, cetyltrimethylammonium bromide, benzalkonium chloride, Poloxamer (231, 182, 184), Tween (20, 40, 60, 80) and lecithin (U.S. Pat. No. 4,783,450); the 1-substituted azacycloheptan-2-ones, particularly 1-n-dodecyl-cyclazacycloheptan-2-one (available under the trademark Azone® from Nelson Research & Development Co., Irvine, Calif.; see U.S. Pat. Nos. 3,989,816, 4,316,893, 4,405,616 and 4,557,934); alcohols such as ethanol, propanol, octanol, benzyl alcohol, and the like; fatty acids such as lauric acid, oleic acid and valeric acid; fatty acid esters such as isopropyl myristate, isopropyl palmitate, methylpropionate, and ethyl oleate; polyols and esters thereof such as propylene glycol, ethylene glycol, glycerol, butanediol, polyethylene glycol, and polyethylene glycol monolaurate (PEGML; see, e.g., U.S. Pat. No. 4,568,343); amides and other nitrogenous compounds such as urea, dimethylacetamide (DMA), dimethylformamide (DMF), 2-pyrrolidone, 1-methyl-2-pyrrolidone, ethanolamine, diethanolamine and triethanolamine; terpenes; alkanones; and organic acids, particularly salicylic acid and salicylates, citric acid and succinic acid.
Percutaneous Penetration Enhancers
, eds. Smith et al. (CRC Press, 1995) provides an excellent overview of the field and further background information on a number of chemical and physical enhancers.
Although many chemical permeation enhancers are known, there is an ongoing need for enhancers that are highly effective in increasing the rate at which a drug permeates the skin, do not result in skin damage, irritation, sensitization, or the like, and can be used to effect transdermal delivery of even high molecular weight drugs such as peptides, proteins, and nucleic acids. Furthermore, it would be a clear advantage commercially if a single enhancer composition could be used to enhance both hydrophilic and hydrophobic drugs. Currently, the enhancers that are used with hydrophilic drugs are not generally effective with hydrophobic drugs, and, conversely, the enhancers that are used with hydrophobic drugs are not generally effective with hydrophilic drugs. It has now been discovered that a combination enhancer, comprised of both a hydrophilic component and a lipophilic component, wherein the hydrophilic component is a hydroxide-releasing agent, is a highly effective permeation enhancer, provide all of the aforementioned advantages relative to known permeation enhancers, and is equally effective with hydrophilic and lipophilic drugs.
SUMMARY OF THE INVENTION
It is thus a primary object of the invention to address the above-described need in the art by providing a novel permeation enhancer composition for enhancing the rate at which an active agent administered to a patient's body surface permeates into and/or through the body surface.
It is another object of the invention to provide such an enhancer composition, wherein the composition contains a hydroxide-releasing agent and a lipophilic co-enhancer.
It is still another object of the invention to provide such an enhancer composition, wherein the lipophilic co-enhancer comprises a fatty acid ester, a fatty alcohol, a fatty ether, or a derivative and/or combination thereof.
It is yet another object of the invention to provide a pharmaceutical formulation containing a therapeutically effective amount of a pharmacologically active agent and an effective permeation enhancing amount of an enhancer composition of the invention.
It is a further object of the invention to provide a drug delivery system for application to a patient's body surface, containing a therapeutically effective amount of a pharmacologically active agent and an effective permeation-enhancing amount of an enhancer composition of the invention.
It is still a further object of the invention to provide a method for enhancing the flux of an active agent through a body surface, wherein the method involves administering the agent to a localized region of a human patient's body surface in combination with an effective permeation enhancing amount of an enhancer composition of the invention.
It is yet a further object of the invention to provide such a method wherein the active agent is intended for local delivery, and drug administration is topical.
It is an additional object of the invention to provide such a method wherein the active agent is intended for systemic delivery, and drug administration is transdermal.
Additional objects, advantages and novel features of the invention will be set forth in part in the description that follows, and in part will become apparent to those skilled in the art upon examination of the following, or may be learned by practice of the invention.
In one aspect of the invention, then, a permeation enhancer composition is provided that is comprised of a hydroxide-releasing agent and a lipophilic co-enhancer, wherein the weight ratio of the hydroxide-releasing agent to the lipophilic co-enhancer is generally in the range of approximately 1:99 to approximately 99:1, preferably in the range of approximately 1:20 to approximately 20:1, and most preferably in the range of approximately 1:2 to approximately 2:1. The hydroxide-releasing agent is generally selected from t
Hsu Tsung-Min
Jacobson Eric C.
LoBello Rose C.
Luo Eric C.
Dermatrends, Inc.
Eberle Shelley P.
Ghali Isis
Page Thurman K.
Reed Dianne E.
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