Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Web – sheet or filament bases; compositions of bandages; or...
Reexamination Certificate
2000-10-13
2003-05-20
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
06565879
ABSTRACT:
TECHNICAL FIELD
This invention relates generally to topical and transdermal administration of pharmacologically active peptidyl drugs, and more particularly relates to methods and compositions for administering peptidyl drugs transdermally.
BACKGROUND
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, degradation of certain drugs via gastrointestinal enzymes 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 and is particularly problematic for high molecular weight drugs such as peptides, polypeptides and proteins. Consequently, a means for enhancing the permeability of the skin is desired to effect transport of the drug into and through intact skin.
In order to increase the rate at which a drug penetrates through the skin, then, various approaches have been followed, each of which involves the use of either a chemical penetration enhancer or a physical penetration enhancer. Physical enhancement of skin permeation includes, 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 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 innocuous compounds that 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; see also); the 1-substituted azacycloheptan-2-ones, particularly 1-n-dodecylcyclazacycloheptan-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; organic acids, particularly salicylic acid and salicylates, citric acid and succinic acid; and certain peptides, e.g., peptides having Pro-Leu at the N-terminus and followed by a protective group (see U.S. Pat. No. 5,534,496).
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 an enhancer that (1) is highly effective in increasing the rate at which a pharmacologically active agent permeates the skin, and (2) does not result in skin damage, irritation, sensitization, or the like. In particular, there is a need for a chemical permeation enhancer that enables the transdermal administration of high molecular weight drugs such as peptidyl 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 method for transdermally administering a pharmacologically active peptide, polypeptide or protein.
It is another object of the invention to provide such a method wherein a hydroxide-releasing agent is employed as a permeation enhancer to increase the flux of a pharmacologically active peptide, polypeptide or protein through a patient's skin or mucosal tissue.
It is still another object of the invention to provide such a method wherein the amount of hydroxide-releasing agent employed is optimized to enhance permeation while minimizing or eliminating the possibility of skin damage, irritation or sensitization.
It is a further object of the invention to provide such a method wherein the active agent is a cosmeceutically effective agent.
It is an additional object of the invention to provide formulations and drug delivery systems for carrying out the aforementioned methods.
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, the invention pertains to a method for topically or transdermally administering a peptidyl drug, by administering the drug and a hydroxide-releasing agent to the body surface of the individual. The hydroxide-releasing agent is administered in an amount and for a time period such that upon administration of the peptidyl drug, the flux of the drug through the skin is enhanced, thus facilitating treatment of a peptidyl drug-responsive condition or disease. The amount of the hydroxide-releasing agent, however, is an amount that will not cause damage to skin or injury to the patient. Typically, a “patch” is used to administer the active agent, in which case the drug and hydroxide-releasing agent are present in one or more drug reservoirs. However, the peptidyl drug and hydroxide-releasing agent may also be administered using a liquid or semisolid formulation, e.g., as a water-based cream or gel as will be discussed in further detail below. In addition, the peptidyl drug and hydroxide-releasing agent may be co-administered, i.e., administered together, or may be administered separately as in, for example, “pretreatment” of an individual's body surface with the hydroxide-releasing agent followed by administration of the peptidyl drug.
In another aspect of the invention, the invention pertains to a composition of matter useful for
Hsu Tsung-Min
Jacobson Eric C.
Luo Eric C.
Dermatrends, Inc.
Eberle Shelley P.
Ghali Isis
Page Thurman K.
Reed Dianne E.
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