Surgery – Means for introducing or removing material from body for... – Treating material introduced into or removed from body...
Reexamination Certificate
1999-07-13
2001-10-16
Bockelman, Mark (Department: 3762)
Surgery
Means for introducing or removing material from body for...
Treating material introduced into or removed from body...
C604S501000
Reexamination Certificate
active
06302874
ABSTRACT:
FIELD OF THE INVENTION
The present invention generally relates to methods for enhancing the effectiveness of cosmetic pharmaceuticals used to improve the appearance of skin. In particular, the present invention relates to use of electroporation-mediated topical delivery of agents, such as Vitamin C.
BACKGROUND OF THE INVENTION
The main factors causing skin aging are natural processes (such as aging), lifestyle factors (such as smoking), and environmental stressors (such as UV radiation, chemical pollutants, etc.). It is now medically recognized that many of these factors damage skin through production of oxy-radical damage. Superoxide and the subsequently generated hydrogen peroxide and hydroxyl radical are oxygen-containing free radicals now known to be generated in vivo under a variety of normal and pathological conditions. An immense amount of work has been done in the last two decades documenting the deleterious behavior of oxygen radicals. These radicals have been implicated as causative agents for everything from sunburn to aging and have been shown to effect skin and other tissues by destroying lipid membranes, breaking down DNA, inactivating enzymes, and the like. As a result of this damage, certain anatomical changes occur, including thinning of the epidermis, thickening of the stratum comeum, reduction of blood supply to the skin, loss of collagen, and formation of age spots, lines and wrinkles.
L-ascorbic acid (vitamin C), a water-soluble antioxidant, can protect fatty tissues from oxy-radical damage by reacting with both superoxide and hydroxyl radicals. It also plays an integral role in collagen synthesis and wound healing by acting as a co-factor for hydroxylation of the proline and lysine residues of procollagen and promoting formation of the triple-helical conformation of mature collagen fibers. This conformation is required for the processing of procollagen to collagen (D. J. Prockop et al., “Intracellular steps in the biosynthesis of collagen” In:
Biochemistry of Collagen
, G. N. Ramachandran and A. H. Reddi (Eds.), Plenum Press, New York, 1976, 163-273; C. I. Levene and C. J. Bates,
Ann. NY Acad. Sci
. 258 [Suppl.]:288-306, 1975). L-ascorbic acid has also been shown to increase both the rate of transcription of procollagen genes and stability of procollagen mRNA (S. Tajima and S. R. Pinnell, Biochem.
Biophys. Res. Commun
. 106:632-637, 1982; B. L. Lyons and R. I. Schwarz,
Nucleic. Acids Res
. 12,2569-2579, 1984) as well as to modulate growth properties of cells (R. Hata et al.,
Eur J Biochem
. 173:261-267, 1988).
In spite of these important activities of L-ascorbic acid for treatment of aging, environmental damage, wound healing, and the like, a drawback of its topical application is its instability. L-Ascorbic acid is chemically defined as an alpha-keto-lactone wherein the number 2 and 3 carbons are double-bonded and contain an acid-ionizable hydrogen in water (pK=4.2). Ascorbic acid is also a moderately strong reductant. These properties, which lead to instability in the ascorbic acid structure, are well known and have been burdensome to pharmacologists when attempting to formulate active ascorbic acid solutions. For example, at higher pH, ascorbic acid increasingly is transformed to the notoriously unstable ascorbate anion. This instability may be due to several causes, among which are the following:
a) Stereochemical strain due to polar repulsive forces. As a result, when the 2-hydroxy group ionizes, two negative charges form in close proximity, thereby favoring ring disruption.
b) Oxidative degradation due to the propensity of the ascorbate anion to act as a reductant. The one-electron oxidation product (dehydroascorbate free radical) tends to disproportionate, forming another ascorbate molecule and the two-electron oxidation product (dehydroascorbate), which is extremely unstable in aqueous solution and breaks down to ultimately form species such as L-threonic acid and oxalic acid. Transition metal ions can catalyze these reactions.
c) Degradation due to water attack. At lower ascorbic concentrations or ionic strength, water itself can react with and degrade the ascorbate molecule.
For these reasons, among others, scientists working in the field have had difficulty in formulating stable solutions of ascorbic acid which would be useful for cosmetic or dermatological needs. Nevertheless, because of the many beneficial pharmaceutical effects attributed to ascorbic acid, numerous attempts have been made to overcome these difficulties, as well as user compliance with the extended application schedule required, by adding minerals or metabolites and L-ascorbic acid derivatives into the formulation. Several commercial products are currently used in cosmetology such as C-Mate (L-ascorbic acid-2-P magnesium salt, neutral pH), Cellex-C™ (serum, pH 2.2), ESTER-CO (topical concentrate, pH 6.7), and products from Intaglio® (pH<3.5) and AGERA® (neutral pH). However, the required duration of therapy is relatively long (weeks to months) and skin irritation will occur with prolonged application of acidic pH formulations.
The cosmetic and therapeutic utility of topically applied Vitamin C and derivatives thereof, is also limited by the lipid-rich stratum comeum, thin layer of skin that acts as highly resistant lipid barrier to penetration of chemical agents into the skin. In both the pharmaceutical and cosmetic arenas, significant efforts have been put forth in attempts to overcome the skin's natural barrier to delivery of functional agents into the skin topically or into systemic circulation topically. Recent progress in skin drug delivery has been summarized in several review articles (M. R. Prausnitz,
Crit. Rev. Therap. Drug Carrier Syst
. 14(4):455-483, 1997; A. K. Banga (Ed.),
Electrically Assisted Transdermal and Topical Drug Delivery
, Taylor & Francis, Bristol, PA, 1998; A. K. Banga et al., TIBTECH, 16:408-412, 1998; G. Cevc,
Exp. Opin. Invest. Drugs
6(12):1887-1937, 1997). Generally, three primary routes across the stratum comeum are available for molecular transport: (1) Normal or chemically modified skin allows diffusion of small molecules, usually following a tortuous intercellular path within the lipids of the stratum comeum. (2) Transcellular pathways crossing both the cells and intercellular lipids of the stratum comeum can be created by electroporation to allow passage of chemical compounds. (3) “Shunt” pathways through the hair follicles and sweat ducts may be utilized during iontophoresis (IPH), pressure-mediated delivery, and liposomal transport.
Electroporation is believed to involve the creation of new transient aqueous pathways (pores) in lipid bilayers by the application of a short electric pulse having a duration in the range from Usec to sec (D.C. Chang et al. (Eds.),
Guide to Electroporation and Electrofusion
, Academic Press, New York, 1992; J. C. Weaver, J
Cell. Biochem
. 51:426-435, 1993; J. A. Nickoloff (Ed.),
Methods in Molecular Biology
, Vols. 47, 48, 55, Humana Press, Totowa, N.J., 1995) and to drive molecules through the pores by electrophoresis (M. R. Prausnitz et al.,
Proc. Nat. Acad. Sci
. 90.10504-10508, 1993; M. R. Prausnitz,
J. Control. Release
40:321-326, 1996; M. R. Prausnitz et al.,
J. Control. Release
38:205-217, 1996; M. R. Prausnitz, et al.,
Bio/Technology
20:1205-1209, 1995; L. Zhang et al.,
J. Bioelectrochem. Bioenerg
. 42.283-292, 1997. For a general discussion of EPT, see co-pending application Ser. No. 08/537,265, filed on Sep. 29, 1995, which is a continuation-in-part of application Ser. No. 08/467,566 filed on Jun. 6, 1995, which is a continuation-in-part of application Ser. No. 08/042,039 filed on Apr. 1, 1993 now abandoned, all of which are incorporated herein by reference.
Electrical studies have shown that short, high-voltage pulses can have dramatic and reversible effects on skin electrical properties. During a pulse, skin resistance drops as much as three orders of magnitude within microseconds. This alteration in skin resistance exhibits either complete or partial r
Hofmann Gunter A.
Zhang Lei
Bockelman Mark
Genetronics Inc.
Gray Cary Ware & Freidenrich
Haile Lisa A.
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