Drug – bio-affecting and body treating compositions – Extract or material containing or obtained from a...
Reexamination Certificate
2001-09-26
2002-03-12
Lankford, Jr., Leon B. (Department: 1651)
Drug, bio-affecting and body treating compositions
Extract or material containing or obtained from a...
C424S195160, C424S401000
Reexamination Certificate
active
06355251
ABSTRACT:
BACKGROUND—SUMMARY
The current invention proposes topical administration of therapeutically effective doses of certain sesquiterpene epoxides (trichothecenes) to chemexfoliate selected areas of the epidermis.
BACKGROUND
Chemexfoliation has been around since the days of ancient Egypt with lactic acid from sour milk used as part of a skin rejuvenation regimen. The middle ages saw tartaric acid from old wine used for the same purpose. Modern day chemical peeling includes such pioneers as P. G. Unna who first described properties of salicylic acid, resorcinol, phenol, and trichloroacetic acid. Baker and Gordon developed deep peeling agents in the 1960s. Alpha and Beta hydroxy acids appeared over the last several decades as mild exfoliants available in many commercially available skin care products. The primary application of chemexfoliation has been, and remains today, rejuvenation of the skin by destruction or damage to the epidermis and sometimes also the dermis.
PRIOR ART TREATMENTS
Prior art chemexfoliants in use today can be grouped into three categories; Superficial Peeling Agents, Medium Depth Peels, and Deep Peels.
Superficial Peeling Agents
Trichloroacetic acid (TCA) 10-35% is safe at lower concentrations. At higher concentrations (>50%) it has a tendency to scar.
Jessner's peel is a combination of salicylic acid (14%), lactic acid (14%), and resorcinol (14%) in alcohol.
Salicylic acid has been used for several decades and is found in various medications ranging from 4% to 17% concentrations.
Carbon Dioxide uses a solid block of CO2 ice dipped in an acetone-alcohol mixture and applied to the skin for 5-15 seconds depending on the desired depth.
Alpha hydroxy acid peels include lactic acid, glycolic acid, tartaric acid and malic acid. Various concentrations can be purchased ranging from 10% to 70% concentrations.
Medium Depth Peels
Combinations peels such as CO2 and TCA 35%, Jessner's and TCA 35%, and Glycolic and TCA 35% are currently being used.
TCA 50% is seldom used today because of risk of scarring.
Full strength phenol (88%) is very caustic an causes immediate keratin agglutination preventing further penetration.
Pyruvic acid is also rarely used today because of difficulty in controlling depth of penetration. An ethyl pyruvate is currently being developed to overcome this issue.
Deep Peels
The Baker Gordon peel is one of the most effective peeling agents currently available. The phenol produces a layer of collagen that is thicker than that produced by laser. However the Baker Gordon formula is not often used today because of laser resurfacing technology.
COMPOSITIONS OF PRESENT INVENTION
The compositions proposed under present invention are not acids nor do they employ freezing. They are protein synthesis inhibitors (PSIs). Accordingly a brief background about protein synthesis and cellular function is presented.
The most fundamental function a cell is protein synthesis (i.e. expression of its DNA). Proteins make up ~60% of a dry cell's mass by weight. In very broad and general terms, as cells mature and differentiate in the body, they reach an equilibrium in protein synthesis and protein degradation and settle down to perform their given function in this relative state of homeostasis. There are two notable exceptions that cause massive perturbations to this homeostasis: 1) when a cell is called upon to grow and divide and 2) when certain secretory cells are called upon to produce large amounts of proteins for secretion. Although the cell signaling signaling pathways, intracellular transduction pathways, and spectrum of protein(s) to be produced are quite different in growth versus secretion, normal growth and secretion events share one major similarity in their end result: massively accelerated protein synthesis. A cell that is called on to grow (cycling cell) has as much as 5 times the protein synthesis activity of a non cycling cell and needs between 2,000 and 5,000 different enzymes and structural proteins to grow and divide. Likewise, secretory cells such as those of the immune system become protein factories producing massive amounts of antibodies, mediators, growth factors, or other proteins when stimulated to do so.
There are also abnormal conditions such as cancer and viral infections that share the same property of hyperactive protein synthesis versus normal quiescent cells. Cancer is a growth and divide type event, and even though the signaling mechanism is different in that it is self-induced intracellularly by several genetic mutations, the end result is also hyperaccelerated protein synthesis characteristic of a cycling cell. Viruses invade a cell, parasitize the host cellular machinery, and convert the cell into a factory producing massive amounts of viral proteins, much like a secretory cell.
Inhibiting protein synthesis affects cells in a dose dependent manner and affects actively cycling cells differently than non cycling cells. At low doses, protein synthesis inhibitors (PSIs) stop actively cycling cells from cycling without killing them (hereinafter referred to as inhibitory or G zero inducing dose). Inhibitory doses also stop hyperaccelerated protein synthesis by secretory cells. At moderate doses PSIs exhibit toxicity to actively cycling cells (hereinafter referred to as the cytotoxic dose). At high doses, PSIs exhibit toxicity to all cells (hereinafter referred to as the toxic dose).
There are roughly 210 epithelial cell types in the body, and only a small handful are normally actively cycling. These include the epidermis, hair, bone marrow, and gastrointestinal mucosa. Epidermal cells cycle on a roughly 24 hour clock and as such would be susceptible to cytotoxicity from PSIs at dose levels not toxic to normal non rapidly proliferating cells. Non nucleated cells such as the non nucleated epidermal squames at the very top of the epidermis would not be affected. The collagen matrix below the epidermis would not be affected. This presents the opportunity for a highly selective epidermal chemexfoliation of the living epidermal cells sandwiched between the epidermal squames on top and the collagen on bottom.
NOVELTY AND UNOBVIOUSNESS OVER PRIOR ART
Novelty and Unobviousness—Overview
Present invention takes a fairly unobvious view and considers the epidermis a “super cancer”. Epidermal basal cells cycle on a roughly 24 hour clock. By contrast, if tumor cells cycled on a 24 hour clock a human would be dead in under a month from the time the tumor was initially detected. Starting with a fairly tiny, clinically undetectable, initial tumor of ~1 Million cells (i.e. 1 &mgr;l mass) and growing it to lethal burden at around a Trillion cells (1 L mass), requires only about 20 cell cycles of all the tumor cells (i.e. 1 M, 2,4,8,32,64,128,256,512,1 Bil, 2,4,8,16,32,64, 128, 256,512, 1 Tril.).
Novelty and Unobviousness Over Prior Art Use of Trichothecene
Prior art has attempted to use trichothecene against hyperproliferative conditions such as cancer, however they have failed. Anguidine, a simple trichothecene, was tested against cancer and abandoned after Phase II testing showed a low tumor response and considerable hematologic toxicity. Prior arts attempt to remedy this failure are embodied in U.S. Pat. Nos. 4,906,452 and 4,744,981 which propose conjugates of trichothecene with monoclonal antibodies to enhance delivery to the tumor and glycosylation of trichothecene to increase blood solubility. Present invention takes a novel and unobvious approach that is exactly opposite to prior art in several respects. First, present invention reverses direction of administration (i.e. administered from tissue side to blood versus prior arts direction of blood to tissue). Second, present invention embraces the non specific internalization properties to deliver the greatest doses to tissues it is applied to and depending on those tissues to retain the trichothecene, preventing it from reaching general circulation (versus prior arts targeted delivery by monoclonal antibodies). Third, present invention embraces the use of macrocyclic trichothecene (versus
Coe Susan D.
Lankford , Jr. Leon B.
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