Drug – bio-affecting and body treating compositions – Topical body preparation containing solid synthetic organic... – Skin burn or open wound treatment
Reexamination Certificate
2001-08-31
2001-10-23
Weber, Jon P. (Department: 1651)
Drug, bio-affecting and body treating compositions
Topical body preparation containing solid synthetic organic...
Skin burn or open wound treatment
C424S078020, C424S078030, C424S283100, C424S450000, C424S725000
Reexamination Certificate
active
06306383
ABSTRACT:
TECHNICAL FIELD OF THE INVENTION
The present invention is related to a process and composition for topically inhibiting Protein Kinase C. More particularly, the present invention relates to topically applying the composition disclosed herein in order to treat the affected skin or underlying structures of humans and animals. Protein kinase C inhibitors have been shown effective in vitro and in a limited fashion orally, but not efficacious when used topically. What is needed is a topical composition which is safe and cost effective.
BACKGROUND OF THE INVENTION
Mukhtar in Pharmacology of the Skin describes the communication between cells as being mediated by different biomolecules, such as hormones. These so called primary messengers bind to specific receptors on the cell surface. The binding of a primary messenger to its receptor conveys a certain information to the cell which is subsequently transduced through the membrane by a chain of signaling. This process involves various membrane structures and leads to the activation of an enzyme located at the intracellular side of the membrane. The stimulated enzyme generates a second messenger which evokes the cellular response; in most cases, by the activation of other enzymes. By these steps, the initial extracellular signal is converted into an intracellular signal. This process is called signal transduction.
The inositide cascade represents one of several signals transducing pathways. In its course, two second messengers, diacylglycerol (DG) and inositol triphosphate (IP 3)., are released. DG remains in the membrane and activates protein kinase C (PKC). IP 3 acts by releasing calcium ions from their intracellular stores. The calcium ions subsequently evoke the cellular response, mainly by activating a protein kinase (PKC)
Protein kinases regulate cellular responses by phosphorylation of substrate proteins (eg. receptors or enzymes) and thereby alter their state of activity. In the case of the inositide cascade, PKC mainly performs this reaction. Sphingosine dose-dependently inhibits PKC, but also binds to calmodulin (CaM) function and therefore inhibits CaM function. Keratinocyte intercellular adhesion molecule-1 (ICAM-1) is thought to be involved in dermal lymphocyte infiltration. The PKC activating phorbol ester, PMA has been reported to induce the expression of ICAM-1 in normal human keratinocytes. This effect can be blocked by a PKC inhibitor and suggests that PKC might play a regulatory role in ICAM-1 expression.
Psoriasis is characterized by a epidermal hyperproliferation and reduced cellular differentiation as well as inflammation. Experimental stimulation of PKC will produce a similar hyperproliferation. The release of reactive oxygen species (ROS) from human leucocytes represents an important part of the acute inflammation. Phorbol ester can induce the same cellular response and is mainly regulated by PKC. This pathway in psoriasis if stimulated by an activator of PKC, may account for epidermal inflammation.
PKC is known to function in cutaneous tumor promotion in that it represents the major cellular receptor for phorbol esters. PKC inhibitors like sphingosine inhibit phorbol ester-induced ornithine decarboxylase activity in the mouse skin.
SUMMARY OF THE INVENTION
The present invention provides a composition and easy to use therapeutic method for inhibiting PKC activity in the skin, muco-cutaneous junction and underlying structures, as well as the disease processes related to it. These processes include, but are not limited to psoriasis, psoriatic arthritis, tumor, cell mediated hyper immunity, seborrheic dermatitis, allergic & contact dermatitis, hypertrophic scar, keloid, carpal tunnel disease 2
nd
to fibrosis, papilloma virus warts, vitiligo, solar elastosis, and any inflammatory conditions in the skin which involve PKC.
The present invention includes a composition for topical treatment of the effects of PKC activity as a second messenger wherein the molecule or molecules are selected from the group consisting of phytosphingosine, sphingosine, sphinganine, curcumin, tetrahydrocurcumin, curcumin analogues, apigenin, hypericin, N-Acetylsphingosine, N-Hexanoylsphingosine, and N-Octanoylsphingosine or W-7 analogue combined with delivery vehicles and penetrating agents optionally containing lecithin, unhydrogenated or hydrogenated, lecithin organogel, Pluronic 127 lecithin organogel. Therapeutically effective amounts of phytosphingosine may be combined at concentrations of 0.01 g to 5 g per 100 grams of formulation for topical application of the composition of this invention. Optionally 0.01 g to 5 g tetrahydrocurcumin may be used by itself or in combination with the phytosphingosine or another PKC inhibitor
DETAILED DESCRIPTION OF THE INVENTION
PKC activity in the skin and the disease processes related to it, include psoriasis, tumor, hypertrophic scar & keloid, cell mediated hyperimmunity, atopy & contact dermatitis, and other processes.
PKC activity in the joint including rheumatoid arthritis.
The term patient refers to mammals, especially humans and animals.
A preferred phospholipid for use in the present invention is phosphatidylcholine, unhydrogenated or hydrogenated, also known as lecithin. Stedman's medical dictionary (21
st
ed., pg. 879) defines lecithin as any group of phospholipids which upon hydrolysis yield 2 fatty acids molecules and a molecule each of glycerophosphoric acid and choline. There are several varieties of lecithin, Soybean lecithin is a preferred lecithin and is the most economical. Lecithins are also found in nervous tissue, hepatic tissue, cardiac tissue and egg yolks. It is there fore understood that any reference to lecithin or phosphatidylcholine is intended to include any combination of lecithin-like phospho-lipid compounds as is well known in the art. Examples of other phospholipids which can be used in accordance with the present invention include phosphatidylethanolamine, phosphatidylserine, phosphatidyinositol, and phosphatidic acid. A mixture of any of the above phospholipids maybe used in the present invention and are present in natural soy lecithins. A hydrogenated lecithin may also be employed which obviates the problem with oxidation.
A preferred penetrating agent and delivery vehicle is lecithin organogel which is a combination of lecithin, organic solvent such as ethanol and water. Lecithin organogels have described as vehicles that are useful in facilitating the delivery of low molecular weight compounds transdermally (Williman et al, Journal of Pharmaceutical Sciences 81:871-874 (1992) which is incorporated herein by reference). The lecithin organogels are obtained by adding small amounts of water to a solution of lecithin in organic solvent. Generally, lecithin organogels are prepared at room temperature by first dissolving lecithin in an organic solvent such as ethanol, isopropyl palmitate or isopropyl myristate and then adding enough water while stirring to obtain the desired gel. Preparation of a variety of lecithin gels, all of which are appropriate in practicing the invention, are described in Scartazzini, et al Journal of Physical Chemistry 92:829-833, 1988, and Luisi, P. L. et al Colloid and Polymer Science 268;356-374. 1990, both of which are incorporated herein by reference in their entirety. The lecithin organogel preferably comprises 1:1 to 1.5:5 (weight/volume) of Phosphlipon 90(PC) (American Lecithin, Oxford, Conn.) ethanol (1 g:1 ml). Water is added to form the desired gel. Other penetrating agents may be used in the composition of the present invention. The composition according to the present invention can be in the form of lotions, salves, creams, ointments, liposomes, giant micelles, and salves.
A gelling agent optionally may be added to the formulation. Gelling agents that are suitable include, but are not limited to Pluronic lecithin organogel, cellulose ethers, alginates, polyacrylates (carbomers), carboxyvinyl polymer, bentonite, gelatin, tragcanth, polyvinylpyrrolidone, polyvinyl alcohol, and polyoxyethylene/polyoxypropylene block copolymers.
Th
Crandall Wilson T
Patten Patricia
Weber Jon P.
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