Method for reducing, inhibiting, and eliminating inflammation and pain with transdermal delivery of iron chelator composition

Abstract

A method for reducing, inhibiting, and eliminating inflammation and pain by using an effective amount of iron chelator composition to balance oxidative activity at a cutaneous site of inflammation and pain. The composition contained in transdermal formulations and administered topically in accordance with the invention can be combined with one or more suitable carriers and can be administered in conjunction with one or more additional therapeutic agents.

Claims

1. A method for reducing, inhibiting, and eliminating inflammation comprising administering directly to a cutaneous site in a patient, a composition of therapeutically effective amount of iron chelator composition for balancing oxidative activity at said site wherein said iron chelator composition is expressed to modulate said inflammation.

2. The method of claim 1, wherein said iron chelator composition is administered topically.

3. The method of claim 1, wherein said administering is after an insult which otherwise results in said inflammation.

4. The method of claim 1, wherein said administering is approximately coincident with an insult which otherwise results to said inflammation.

5. The method of claim 1, wherein said administering is to a site of inflammation or potential inflammation.

6. The method of claim 1 where said administering further modulates swelling.

7. The method of claim 1, wherein said iron chelator composition is administered as a liquid, cream, and lotion.

8. A method for reducing and inhibiting swelling and pain associated with inflammation in a patient comprising administering directly to a cutaneous site in said patient, a therapeutically effective amount of iron chelator composition for balancing oxidative activity at said site wherein said iron chelator composition is expressed to modulate said swelling and pain.

9. The method of claim 8, wherein said iron chelator composition is administered topically.

10. The method of claim 8, wherein said administering is after an insult which otherwise results in said swelling and pain.

11. The method of claim 8, wherein said administering is approximately coincident with an insult which otherwise results to said swelling and pain.

12. The method of claim 8, wherein said administering is to a site of inflammation or potential inflammation.

13. The method of claim 8, wherein said administering further modulates inflammation.

14. The method of claim 8, wherein said iron chelator composition is administered as a liquid, cream, and lotion.

15. A method for balancing infiltration of macrophage iron associated with inflammation in a patient comprising administering directly to a cutaneous site in said patient, a therapeutically effective amount of iron chelator composition for balancing oxidative activity at said site wherein said iron chelator composition is expressed to balance said infiltration of macrophage iron.

16. The method of claim 15, wherein said iron chelator composition is administered topically.

17. The method of claim 15, wherein said administering is after an insult which otherwise results in said inflammation.

18. The method of claim 15, wherein said administering is approximately coincident with an insult which otherwise results to said inflammation.

19. The method of claim 15, wherein said administering is to a site of inflammation or potential inflammation.

20. The method of claim 15, wherein said iron chelator composition is administered as a liquid, cream, and lotion.

Description

DETAILED DESCRIPTION

[0041] The method of the present invention provides a method of reducing, inhibiting, and eliminating inflammation and pain in a patient, which method comprises administering to the patient a therapeutically effective amount of an iron chelator composition, wherein the composition is contained in the topical transdermal formulations.

[0042] The method of the present invention can be used for reducing, inhibiting, and eliminating (e.g., inhibiting the onset of, inhibiting the escalation of, decreasing the likelihood of acute inflammation and chronic inflammation). The inflammation treatable or preventable in accordance with the method of the present invention can include inflammation that results from, e.g., contact with a noxious stimulus, injury, infection, autoimmune reaction, and allergic reaction, including allergic reactions associated with cellular histamine and pro-inflammatory cytokine release.

[0043] The method of the present invention providing the administration of the iron chelator composition can be in combination with one or more further therapeutic agents and includes simultaneous (concurrent) and consecutive administration in any order. The regulation or administration of the composition can occur after induction of inflammation or pain, but preferably occurs simultaneously with induction of inflammation and pain. The induction of inflammation and/or pain can be the result of sports-related activities, hard labor, blister, repetitive trauma inducing activities or the undertaking of surgery.

[0044] The method of the present invention providing the administration of the iron composition can also be administered to an individual having rheumatoid arthritis to reduce swelling and pain associated with arthritis. Generally, inflammatory disorders include any disorder or condition associated with inflammation, i.e., inflammation of the bowel or any other organ, chemically induced inflammation, inflammation due to repetitive trauma. Each of these conditions, disorders, injuries or inflictions is encompassed by the phase insult resulting in inflammation or pain

[0045] The method of the present invention providing the administration of the iron composition refers inhibition as used herein refers to any delay in the onset of a condition, particularly inflammation or pain. The reduction as used herein refers to a decrease of at least 10%, and more preferably at least a 25% decrease in activity is preferred, with at least about 50% being particularly preferred and about a 95-100% decrease being especially preferred.

[0046] The method of the present invention providing the administration of the iron composition further comprises an iron chelator wherein the iron chelator is selected from the group comprising M30, melatonin, deferoxamine (DFO), deferasirox, deferiprone, deferitrin, L1NAII, CP502, IOX2, IP6, ethylenediaminetetraacetic acid (EDTA) or combinations thereof. In the most preferred embodiment, the iron chelator is melatonin.

[0047] The method of the present invention providing the administration of the iron composition for the reduction, inhibition, and elimination of inflammation and pain wherein the inhibition as used herein refers to any delay in the onset of a condition, particularly inflammation or pain. Reduction as used herein refers to a decrease of at least 10%, and more preferably at least a 25% decrease in activity is preferred, with at least about 50% being particularly preferred and about a 95-100% decrease being especially preferred. The reduction is compared to a control concentration of administration of the biologically active composition, wherein the control concentration can be zero.

[0048] The method of the present invention providing the administration of the iron composition reduces an elevation of IL-1beta by at least 30%, preferably 40%, more preferably 50%, still more preferably 60% and most preferably 70-100%.

[0049] The method of the present invention providing the administration of the iron composition suppresses the activation of macrophages and reduces an elevation of IL-1beta level by at least 30%, preferably 40%, more preferably 50%, still more preferably 60% 30 and most preferably 70-100%.

[0050] The method of the present invention providing the administration of the iron composition, via topical transdermal formations, reduces macrophage iron infiltration in response to an inflammatory stimulus. In an embodiment herein, the macrophage iron infiltration is decreased as it is seen in a normal individual in response to an inflammatory stimulus.

[0051] The method of the present invention providing the administration of the iron chelator composition wherein the composition is for chelating free iron inside the cell and therefore preventing the iron-driven oxygen toxicity i.e., acute or chronic inflammatory diseases with oxidative stress.

[0052] The method of the present invention providing the administration of the iron chelator composition applies in anticipation of pain, independent of an inflammatory inducing agent. In this embodiment, thermal sensitivity measured in withdrawal time can be reduced.

[0053] The method of the present invention providing the administration of the iron chelator composition wherein the composition can be formulated according to known methods to prepare pharmaceutically useful compositions. By way of example, the pharmaceutical compositions can be formed by combining composition in admixture with a pharmaceutically acceptable carrier vehicle. Therapeutic formulations are prepared for storage by mixing the active ingredient having the desired degree of purity with optional physiologically acceptable carriers, excipients or stabilizers (Remington's Pharmaceutical Sciences 16th edition, Osol, A. Ed. (1980)), in the form of aqueous oil based solutions.

[0054] The method of the present invention providing the administration of the iron chelator composition further provides acceptable carriers, excipients or stabilizers are nontoxic to recipients at the dosages and concentrations employed, and include buffers such as antioxidants including ascorbic acid; low molecular weight (less than about 10 residues) polypeptides; hydrophilic polymers such as polyvinyl pyrrolidone; chelating agents such as EDTA; and/or nonionic surfactants such as Tween, Pluronics or PEG. Transdermal formulations are particularly preferred for an efficient and quick delivery method of active agent to targeted location system locally or systematically.

[0055] The method of the present invention providing the administration of the iron chelator composition wherein dosages and desired drug concentrations of pharmaceutical compositions of the present invention may vary depending on the particular use envisioned. The determination of the appropriate dosage or route of administration is well within the skill of an ordinary physician.

[0056] The method of the present invention providing the administration of the iron chelator composition wherein modulators that enhance the anti-inflammatory and pain reduction activity of cytokine can be identified and administered to an individual in need thereof in conjunction with or independently iron chelator composition. Modulation is a change of about at least 10-30%, preferably 40-50%, more preferably at least 50-75%, or most preferably, at least 75-100%. As discussed herein, changes in cytokine activities can be determined by identification of changes in pain and inflammation responses. Such responses can be determined by identification in changes in the presence of TGF, IL-1beta and immune cell infiltrate as well as mechanical and thermal sensitivity and physical swelling.

[0057] The method of the present invention providing the administration of the iron chelator composition wherein the transdermal formulations overcome several difficult problems inherent in incorporating high concentrations (greater than about 2% w/w) of aqueous-soluble, charged inorganic salts (e.g., strontium salts) into aesthetic (e.g., pleasant-feeling, elegant, etc.) and functionally active topical products (i.e., products which retain their cosmetic, therapeutic, or other functional characteristics).

[0058] The method of the present invention providing the administration of the iron chelator composition wherein the composition is contained in the transdermal formulations that are miscible and will remain in solution. Consequently, in accordance with the inventive method, the transdermal formulations can be conveniently applied to the skin in the area of pain and inflammation by spaying or misting, or by any other desired liquid application technique. The application can then be reapplied as needed up to as often as once every 1-3 hours.

[0059] The embodiments were chosen and described to best explain the principles of the invention and its practical application to persons who are skilled in the art. As various modifications could be made to the exemplary embodiments, as described above with reference to the corresponding illustrations, without departing from the scope of the invention, it is intended that all matter contained in the foregoing description and shown in the accompanying drawings shall be interpreted as illustrative rather than limiting. Thus, the breadth and scope of the present invention should not be limited by any of the above described exemplary embodiments, but should be defined only in accordance with the following claims appended hereto and their equivalents.

[0060] Having illustrated and described the principles of the present invention in a preferred embodiment, it will be apparent to those skilled in the art that the embodiment can be modified in arrangement and detail without departing from such principles. Any and all such embodiments are intended to be included within the scope of the following claims.