Patent Application
20230165806
The present invention relates generally to the field of medicine and disease treatment. More particularly, it concerns methods and compositions for topical therapy of melanoma and skin fibrosis.
The skin is the first line of defense of the human body system against microorganisms, ultraviolet exposure, and toxic chemicals. Therefore, proper wound healing is a crucial part of skin tissue damage. Skin is made of three layers, epidermis, which create waterproof barrier and tone of our skin. The dermis comprises connective tissues, sweat glands, hair foliage, and the hypodermis layer forms fat and connective tissues. Self-repair is beneficial, but abnormal repair triggers fibrosis, malfunctioning skin function, and impairing appearance. About 30,000 people in the USA have skin fibrosis. The disease affects about 1 in 2,500 to 3,500 Caucasian newborns. It is also common in southern border regions of the USA. It affects about 1 in 100,000 Asian-Americans and 1 in 17,000 African-Americans. In most cases, skin fibrosis develops due to chemotherapeutic, radiation exposure, aberrant injury, environmental pollution, and genetic mutation. The skin fibrosis diagnosis is very impenetrable and visible in the later stage of the disease. One of the traditional methods to diagnose skin fibrosis is using skin biopsy. Current treatments for skin fibrosis consist of medication and surgery. But most treatments are only improving the fibrotic condition. The topical treatment is administered to enhance the inflammation, itching, burning, and pain due to fibrosis. Laser surgery is available to pierce and drain the fibrotic skin regions to relieve pain. Therefore, we need an alternate approach to reverse the fibrotic cells into healthy cells. Before identifying any solution, let’s discuss the physiology and signaling pathways of disease.
Fibrosis usually accompanies chronic inflammation and an increase of fibrous connective tissues in the dermis or subcutis. This condition characterizes the proliferation of fibroblasts and collagen fibers in the dermis or surrounding hair follicles, usually parallel to the epidermis. Fibrosis can develop further into the dermis and subcutis in more severe cases. Compared to the non-fibrotic dermis, areas of fibrosis may appear slightly basophilic; however, this might vary depending on the fibrotic lesion’s staining quality and development. Fibroblasts are generally accompanied by inflammatory cells in early fibrosis (primarily when associated with an epidermal ulcer); fibroblasts are larger and more active, and collagen fibers are less compact and disordered. The fibroblasts become smaller, and more spindle shaped as fibrosis progresses, the collagen fibers become more ordered and compact, and inflammation decreases. In difficult situations, hair follicles in the fibrotic region may be lost. The microvasculature (endothelial cells, platelets, capillaries) system is affected, and the disease is known as “Raynaud’s phenomenon”. Typically, skin fibroblasts synthesize little extracellular matrix (ECM) due to negative signaling and inhibitory influence of the non-cellular matrix. But due to the over-activation of fibroblast, different growth factors like IL-1, prostaglandin E, PDGF, connective tissue growth factor (CTGF), IL-6, and TGF-β. This upstream activation triggers the release of extracellular matrix and accumulates in fibroblast cells’ outer or cytoplasmic regions. In fibrosis, the cells become more rigid, lose their functionality, and apoptosis incidence stops. And eventually, all these tissue abnormality leads to organ failure.
The American Cancer Society estimates that over 106,000 new cases of skin melanoma will be diagnosed in 2021 in the United States. Estimated mortality will exceed 7100 Americans in 2021, and the mortality rate is expected to continue to increase rapidly over the next few decades. Among Caucasian people, the incidence of melanoma will grow 3-5%, making it fastest-growing cancer worldwide. There are many risk factors for melanoma, including oncogenes, smoking, and excessive exposure to the sun. Besides, some oncogenes that change mole (common skin growth) or normal skin region are responsible for melanoma. Most common oncogenes are BRAF, NRAS, CDKN2A, and NF1 are responsible for melanoma. Despite the devastating health effects of skin melanoma, current treatments include surgical excision, chemotherapy, electrodesiccation or Mohs surgery, curettage, and cryotherapy. However, unfortunately, these treatments are highly effective only against more localized cancer, rather than multiple lesions or those located at anatomically sensitive skin regions. For instance, topical gel or creams currently effectively treat the skin diseases located on superficial areas, but not the deeper skin layer where many other lesions manifest. Additional limitations include that some topical products like hydroquinone formula, fluorouracil, and Efudex create inflammation, burning, stinging, swelling when applied to the skin, which decreases patient compliance.
Heretofore, the requirements of ameliorating skin fibrosis and melanoma while avoiding side effects and other undesirable consequences have not been fully met. In view of the foregoing, there is a need in the art for a solution that simultaneously solves all of these problems.
The following drawings form part of the present specification and are included to further demonstrate certain aspects of the present invention. The invention may be better understood by reference to one or more of these drawings in combination with the detailed description of specific embodiments presented herein.
The disclosure of this application is technically related to co-pending U.S. Ser. No. ______ (attorney docket number UTEP2022-005-2), filed Nov. 21, 2022, the entire contents of which are hereby expressly incorporated by reference for all purposes.
Embodiments of this disclosure include methods and formulations that will ameliorate skin fibrosis. While not being bound by theory, the methods and formulations induce apoptosis of fibrosed cells.
A topical solution-based therapy combines an ionic liquid with a BCL-2 inhibitor. The ionic liquid based on choline bicarbonate and octanoic acid (COA) has been reintroduced as a highly effective method of transporting tiny hydrophobic molecules to the skin. By inhibiting the BCL-2 protein of a specific cell, the BCL-2 inhibitor Navitoclax (NAVI) was also very successful and safe chemotherapy for treating cancer. The COA/NAVI combination was created to promote skin penetration and drug retention in the target area for a more extended period, increasing therapeutic efficiency. Despite NAVI’s developing potential as a chemotherapeutic drug, its use is restricted because of the danger of severe thrombocytopenia. As a result, the regulatory body has limited their administration route to oral rather than intravenous or intramuscular.
The main challenges in treating fibrosis with chemotherapeutics are epidermal layer penetration, the appropriate concentration, and drug retention within the layer for a more extended period. The COA ionic liquid, as created, is intended to improve NAVI skin permeation, and keep the payload within the dermis and subcutaneous layer of the skin. NAVI is an FDA-approved hydrophobic anti-apoptotic protein B cell lymphoma/leukemia (BCL-2) inhibitor, making it a good candidate for COA enhanced negation of these variables. NAVI is a BH3 mimetic drug that binds directly to BCL-2, BCL-xL, and Bcl-w. BH3 mimetics are tiny molecules that inhibit anti-apoptotic BCL-2 family members. Individual anti-apoptotic factors like BCL-2, BCL-xL, BCL-W, and MCL are blocked. COA improves NAVI skin permeability and increases its solubility by up to 150 µg/mL. With the development of COA/NAVI formulations, we overcame the clinical limitation of NAVI and facilitated its topical application to accelerate the treatment of local fibrosis. The COA/NAVI formulation delivers and maintains the drug at the desired fibrosis site for a more extended period, as confirmed by a pigskin in vitro permeation test (IVPT). In vitro studies performed on the human skin fibrotic skin fibroblast cell line Hs27 show its potential use as a chemotherapeutic agent for fibrosis treatment, and COA/NAVI shows significantly greater efficacy than free NAVI. In vivo studies were performed in a bleomycin-induced mouse model to evaluate the drugs’ effectiveness, safety, and bio distribution. The results of studies and general observations indicate that the COA/NAVI formulation can be considered an effective and safe treatment approach for treating cutaneous fibrosis.
A topical solution-based treatment comprises an ionic liquid and BCL-2 inhibitor. The Choline Octanoate (COA) ionic liquid was reported as a very effective agent for delivering small hydrophobic molecules through the skin. The BCL-2 inhibitor navitoclax (NAVI) was also a very effective and safe chemotherapeutic to treat cancer by inhibiting the BCL-2 protein of a specific cell. The COA/NAVI combination was specifically designed to improve skin penetration and enhance retention of the drug in the target area for an extended time to enhance therapeutic efficiency. Despite the emerging potential of NAVI as a chemotherapeutic agent, its applications are limited due to the risk of severe hematotoxicity. Therefore, the regulatory authority has restricted their route of administration to oral instead of intravenous and intramuscular.
The major challenges of melanoma treatment with chemotherapeutics are inadequate epidermal layer penetration, inadequate concentration, and poor drug retention within the layer for extended time periods. The as-developed ionic liquid COA is designed to enhance the skin permeation of NAVI and hold the payload within the dermis and subcutaneous layer of the skin. NAVI is a hydrophobic, anti-apoptotic protein B cell lymphoma/leukemia (BCL-2) inhibitor approved by the FDA for cancer treatment, making it an ideal candidate for COA enhancement negation of these factors. NAVI, a BH3 (BH3 mimetics are small compounds that antagonize anti-apoptotic BCL-2 family proteins) mimetic drug directly binds with BCL-2, Bcl-xL, and Bcl-w. It blocks individual anti-apoptotic factors like BCL-2, BCL-xL, BCL-W, and MCL. COA not only enhances skin permeation of NAVI but also increases solubility up to 150 µg/mL. With the development of COA/NAVI formulation, we have overcome the clinical limitation of NAVI and facilitated their topical application to accelerate local melanoma treatment. COA/NAVI formulation delivers and holds the drug for an extended period at the targeted melanoma site, confirmed by in vitro permeation test (IVPT) using porcine skin. In vitro studies conducted on A375 human melanoma cells line demonstrate their potential use as a chemotherapeutic for treating melanoma, and COA/NAVI shows significantly higher efficacy than free NAVI. In vivo studies were conducted on an A375 xenograft mouse model to evaluate drug efficacy, safety, and biodistribution. The findings from comprehensive studies and observations reveal that the COA/NAVI formulation can be an effective and safer therapeutic approach for treating skin melanoma.
The components of the formulation compound can be substituted partially or wholly with other components that provide equivalent functionality. Examples of components that can be substituted include the following.
The choline octanate can be produced by reacting at least two members selected from the group consisting of choline bicarbonate, octanoic acid, octenoic acid or geranic acid. More specifically choline bicarbonate and at least one member selected from the group consisting of octanoic acid, octenoic acid or geranic acid.
Specific exemplary embodiments will now be further described by the following, nonlimiting examples which will serve to illustrate in some detail various features. The following examples are included to facilitate an understanding of ways in which embodiments of the present disclosure may be practiced. However, it should be appreciated that many changes can be made in the exemplary embodiments which are disclosed while still obtaining like or similar result without departing from the scope of embodiments of the present disclosure. Accordingly, the examples should not be construed as limiting the scope of the present disclosure.
Mice were randomly distributed into four groups and treatments were given for four weeks. Our treatment groups were untreated, NAVI (50 µM) (PO), topical administration of COA (50%), and COA/NAVI (50 µM). (a)
Referring to
Referring to
Referring to
Referring to
Referring to
Referring to
Referring to
All of the methods disclosed and claimed herein can be made and executed without undue experimentation in light of the present disclosure. While the compositions and methods of this invention have been described in terms of preferred embodiments, it will be apparent to those of skill in the art that variations may be applied to the methods and in the steps or in the sequence of steps of the method described herein without departing from the concept, spirit and scope of the invention. More specifically, it will be apparent that certain agents which are both chemically and physiologically related may be substituted for the agents described herein while the same or similar results would be achieved. All such similar substitutes and modifications apparent to those skilled in the art are deemed to be within the spirit, scope and concept of the invention as defined by the appended claims.
This application is a utility conversion and claims priority to U.S. Ser. No. 63/264,295, filed Nov. 19, 2021, the contents of which are incorporated herein by reference in their entirety for all purposes.
| Number | Date | Country | |
|---|---|---|---|
| 63264295 | Nov 2021 | US |
