Methods for treating basal cell carcinoma and glioblastoma

Abstract

To provide methods of treating basal cell carcinoma or glioblastoma.SOLUTION: A composition for treating glioblastoma (GBM) comprises coal tar or a coal tar product.SELECTED DRAWING: None

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application is a continuation-in-part of U.S. Patent Application No. 16 / 155,558, filed October 9, 2018, which is incorporated herein by reference in its entirety.

[0002] This application relates to methods of treating basal cell carcinoma and glioblastoma by administering coal tar and / or coal tar products. [Background technology]

[0003] Basal cell carcinoma

[0004] The basal layer of the mammalian epidermis, or stratum germinativum, is the deepest of the five layers of the epidermis and produces new skin cells as existing cells die. This forms a continuous layer of cells and most often becomes neoplastic after prolonged exposure to ultraviolet light from the sun or artificial sources such as tanning beds, which damage the cells' DNA. Basal cell carcinoma (BCC) most commonly appears on the skin of the head, neck, and arms, and less frequently on areas of the body covered by clothing, such as the trunk and legs. The appearance of BCC is quite variable, appearing as non-healing growths or sores, or as slightly raised growths that are translucent, pink, pearly white, brown, black, or blue. Occasionally, they can be white, scar-like lesions with a waxy appearance, called morphemic BCC. In rare cases, BCC can migrate to nearby muscle, nerves, or bone, causing loss or damage to these tissues. A schematic diagram of BCC is shown in Figure 1.

[0005] Current treatments for BCC include in-office surgical excision, cryosurgery (liquid nitrogen freezing), curettage and electrocoagulation, electrosurgery (electric needle ablation), local chemotherapy with agents such as 5-fluorouracil (5-FU) and imiquimod, radiation (discs), electronic skin surface brachytherapy (ESSB), and laser therapy. Mohs surgery, used for larger BCC tumors with a high risk of recurrence, involves repeated surgical removal and freezing of cells, layer by layer, with each layer immediately examined microscopically to determine whether any remaining cancerous cells remain. This is followed by closure of the opening with sutures, skin grafts, or plastic surgery, as needed. Mohs surgery has the highest cure rate and is often used for BCCs on the face, where the need for skin preservation is paramount.

[0006] Glioblastoma

[0007] Glioblastoma is a stage IV glioma, a cancer of the glial cells of the brain and spinal cord. It is an aggressive, malignant tumor that is always fatal and is the most common type of brain tumor. Once a patient has glioblastoma, the expected median overall survival is 14 to 17 months. Glioblastomas form from a type of cell called astrocytes; therefore, they are sometimes called astrocytomas. According to Wikipedia, "Glioblastomas may contain two or more cell types (i.e., astrocytes, oligodendrocytes). Also, one cell type may die in response to certain treatments, while the other cell type continues to proliferate. Glioblastomas are the most aggressive type of glial tumor because they grow rapidly and spread to nearby tissues. Approximately 50% of astrocytomas are glioblastomas, making them extremely difficult to treat." Glioblastoma multiforme (GBM) accounts for over 60% of all brain tumors in adults. Hanif et al., 2017, Asian Pac. J. Cancer Prev. 18:3-9. The incidence of glioblastoma is 3.19 per 100,000. Thakkar et al., 2014, Cancer Epidemiol. Biomarkers Prev. 10:1985-96.

[0008] Standard treatment consists of surgical resection, followed by radiation therapy within 1–4 weeks, followed by chemotherapy. Robotic stereotactic radiosurgery is often preferred when tumors are deemed inoperable due to their location in the brain or the patient's general health. Experimental treatments include immunomodulators, biologics such as antibody-drug conjugates, boron neutron capture therapy, and gene therapy. One such gene therapy is VAL-083 (dianhydrogalactitol), a DNA-targeted agent currently undergoing phase 2 and 3 clinical trials. Murphy et al., Transl Res. 2013 Apr;161(4):339–354. An inducible adenoviral vector, Ad-RTS-hIL-12, encoding the human inflammatory cytokine interleukin-12 (IL-12), and its oral activator ligand, Veredimex, are in clinical development for the treatment of adult recurrent or progressive glioblastoma multiforme and have been shown to extend life expectancy by approximately 6 months over current standard treatments.

[0009] By the time glioblastoma symptoms are felt, its tentacles have spread throughout the brain. Because the tentacles wrap around brain neurons without the visible center typically found in other cancers, tumor injections are currently unwise. Because there is no known method to identify the location of the nucleus, tumor injections are usually ineffective. Surgery is generally the first course of treatment, providing symptomatic relief due to a reduction in pressure caused by the tumor's bulk within the cranial cavity. On average, 98% to 99% of tumor cells are removed. Fluorescence-guided resection is often used to remove as much tumor tissue as possible with the goal of prolonging survival. (Stummer et al., 2000, J. Neurosurg. 93:1000-1013) MRI-guided laser ablation is another method for removing as much malignant tumor as possible. (Kubben et al., 2011, The Lancet 12:1062-1070) Another method for localizing glioblastoma cells before resection uses the non-fluorescent prodrug 5-aminolevulinic acid (5-ALA), which causes a fluorescent porphyrin to aggregate on malignant glioma cells, which can then be visualized under blue light during craniotomy. 5-ALA can be administered intravenously or orally to glioblastoma patients.

[0010] Resection is often followed by postoperative stereotactic radiosurgery. C-methionine positron emission tomography (MET-PET) imaging helps locate and target residual disease within the partially collapsed surgical cavity. P.M.Wald, et al., International Journal of Radiation Oncology, Biology, Physics. Volume 96, Number 2S, Supplement 2016. Despite these procedures, glioblastoma cells survive or have already metastasized to areas beyond the surgeon's reach, resulting in tumor regrowth. Because regrowth is rapid, chemotherapy treatment is usually immediate.

[0011] For decades, no new chemotherapy agents capable of crossing the blood-brain barrier (BBB) ​​have been approved for glioblastoma. Temozolomide, a DNA alkylating / methylating agent, remains the most widely used and is taken during radiation therapy. Other agents include carmustine, a dialkylating agent; lomustine, an alkylating agent; vincristine, which binds to tubulin protein; cisplatin, an alkylating agent; bevacizumab, an angiogenesis inhibitor; etoposide, an inhibitor of DNA topoisomerase II; and procarbazine, an alkylating agent. No new or repurposed small molecules have been developed to favor biologics and devices that allow for more precise targeting of radiation.

[0012] The blood-brain barrier (BBB) ​​prevents most pharmaceutical compounds from moving from the blood to the brain, and only small molecules can perform these functions. In addition to the BBB, glioblastomas form an additional barrier in the peripheral region called the blood-brain tumor barrier (BBTB), creating a double barrier to drugs. Various drug transporter- and receptor-mediated drug delivery systems selectively enhance drug delivery and explore the use of cell-permeable tumor-targeting peptides on the surface of nanoparticles. Dong X, Theranostics. 2018;8(6):1481-1493.

[0013] Bevacizumab, part of a class of drugs called monoclonal antibodies, is used to extend the time between initial treatment and tumor regrowth by activating the immune system to attack surviving glioma cells. Bevacizumab is delivered by intravenous infusion.

[0014] One experimental approach to treating glioblastoma cells after surgery involves the local delivery of chemotherapy agents to biodegradable polylactic acid scaffolds. Mesenchymal stem cells delivered to the surgical resection cavity on the polylactic acid scaffolds are thought to result in tumor death. Sheets et al., "Image-Guided Resection of Glioblastoma and Intracranial Implantation of Therapeutic Stem Cell-Seeded Scaffolds," J. of Visualized Experiments (Jul 2018). Other studies support the use of encapsulated therapeutic stem cells implanted into the tumor resection cavity to induce cell death in gliomas. Kauer et al., Nat Neurosci 15:197-204.

[0015] The U.S. Food and Drug Administration has approved Tumor Treating Fields (TTFields), a cap-like device that sends a gentle electrical charge through the skull to disrupt cancer cell division. The goal is to slow the rate of tumor growth or metastasis while avoiding damage to normal cells. While TTFields is not a cure, it has the advantage of avoiding the pain, nausea, fatigue, or diarrhea associated with chemotherapy and radiation.

[0016] Irradiated boron isotopes (also known as boron-neutron recapture) have been studied for decades as a method of targeting glioblastoma. In a recent clinical trial, patients with malignant glioblastoma treated with boron-neutron recapture therapy in combination with standard radiation therapy lived significantly longer than patients receiving standard therapy.

[0017] coal tar

[0018] Coal tar is made by heating coal in a coke oven to remove volatile materials. A description of the coking process can be found on the Cooper Creek Chemical Corporation website under the reference titled "How is Crude Coal Tar Derived." Coal tar is a mixture of compounds primarily composed of polycyclic aromatic hydrocarbons, including phenanthrene, acenaphthene, fluorene, anthracene, and pyridine. Coal tar is insoluble in water but is largely soluble in benzene and partially soluble in alcohol, ether, chloroform, acetone, carbon disulfide, chloroform, and methanol.

[0019] Virtually all commercial coal tar is produced as a by-product of the production of blast furnace coke from coal. Modern coke ovens are based on the dry distillation of coal in large horizontal chambers. The chambers are constructed of ceramic materials to allow the coal to be heated to temperatures exceeding 1,100°C. This dry distillation breaks down the coal into gas, liquid (tar), and solid coke. The gas and tar are collected in a series of condensers and coolers and processed to produce specific commodities and dry fuel gas.

[0020] The liquid product, coal tar, contains a complex mixture of hydrocarbons and other compounds containing various amounts of oxygen, sulfur, and nitrogen. A key feature of all these coal tar components is their highly aromatic chemical structure, a result of the high temperatures experienced in the coke oven.

[0021] When coal tar is used as a drug, pitch (27% of coal tar) can be vaporized above 400°C and removed from the final drug by the supplier. Gas chromatography or HPLC can be used to ensure that coal tar USP used to treat basal cell carcinoma or glioblastoma is pitch-free and meets established viscosity standards.

[0022] Recovery of specific coal tar fractions is primarily based on their boiling range and is carried out in standard commercial distillation equipment. Typically, emphasis is placed on the following three fractions in order of boiling range: 1. Light oil, BTX fraction. This fraction contains mainly compounds with a single aromatic ring, namely benzene, toluene, and xylene, hence the term "BTX." The boiling points of these three compounds are 80, 111, and 138-144°C, respectively. 2. Naphthalene fraction, which contains most of the valuable chemical naphthalene, which has a boiling point of 218°C. 3. Distillate fraction. This is the remaining distillable fraction of coal tar. The high-boiling, non-distillable portion, commonly called pitch, is removed from the still as a liquid. This is usually more than half of the original tar.

[0023] The distillate fraction leaves the still as a vapor from the top of the distillation column and is condensed for recovery. The compound that makes up the majority of the distillate fraction is known as coal tar for medical purposes.

[0024] For more information on the above processes, see Kirk-Othmer Encyclopedia of Chemical Technology. 1997. New York: John Wiley & Sons, Inc. Volume 23. "Tars and Pitches."

[0025] As a quality control measure, various methods known in the art can be used to monitor and quantify the top 17 fractions from the distillation fraction (see Example 4). For example, the 17 fractions are separated using classical column chromatography and monitored by thin layer chromatography (TLC) where the mobile phase or eluent is pure hexane (for the first 15 fractions), ethyl acetate (for fraction 16), and methanol (for fraction 17).

[0026] Therapeutic Uses of Coal Tar

[0027] One coal tar solution for topical use is described on the Universal Preserva-A-Chem Inc. website under the product name "Coal Tar Topical Solution USP," which lists the chemical formula, properties, and several synonyms. Coal tar solutions are often referred to as liquor carbonis detergens (LCDs).

[0028] According to Wikipedia, "Coal tar was discovered around 1665 and was used for medicinal purposes as early as the 1800s. It is on the World Health Organization's list of essential medicines and is one of the most effective and safe medicines needed in the health system. Coal tar is available over the counter as a generic drug. Coal tar was one of the important starting materials for the early pharmaceutical industry."

[0029] Coal tar is available in the United States as United States Pharmacopeia (USP) grade with a maximum residue on ignition of 2.0%. Coal tar ointment USP (obtained by combining coal tar with polysorbate 80 (a sorbitan monooleate polyoxyethylene derivative) and blending it with zinc oxide paste) and coal tar topical solution USP (made by combining coal tar with polysorbate 80 and diluting it with ethanol to an ethanol content of 81.0–86.0%) are also available in the United States.

[0030] Coal Tar USP is approved in the United States for use in denatured alcohol, formulations 38-B and 38-F. Numerous products, coal tar strengths, dosage forms, routes of administration, and branded or generic forms are available. Coal Tar USP is known to penetrate the germ layer.

[0031] Raw coal tar is known to cross the blood-brain barrier (BBB) ​​and have neurological effects. The BBB protects the brain from harmful charged chemicals circulating in the blood by preventing them from entering the brain. Therefore, in order to cross the BBB, pharmacological agents must be nonpolar.

[0032] The American Society of Health-System Pharmacists; Drug Information 2016, Bethesda, MD, describes the well-established use of coal tar products for dermatological disorders. Coal tar has been used to manage dandruff, seborrheic dermatitis, and psoriasis by reducing the number and size of epidermal cells produced. This suggests that coal tar extracts oxygen from the skin, thereby inhibiting cell renewal (mitosis) and reducing the size and number of cells in the germinal and stratum corneum. Another suggestion is that coal tar, formulated into various soaps and shampoos, exerts its therapeutic effect in patients with dandruff, seborrheic dermatitis, or psoriasis by penetrating the epidermis and removing the scaling caused by these skin disorders. Polyphenolic substances and peroxides in coal tar may react with sulfhydryl groups in the epidermis, resulting in skin effects similar to those resulting from sun exposure. This effect could theoretically reduce epidermal proliferation and skin infiltration.

[0033] Coal tar preparations are used topically, alone or in combination with other drugs (e.g., salicylic acid or sulfur), to suppress dandruff, seborrheic dermatitis, or psoriasis. Although there are few well-controlled studies demonstrating their effectiveness, coal tar preparations are used to relieve the itching and scalp flaking associated with dandruff, the itching, irritation, and peeling associated with seborrheic dermatitis, and the itching, redness, and scaling associated with psoriasis, and are generally considered effective.

[0034] Combinations of coal tar components for treating disorders responsive to dihydrofolate reductase (DHFR) inhibition are disclosed in U.S. Patent No. 6,337,337. DHFR catalyzes the NADPH-dependent reduction of 7,8-dihydrofolate (H2F) to 5,6,7,8-tetrahydrofolate (H4F), which is necessary to maintain intracellular levels of H4F, an essential cofactor in the synthesis pathways of purines, thymidylate, and several amino acids. The coal tar compositions of the present invention described in the '337 patent are believed to inhibit the transfer of hydrogen ions on NADPH to dihydrofolate reductase, thus preventing the intranuclear metabolism of tetrahydrofolate. Because neoplastic cells are more sensitive than slow-dividing normal cells to the resulting interference with DNA synthesis, repair, and cell replication, cancers responsive to antifolate therapy, such as those detailed in the '337 patent, are known to not divide but to "explode" upon treatment with coal tar products. The '337 patent describes a coal tar composition as functionally replicating the antifolate methotrexate for the treatment of certain cancers.

[0035] Coal tar toxicity

[0036] A comprehensive review of coal tar toxicity by the US Department of Health and Human Services was published in 2002 and can be found in the Creosote Toxicity Profile, available on the website of the Agency for Toxic Substances and Disease Registry. This document reviews studies that provided mixed evidence regarding whether coal tar causes squamous cell carcinoma and other tumors. Many of the studies reviewed involved long-term occupational exposures in the air or in factories, often over the past several decades, when industrial standards for hygiene and worker safety were not as stringent as they are today. Furthermore, when information was found to provide evidence of tumorigenicity, the observed effects may have required a combination of chronic exposure to coal tar or its products and exposure to sunlight.

[0037] Notably, the study found no statistical correlation between the use of coal tar products on human skin and cancer incidence. Perhaps the best data on human coal tar use comes from users of coal tar for psoriasis. In particular, the study by Bhate et al., summarized on page 136 of the government review, used a large population, was placebo-controlled, and examined a wide range of cancers. The study found that the incidence of cancer (total, skin, breast, cervical, genitourinary tract, bronchial, gastrointestinal tract, lymphoma, or other) was not significantly greater in 2,247 patients with psoriasis than in 4,494 age-matched controls without psoriasis.

[0038] Other studies have not found any reproductive risks in humans, and despite the many reported studies in the review, no significant biological risks to humans (other than benign tar warts in creosote tar workers exposed for 5-40 years) involving the central nervous system have been identified.

[0039] Some studies examined the effects of some of the components of coal tar (rather than the effects of coal tar as a whole). Although some of the studies reviewed are considered insufficient by current standards, the results nevertheless indicate that coal tar creosote and its components can induce skin tumors and act as tumor initiators and promoters. Nevertheless, the International Agency for Research on Cancer, the American Conference of Governmental Industrial Hygienists, the National Toxicology Program, and the Occupational Safety and Health Administration have reported that coal tar components present at levels above 0.1% have not been identified as probable or confirmed human carcinogens. Summary of the Invention [Means for solving the problem]

[0040] Provided herein is a method for treating basal cell carcinoma or glioblastoma, comprising administering a therapeutically effective amount of a coal tar product to a patient in need of treatment. In some embodiments, the coal tar product is coal tar USP, coal tar ointment USP, or coal tar topical solution USP. In some embodiments, the coal tar product is applied topically to the basal cell carcinoma. In some embodiments, the coal tar product is present in a pharmaceutical composition.

[0041] Also provided herein are methods for treating basal cell carcinoma or glioblastoma, comprising administering to a patient in need thereof a coal tar product in combination with another therapeutic treatment effective in treating basal cell carcinoma or glioblastoma. In some embodiments, the other therapeutic treatment is a treatment for basal cell carcinoma or glioblastoma, including surgical excision, curettage and electrocoagulation, Mohs micrographic surgery, radiation, cryosurgery, photodynamic therapy, laser surgery, imiquimod, 5-fluorouracil, vismodegib, or sonidegib. In some embodiments, the treatment is a treatment for glioblastoma used alone or in combination with surgical removal, radiation, chemotherapy, tumor-treating electric fields, bevacizumab, polylactic acid or similar scaffolds, or encapsulation.

[0042] Current treatments for basal cell carcinoma typically require surgical removal because cells in the basal layer are not completely killed by current topical treatments. This commonly results in scarring at the surgical site. Surprisingly, unlike current topical treatments, coal tar products penetrate the basal layer and kill neoplastic basal cell carcinoma cells capable of metastasizing. Thus, after coal tar product treatment, remnants of basal cell carcinoma or glioblastoma can be easily cryo-removed, leaving the skin intact as the epidermis heals.

[0043] As an alternative to cryotherapy, any remaining basal cell carcinoma can be scraped off (curettage) by a medical professional, similar to the current method of removing actinic keratosis. The advantage of cryotherapy or curettage is faster removal and restoration to a normal appearance.

[0044] In some embodiments, the coal tar product is administered prior to the other therapeutic treatment. In some embodiments, the coal tar product is administered after the other therapeutic treatment. In some embodiments, the coal tar product is administered simultaneously with the other therapeutic treatment.

[0045] In some embodiments, the coal tar product and the other therapeutic treatment are administered together in a single pharmaceutical composition. In some embodiments, the coal tar product and the other therapeutic treatment are administered separately in different pharmaceutical compositions. In some embodiments, the coal tar product is administered topically or as a therapeutic dressing to the lining of the postoperative cavity, and the other therapeutic treatment is administered topically, orally, intravenously, or subcutaneously using a device (e.g., gamma knife). In some embodiments, the coal tar product is administered intravenously, and the other therapeutic treatment is administered topically, orally, intravenously, or subcutaneously using a device (e.g., gamma knife).

[0046] Following treatment with coal tar products, and optionally other therapeutic treatments, daily or frequent (e.g., once weekly, twice weekly, three times weekly, four times weekly) application by the patient of low concentrations of coal tar products (e.g., coal tar USP as a 0.1% to 0.5% alcoholic solution) to the affected area is recommended to prevent or delay the recurrence of basal cell carcinoma.

[0047] Application of a coal tar product (e.g., 0.00005% to 0.5% coal tar USP in ethanol, lactic acid, or dipropylene glycol (DiPG) solution, or in a mixture containing 50% DMSO, 35% PEG 400, and 15% ethanol and excipients, or incorporated into a delivery vehicle such as a polylactic acid scaffold) to the surgical cavity prior to closure, prior to or following removal of the glioblastoma and, optionally, another therapeutic treatment. See Figure 2.

[0048] Thus, disclosed herein are methods for preventing basal cell carcinoma, comprising administering a therapeutically effective amount of a coal tar product to a patient previously treated for basal cell carcinoma. In some embodiments, the coal tar product is administered to an area of ​​the patient's skin where basal cell carcinoma previously appeared and was treated, and the method prevents the recurrence of basal cell carcinoma. In some embodiments, the coal tar product is administered to an area of ​​the patient's skin near (within about 1 or 2 inches of) an area where basal cell carcinoma previously appeared and was treated, and the method prevents the appearance of new basal cell carcinoma.

[0049] The patent or application file contains at least one drawing executed in color. Copies of this patent or patent application publication with the color drawing(s) will be provided by the Office upon request and payment of the necessary fee. [Brief explanation of the drawings]

[0050] [Figure 1] Figure 1 shows a schematic diagram of a basal cell carcinoma and a typical incision for surgical removal.

[0051] [Figure 2] FIG. 2 shows a growth inhibition bar graph of an assay performed at the National Cancer Institute of a coal tar-derived composition (see Example 4) against the CNS cancer cell lines glioblastoma SF-268 and astrocytoma U251.

[0052] [Figure 3]3A-3C show the basal cell carcinoma on the patient's forehead before the first treatment (see Example 1). A, before treatment; B, during treatment; C, after treatment.

[0053] [Figure 4] Figures 4A-4C show basal cell carcinoma on the right forehead of the same patient, occurring 4 years after the basal cell carcinoma in Figures 3A-3C was treated. A, before treatment; B, during treatment; C, after treatment. See Example 1.

[0054] [Figure 5] Figures 5A-5B show two basal cell carcinomas on the left and right foreheads of the same patient, occurring four years after the basal cell carcinoma in Figures 4A-4B was treated. See Example 1. Before and after photographs of the left and right basal cell carcinomas are shown in 5A (before treatment with coal tar USP) and 5B (after treatment with coal tar USP).

[0055] [Figure 6] Figures 6A-6B show close-ups of the basal cell carcinoma on the patient's right forehead before (A) and 4 months after (B) daily topical treatment and after final cryotherapy. The arrow and circled area in 6B indicate the location of the basal cell carcinoma.

[0056] [Figure 7] Figures 7A-7B show the right and center forehead of a patient in whom large basal cell carcinomas appeared 4 and 1 year prior to the time the photographs were taken. See Example 1. A, Area after removal of the last basal cell carcinoma and prophylactic treatment with 0.1% coal tar USP dissolved in alcohol applied via cotton ball once or twice daily. B, Close-up of the rightmost portion of A.

[0057] [Figure 8] 8A-8B show close-ups of a patient's left forehead before and after 12 days of twice-daily topical application of a 0.3% composition of Example 4 in alcoholic solution. The images show loss of early-stage BCC growth and BCC shrinkage. A, before application; B, after 12 days of application.

[0058] [Figure 9] 9A-9C show photographs of pre-treatment (A), during treatment (B), and after treatment (C) of a treated basal cell carcinoma emerging from blemished skin on the patient's forehead in Example 4 and treated twice daily with the composition of Table 12 for 12 days (B) and then for an additional 14 days (C). DETAILED DESCRIPTION OF THE INVENTION

[0059] "Administering" refers to providing a coal tar product or a pharmaceutical composition comprising a coal tar product to a patient in need thereof by any means known in the medical arts, including self-administration by the patient as well as administration by a physician or other healthcare provider. "Administering" also includes local delivery of a coal tar product directly into or onto a target tissue, such as topical administration to or injection into a basal cell carcinoma or local delivery to the lining of a surgical cavity following removal of a brain tumor.

[0060] "Coal tar products" refers to therapeutic agents derived from coal tar. In some embodiments, coal tar products are effective in treating basal cell carcinoma. In some embodiments, coal tar products are effective in treating glioblastoma. Examples of "coal tar products" include Coal Tar USP, Coal Tar Topical Solution USP, and Coal Tar Ointment USP.

[0061] "Patient" preferably refers to a human, but may also refer to a companion animal such as a dog or cat, or a farm animal such as a horse, cow, pig, or sheep.

[0062] "Pharmaceutically acceptable" refers to a carrier, diluent, or excipient that is compatible with the other ingredients of the formulation and not deleterious to the patient to whom the formulation is administered.

[0063] "Therapeutically effective amount" refers to the amount of coal tar product that will bring about a desired change in the physiology of a patient to whom the coal tar product is administered, such as a reduction in the size of a basal cell carcinoma or glioblastoma.

[0064] Surprisingly, coal tar USP in a pharmaceutically acceptable carrier has been found to be effective against cancers that do not respond to antifolate therapy, such as methotrexate. In particular, unexpectedly, coal tar USP in an acceptable pharmaceutical carrier has been shown to be effective in locally treating basal cell carcinoma. Currently, basal cell carcinoma is often treated with Mohs surgery, in which successive layers of skin are sectioned until no further cancer cells are observed under high magnification in a sample section. However, this method is not a cure and is commonly repeated. Chemical bathing of the basal layer with anticancer agents derived from coal tar products, as disclosed herein, provides patients with a more complete and less disfiguring treatment. Furthermore, low-dose follow-up applications have been shown to prevent recurrence in the immediate and wider adjacent areas of the initially treated basal cell carcinoma.

[0065] Equally surprising, coal tar USP at a concentration of 100 μg / ml in an acceptable pharmaceutical carrier inhibited the in vitro growth of glioblastoma multiforme cells (U251, grade IV astrocytoma) by 100% and the in vitro growth of astrocytoma cells (SF-268 cell line) by 91% in assays completed at the National Cancer Institute (NCI). See Figure 2. The use of coal tar-based therapeutics in these cancers offers a preferred treatment option over surgical resection, which is rarely curative because some cancerous cells persist, regrow, or metastasize.

[0066] Optionally, if surgical removal of the tumor is recommended, the local application of a coal tar-based therapeutic agent to the lining of the surgical cavity after tumor resection, alone or in combination with other drugs or treatments, provides additional cell kill of glioblastoma multiforme cells that are left in place due to being beyond the reach of surgical instruments or in close proximity to highly functional neurons, such as those capable of speech.

[0067] Without intending to be bound by theory, one possible explanation for the effectiveness of coal tar products in treating glioblastoma is based on their non-competitive binding, electron transport, or allosteric effect on NADPH. Tumor cells are more responsive than slower-dividing normal cells to the resulting interference with DNA synthesis, repair, and cell replication that results from inhibition of NADPH hydrogen transfer.

[0068] Furthermore, tumorigenic cells generally require higher levels of NADPH than wild-type cells, for example, due to their greater mitotic activity and the need for antioxidant function, especially during chemotherapy or radiotherapy. NADPH is used by glioblastomas to survive radiation therapy by increasing the production of deoxynucleotides and antioxidants, specifically glutathione and thioredoxin, which help reduce post-radiation oxidative stress and repair radiation-induced DNA damage. Inhibiting the production of enzymes that produce NADPH has resulted in greater sensitivity of glioblastomas to radiation both in vitro and in vivo. See Spitz et al., 2004, Cancer Metastasis Reviews 23:311-322. Glioblastomas differ from surrounding normal tissues in terms of NADPH metabolism, and inhibition of the NADPH-producing enzyme isocitrate dehydrogenase 1 (IDH1) sensitizes glioblastomas to radiation in vitro and in vivo by inducing NADPH-dependent cellular senescence. Therefore, inhibiting NADPH production may enhance the efficacy of radiation therapy for glioblastomas. Temozolid, the main radiosensitizer currently in use, has only modest efficacy. Although temozolid is widely used in combination with surgery and radiation, most glioblastoma patients still die from recurrence within the high-dose radiation field. (Wahl et al., 2017, Cancer Res. 77:960-970)

[0069] Thus, disclosed herein are methods for sensitizing glioblastoma to radiation therapy by inhibiting or interfering with the ability to reduce NADPH, comprising administering a therapeutically effective amount of a coal tar product to a patient having glioblastoma. In some embodiments, the patient is then administered a therapeutically effective dose of radiation, either simultaneously with or after administration of the coal tar product.

[0070] In some embodiments, the methods of treating basal cell carcinoma disclosed herein, when using chemotherapy ointments or creams, eliminate the need for surgical removal of basal cell carcinoma growths and the risk to adjacent skin. The agents disclosed herein are not harmful to normal skin and only attack and kill basal cell carcinoma cells.

[0071] Combination drugs are generally more effective than single-molecule drugs because malignant cells can often resist exposure to a single chemical, but when two or more are combined, the therapeutic response is generally stronger, often sufficient to halt cell growth and induce tumor cell death. Coal Tar USP, a combination of many molecules in one drug, has the advantage of overwhelming the defenses malignant cells use to become drug-resistant.

[0072] The effectiveness of coal tar described herein against two tumor types that are not responsive to dihydrofolate reductase (DHFR) inhibition, basal cell carcinoma and glioblastoma, is surprising in light of the teachings of U.S. Pat. No. 5,337,337, which discloses the antitumor effects of coal tar products occur via a mechanism similar to that of DHFR.

[0073] Pharmaceutical Composition

[0074] When the coal tar products disclosed herein are administered to humans or animals as pharmaceuticals, they are generally provided in a pharmaceutical composition comprising, for example, about 0.00005-3%, about 0.001-2.5%, about 0.5-2%, or about 1-1.75% (w / w, w / v, or v / v) of the coal tar product in combination with one or more pharmaceutically acceptable carriers. In some embodiments, the pharmaceutical composition comprises about 0.00005%, about 0.001%, about 0.01%, about 0.03%, about 0.05%, about 0.075%, about 0.1%, about 0.2%, about 0.3%, about 0.4%, about 0.5%, about 0.6%, about 0.7%, about 0.8%, about 0.9%, about 1.0%, about 1.1%, about 1.2%, about 1.3%, about 1.4%, about 1.5%, about 1.6%, about 1.7%, about 1.8%, about 1.9%, or about 2% (w / w, w / v, or v / v) of a coal tar product in combination with one or more pharmaceutically acceptable carriers.

[0075] In some embodiments, the pharmaceutical composition comprises about 2% w / w coal tar USP diluted with DMSO, ethanol, or dipropylene glycol (DiPG).

[0076] Dosage levels of the coal tar product in the pharmaceutical composition may be varied to provide an amount of coal tar product that is not toxic to the patient and achieves the desired therapeutic response for a particular patient and mode of administration.

[0077] Dosage levels will depend on a variety of factors, including the activity of the particular coal tar product, the route of administration, the time of administration, the rate of excretion or metabolism of the coal tar product, the rate and extent of absorption, the duration of treatment, whether other drugs are also being administered to the patient, the age, sex, weight, condition, general health, and past medical history of the patient being treated, and similar factors well known in the medical arts.

[0078] Generally, an appropriate daily dose of the coal tar products disclosed herein is the amount of coal tar product that is the lowest effective dose to produce a therapeutic effect. Such an effective dose will generally depend on the factors described above. Generally, oral, intravenous, and subcutaneous doses of coal tar products for a patient range from about 0.0001 to about 200 mg per kilogram of patient body weight per day, or from about 0.001 to about 100 mg per kilogram, or from about 0.01 to about 100 mg per kilogram, or from about 0.1 to about 100 mg per kilogram, or from about 1 to about 50 mg per kilogram.

[0079] The coal tar product can be administered as a single dose daily, once daily, twice daily, three times daily, or more frequently. Other schedules include every other day, three times a week, twice weekly, weekly, or every other week. The administration schedule can include a "drug holiday," i.e., a period during which the coal tar product is not administered. For example, the coal tar product can be administered for two weeks on, one week off, or three weeks on, one week off, or four weeks on, one week off, etc., or continuously without a drug holiday. The coal tar product can be administered orally, intravenously, intraperitoneally, topically, transdermally, intramuscularly, subcutaneously, intranasally, sublingually, by inhalation, or any other route.

[0080] To prepare pharmaceutical compositions, coal tar products are generally dissolved in a solvent. Some coal tar solvents consist of neutral, acidic, or basic cyclic compounds characterized by the presence of a six-membered ring in the molecule, and most are mutually soluble. Coal tar USP is slightly soluble in water and partially soluble in acetone, alcohol, carbon disulfide, chloroform, ether, and methanol. These solvents may be used alone or in combination. Other solvents may also be used.

[0081] For use in basal cell carcinoma requiring delivery to the basal layer, the preferred solvent system for coal tar USP is a mixture of ethanol (IPA 99%), dipropylene glycol (DiPG), PEG 400 monostearate, and acetic acid. The preferred ratios are 48-50% ethanol, 30% DiPG, 15% PEG 400, and 3-5% acetic acid. Residual pitch (or solutes) will precipitate immediately after mixing or within 24 hours of mixing and will adhere to the plastic container or can be removed by filtration through a porous membrane.

[0082] Dipropylene glycol, chemical formula CH 14 O3 is a mixture of three isomeric chemical compounds: 4-oxa-2,6-heptanediol, 2-propan-1-ol, and 2-propan-1-ol. It is a colorless, nearly odorless liquid with low toxicity and a molar mass of 134.173 g / mol. Dipropylene glycol is miscible with water and soluble in ethanol, making it commonly used in pharmaceutical formulations.

[0083] It is well known that DiPG is a skin-penetrating agent and one of the preferred diluents for delivering topical drugs to the skin. The MSDS for DiPG can be found on the Environmental Working Group's Cosmetics Database website. The minimal amount of acetic acid in the solvent mixture helps soften and exfoliate the corneocytes of the stratum corneum, where the lipids in these cells could otherwise trap the drug.

[0084] Other solvents or partial solvents for polycyclic aromatic hydrocarbons found in coal tar, USP, are isopropyl myristate, PEG 600, Cremophor® EL PEG-35 castor oil, ethanoic acid (acetic acid aqueous solution), avocado oil, sesame oil, tocopherol oil (vitamin E), and castor oil. Other, more exotic oils, including clove leaf oil, rosemary oil, geranium oil, lemon oil, and juniper berry oil, can also serve as either solvents or odor-masking diluents. These solvents and diluents can be used alone or in combination with other solvents.

[0085] For delivery of coal tar USP to basal cell carcinoma, xanthan gum (e.g., from CP Kelco) or guar gum can be added to aqueous formulations at concentrations of about 0.5% to about 2.5% by first wetting the gum in one or more oil solvents or flavorings for at least 1 hour, then adding this mixture to the coal tar USP solution and mixing together for 45 to 60 minutes at a speed sufficient to create a vortex. This creates a gel consistency, allowing the drug to stay in place on the basal cell carcinoma, which is particularly useful when treating basal cell carcinoma above the eye or at the hairline where spillage might otherwise occur. To increase adhesion to the skin on the forehead and other locations, smaller amounts of xanthan gum (<0.5%) can be added to maintenance-level formulations (e.g., 0.1% coal tar USP).

[0086] Techniques and methods for the topical delivery of coal tar products to basal cell carcinoma include unit-dose dispensing devices, needles, microneedles, needle-free injection devices, injection pads, saturated wipes, pre-filled applicators such as adhesive bandages or tabs, creams, gels, and ointments, including petrolatum-based ointments.

[0087] A preferred method of topical delivery of a coal tar product to a basal cell carcinoma is simply to manually apply the coal tar product to the basal cell carcinoma. In this embodiment, the coal tar product is preferably in the form of a cream, ointment, lotion, or other similar product, and is placed on the basal cell carcinoma, avoiding surrounding normal tissue as much as possible. Either the patient or a healthcare provider may apply the coal tar product to the basal cell carcinoma. The amount of cream, ointment, lotion, or other form of product to be applied depends on the size and / or location of the basal cell carcinoma and is easily ascertained by the patient or healthcare provider applying the coal tar product.

[0088] In some embodiments, the coal tar product can remain at the application site on the basal cell carcinoma, i.e., it is not wiped off or removed after a period of time. However, in some cases, it may be desirable to wipe off the coal tar product after a period of time, such as 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, or more.

[0089] In some embodiments, the coal tar product is applied to the basal cell carcinoma using a foam or cotton pad. In some embodiments, the coal tar product is applied using a bandage to seal the ointment, cream, or other topical delivery composition against the basal cell carcinoma. The length of time the bandage is left in place depends on various factors, such as the dose of coal tar product applied and the nature of the basal cell carcinoma (e.g., size, location).

[0090] Delivery to central nervous system (CNS) tumors

[0091] Drugs that cross the blood-brain barrier (BBB) ​​are generally small, nonpolar, lipid-soluble molecules that permeate by diffusion. While permeability depends on many factors (e.g., molecular shape, flexibility, surface area), the two main properties that affect permeability are size and solubility. The molecular weight threshold for permeability is approximately 400 Da. Coal tar USP (with pitch removed) weighs between 210 and 250 Da. Regarding the solubility threshold, if a drug forms fewer than seven hydrogen bonds with water, it is more likely to cross the BBB. Coal tar USP is slightly soluble in water and more soluble in lipids.

[0092] A discussion of the BBB and ways to overcome it can be found on the Quora website under the question answered by Jens Mowatt, "What mechanisms allow drugs to cross the blood-brain barrier?" A summary of the properties of drugs that cross the BBB can be found in Pardrige, 2012, J. Cereb. Blood Flow. Metab. 32:1959-1972.

[0093] Once a drug crosses the BBB, it must partition into an aqueous environment. To ensure that coal tar USP maintains its integrity in this aqueous environment, it can be formulated with the solvent dipropylene glycol, lipids, and optionally alcohol to maintain its hydrophobicity for crossing the BBB and to maintain a low lipid content to avoid uptake by peripheral tissues and loss of drug properties or dosage once in the brain.

[0094] For brain delivery, sustained-release nanoinjectables, including liposomes, polymer nanoparticles, nanocrystals, microspheres, drug-embedded polymers, and antibody-drug conjugates, are preferred. Transmucosal delivery, inhalation, and oral formulations are also preferred. Such noninvasive delivery methods of coal tar USP are preferred over injection because it is difficult to locate the core of a glioblastoma tumor when it extends its tentacles around nerves. Unless the tumor's center is located, injection therapy is ineffective. Several antibiotics with a true benzene ring are used to treat CNS infections and cross the blood-brain barrier, so coal tar USP delivered by inhalation or through nasal mucosal tissue is expected to be effective. These include isoniazid, pyrazinamide, linezolid, fluconazole, and fluoroquinolones. Furthermore, quinoline, one of the major compounds in coal tar USP, crosses the blood-brain barrier by passive diffusion.

[0095] As an alternative to encapsulation with a non-polar coating, drug delivery of coal tar products to glioblastoma through the bloodstream and the blood-brain barrier can be achieved by removing any charged particles from the coal tar, as described in U.S. Pat. No. 5,354,475.

[0096] Coal tar products can also be directly injected into the brain or surgically implanted to treat glioblastoma.This approach has the advantage of reducing the side effects of the interaction between coal tar products and other tissues or organs.One possibility is to use implantable slow-dissolving polymer wafers containing coal tar products.Such slow-dissolving polymer wafers containing carmustine (GLIADEL®) have been approved by the US Food and Drug Administration for treating glioblastoma, and can be adapted by those skilled in the art to deliver coal tar products to glioblastoma.For the discussion of GLIADEL®, see Perry, et al., 2007, Curr.Oncol.14:189-194.

[0097] Nasal administration of drugs for the treatment of neurodegenerative diseases has proven to be a viable method of bypassing the blood-brain barrier, including for large polar molecules, via the olfactory and trigeminal nerves, despite some issues related to irregular drug absorption, variable absorption in different brain regions, and nasal congestion. Current intranasally delivered drugs include antimigraine medications such as IMITREX® (sumatriptan), ZOMIG® (zolmitriptan), MIGRANAL® (dihydroergotamine), and SINOL-M®. Additional examples include peptide drugs such as desmopressin, which are used in hormonal therapy and administered intranasally to avoid drug degradation after oral administration. Syntocinon can be administered intranasally to increase the duration and intensity of contractions during labor. Intranasal calcitonin is administered for various conditions, and intranasal midazolam is used to treat seizure episodes in children. Studies have also shown that intranasal naloxone for opiate overdose can be as effective as injections. Additionally, many recreational drugs are taken intranasally.

[0098] Pulmonary drug delivery is an effective method for both local and systemic treatment. In general, the lungs are permeable to both smaller and larger molecules, as well as lipophilic and water-soluble small molecules. Benzene in coal tar USP enters the bloodstream via the respiratory route. Some compounds also found in coal tar USP, namely pyrene (see U.S. Patent Application Publication No. 2009 / 0238754 and WO 2009 / 117042) and naphthalene (see Freed et al., 2002, Peptides 23:157-65), cross the blood-brain barrier. Seizures are also treated with drugs delivered via the lungs, including STACCATO®, an investigational epilepsy drug from Engage Therapeutics.

[0099] Postoperative delivery of coal tar products to the cavity bed of resected tumors offers another method to reduce tumor regrowth and metastasis and extend lifespan.

[0100] Further Delivery Methods

[0101] A variety of other methods known in the art may be used to deliver coal tar products for use in the treatment methods described herein.

[0102] For example, liposome delivery is a well-established method for delivering drugs, especially drugs used to treat cancer.See, for example, Drummond et al., 1999, Pharmacol.Rev.51:691-743.Liposomes are non-toxic and biodegradable, and can provide better solubility and stability of drugs and slower release than free administration.A recent variant of liposome technology that can be used in the methods described herein is the cell-penetrating peptide amphiphile-integrated liposome system for enhancing the delivery of anticancer drugs to tumor cells, as described in Sardan et al., 2013, Faraday Discuss 166:269-83.

[0103] Another possible method of delivering coal tar products is via a microneedle patch, which is an array of needles hundreds of microns long that can deliver drugs to the skin in a painless and simple manner. See, e.g., Prausnitz, 2017, Ann. Rev. Chem. Biomol. Eng. 8:177-200.

[0104] Transdermal patches are also a possible delivery method, providing for the movement of drugs across the skin for absorption into the systemic circulation, relying either on passive means that do not disrupt the stratum corneum, or active means that do. See, e.g., Pastore et al., 2015, Br. J. Pharmacol. 172:2179-209.

[0105] Excipients known to be compatible with normal brain tissue function as diluents, solvents, penetration enhancers and time-release agents to maximize the benefits of the coal tar product.

[0106] example

[0107] Example 1 Treatment of basal cell carcinoma on human skin

[0108] An ointment consisting of 95% petrolatum and 5% coal tar solution USP (see U.S. Pat. No. 6,337,337 and Example 4 below) was applied twice daily for 13 days to a basal cell carcinoma on the forehead of a human female. The BCC before, during, and after treatment are shown in Figures 3A, 3B, and 3C, respectively.

[0109] Four years later, the same patient underwent treatment for a basal cell carcinoma on the right forehead. Treatment consisted of twice-daily applications for 10 days of a liquid solution containing purified coal tar (Koppers, Inc., Pittsburgh, PA., brand NSR, Stickney Plant, LDO number 2006-0566, sample 06-244) at a concentration of approximately 2% in 65% ethanol and 35% polyethylene glycol (PEG) 400 v / v. Table 110 lists compounds found in Koppers coal tar products sold to the industry for the manufacture of antidandruff shampoos. This treatment was combined with cryotherapy using liquid nitrogen to freeze and remove the basal cell carcinoma. The results of the treatment are shown in Figures 4A (before treatment) and 4B (after treatment). On the day of the last treatment and just prior to removal, the tumor was observed to be desquamating and beginning to peel off.

[0110] The same patient's third treatment, performed 4 years after the second treatment, revealed two basal cell carcinomas on the same subject's forehead, one on the left and one on the right. No forehead treatments were performed during the intervention period. To shrink these basal cell carcinomas, two coal tar USP preparations were used: coal tar USP (Spectrum Chemical; CAS No. 8007-45-2; available on the VWR website under "Coal tar USP") was combined with a mixture of 120-grain vinegar (Fleischmann's, 12% acetic acid) and grapeseed oil (Columbus Foods) as shown in Table 3 and applied twice daily. A second preparation using the same Spectrum coal tar USP was also applied twice daily to both basal cell carcinomas. This second preparation is also included in Table 3. The basal cell carcinoma on the right forehead above the right eye shrank by approximately 50% before cryotherapy. The basal cell carcinoma on the left side also shrank by approximately 50%. Before and after photographs of the left basal cell carcinoma are shown in Figure 5A (before treatment with coal tar USP) and 5B (after treatment with coal tar USP). Figures 6A and 6B show both the left and right basal cell carcinomas on the patient's forehead before treatment and at the completion of topical coal tar treatment, when cryotherapy removed the remaining basal cell carcinoma on the right side.

[0111] Figures 6A and 6B show close-ups of the patient's right forehead basal cell carcinoma before (A) and 4 months (B) of daily topical treatment as described in the paragraph above, and after final cryotherapy.

[0112] Figure 7A shows the right and center forehead of a patient in whom a large basal cell carcinoma appeared 4 years ago (Figure 4) and again 1 year ago (Figure 5). Since the removal of the last basal cell carcinoma, this area has been treated once or twice daily with 0.1% coal tar USP dissolved in alcohol applied via cotton ball, and no new basal cell carcinomas have developed. Figure 7B is an enlarged view of a portion of Figure 7A; the white area is a scar from the previous surgery for removal of the basal cell carcinoma.

[0113] The patient had a purple spot in the center of her forehead for six months that eventually gave rise to a new basal cell carcinoma (see Figure 9A), at which point the composition of Table 12 in Example 4 was applied twice daily for 21 days, at which point the cyst had flattened, dried, and shrunk in diameter (see Figure 9B).

[0114] Example 2 Astrocytoma and Glioblastoma Multiforme Treatment

[0115] Currently, dihydrofolate reductase (DHFR) inhibitors are not used or under clinical trial for the treatment of astrocytoma or glioblastoma. It is therefore surprising that coal tar USP is effective in killing two of these brain cancer cell lines, SF-268 and U-251. However, studies conducted at the National Cancer Institute showed that coal tar products (see Example 4 below) inhibited the in vitro growth of glioblastoma multiforme cells (U251, grade IV astrocytoma) by 100% and the in vitro growth of astrocytoma cells (SF-268 cell line) by 91%. See Figure 2.

[0116] Example 3 formulation [Table 1]

[0117] This formulation is suitable for intravenous infusion and may be used at a dose and schedule of 10 mg / kg to 15 mg / kg every 2 to 3 weeks. Other injection routes, such as intramuscular, subcutaneous, or intraperitoneal, may also be used.

[0118] Another formulation is shown below. In this formulation, water is used in combination with xanthan gum to make a gel. To mask the odor of coal tar USP, a minimal amount of wintergreen oil (e.g., 0.025%) or 1% to 2% of vanilla, floral, or similarly pleasant fragrance oil can be added. This formulation is suitable for topical administration. [Table 2]

[0119] Another formulation contains an aqueous acetic acid solution in the form of white vinegar (120 grains or 12% acetic acid) and grape seed oil to create an oil / water emulsion, which must be shaken before application to the skin. This formulation was used to treat basal cell carcinoma in the patient disclosed in Example 1 above. [Table 3]

[0120] The formulations in Table 3 were prepared as follows: The 1.12% aqueous acetic acid solution and grape seed oil were added to a mixing vessel and stirred on low for 15 minutes. 2. The coal tar was added to the mixing vessel and stirred at medium speed with a small vortex for 45 minutes. 3. The mixture was passed through a homogenizer and filtered to remove particulates.

[0121] Hexane is not used in this formulation due to its suspected central nervous system damage.

[0122] In one embodiment of the formulation in Table 3, the ingredients were sourced as follows: [Table 4]

[0123] Coal tar topical solution can be used in place of coal tar, USP, particularly in methods for treating basal cell carcinoma. The United States Pharmacopoeia, in its USP Monograph for "Coal Tar Topical Solution," provides the following instructions on how a coal tar topical solution may be made: [Table 5]

[0124] Mix the coal tar with 500g of washed sand and add polysorbate 80 and 700ml of alcohol. Allow the mixture to macerate in a sealed container for 7 days with frequent stirring. Filter and rinse the container with enough alcohol to bring the product volume to 1000ml. Store the product in a sealed container. The alcohol content is 81%-86%.

[0125] Yet another formulation suitable for topical use in the treatment of basal cell carcinoma is: [Table 6]

[0126] Ethanol, dipropylene glycol, and polyethylene glycol 600 are combined and mixed for 20 minutes. Coal tar is added to the mixture and blended for 60 minutes. Finally, grape seed oil is added and the formulation is mixed for an additional 60 minutes.

[0127] For a formulation suitable for injection, ethanol SDA 40B, 200 proof, is replaced with a denatured, sterilized, ethanol solution made with USP Water for Injection, 70%.

[0128] Other preparations suitable for treating basal cell carcinoma include: [Table 7] [Table 8] [Table 9]

[0129] Table 10 discloses solvent mixtures that may be used to prepare formulations of coal tar products. [Table 10]

[0130] Example 4 Coal tar-derived compositions

[0131] This example discloses a composition derived from liquid carbonaceous detergents (liquor carbonis detergents) from Koppers, Inc. via fractional distillation and standard GCMS. It contains a mixture of 17 fused tricyclic arenes. The National Cancer Institute and other research institutes have shown that the individual molecules comprising this "cocktail" have minimal or no effect as oncolytic agents. In vitro assays also showed that the composition does not inhibit the function of the pentose phosphate pathway in normal cells.

[0132] The composition is soluble in ethyl alcohol, DMSO, acetic acid, IPA, dichloromethane, and dimethylformamide and is described in U.S. Patent No. 5,337,337 (see column 4, lines 20-36 of the table reproduced immediately below as Table 11 of the present application). [Table 11]

[0133] Those skilled in the art will appreciate that there may be some variation in the concentrations of the individual components that make up the composition, particularly some of the lower concentration components may be omitted.

[0134] Optionally, compounds commonly defined as tar pitch can be removed from the composition before therapeutic use. To remove tar pitch and solid particulates not dissolved by the solvent, depth filtration can be used, for example, as described in the Wikipedia website entry "Depth Filter."

[0135] The dark or brown discoloration of basal cell carcinoma caused by the continuous application of coal tar-based ointments or solutions can be a cosmetic problem for patients. One method for lightening the compound is to dilute it with one of the solvents described herein and then filter the solution through activated charcoal.

[0136] As an alternative to preparing compositions from coal tar, compositions can be prepared by obtaining the individual chemical components listed above and mixing them in the desired proportions. One such possibility is the composition manufactured by SPEX CertiPrep, CRM Division, Metuchen, NJ, whose ingredients are listed in Table 12 below. A final concentration of 1.27% of chemically replicated coal tar in DMSO solution is sufficient for use as a topical agent for BCC and can be diluted as needed for use in the treatment of glioblastoma. Compositions prepared by mixing the individual components generally do not contain pitch. pH adjustment can be controlled by the addition of sodium phosphate. [Table 12]

[0137] 1.27% (w / w) of the above hydrocarbon mixture is mixed with 98.73% (w / w) of DMSO solvent to obtain the final formulation. Different amounts of hydrocarbon mixture and DMSO solvent may be combined.

[0138] Mechanism of action

[0139] The pentose phosphate pathway produces NADPH (nicotinamide adenine dinucleotide phosphate, reduced form) at high rates in all neoplastic cells for the metabolism of tetrahydrofolate and rapid DNA synthesis, mitosis, and to produce enzymes to counteract oxidative stress. This composition inhibits the hydrogen donor function of NADPH during the conversion of dihydrofolate to tetrahydrofolate, either through electronic interference with NADPH, noncompetitive binding, or an allosteric effect. This stops neoplastic cell mitosis and prevents progressive drug resistance by reducing the cells' ability to recycle glutathione and thioredoxin, which scavenge excess reactive oxygen species (ROS). The role of NADPH as an essential source of reducing power to neutralize high ROS levels in cancer cells can be found in Cairns & Harris, 2011, Cold Spring Harbor Symposia on Quantitative Biology 76:299-311.

[0140] Research Test

[0141] The composition from Koppers, Inc. was tested at the National Cancer Institute in a single dose of 100 μg / ml of cancer cell lines on a panel of 60 cells and was shown to be cytotoxic at a level of 100% against glioblastoma multiforme cells (U251) and 91% against astrocytoma cells (SF-268). See Figure 2.

[0142] This composition reduces the adhesion of certain neoplasms to type IV collagen. Type IV collagen is responsible for the high density of cancer tumors. As an adjuvant therapy, inhibiting cancer cell adhesion to type IV collagen promotes drug penetration into tumors by reducing tumor density and the "outward" systolic pressure that tumors exert to flush out chemotherapy drugs. In certain embodiments, coal tar products can be combined with other chemotherapy drugs or injected alone before the use of other drugs to increase tumor porosity and reduce the ability of tumors to flush out drugs through systolic pressure. [Table 13]

[0143] Glioblastoma is a highly vascularized tumor with cells tightly packed with high levels of type IV and type VI collagen. It has been shown that type IV and type VI collagen promote upregulation of vascular endothelial growth factor, an angiogenesis stimulator, in human glioblastoma cell lines U251, U87MG, and LN229. (Mammoto et al., "Role of collagen matrix in tumor angiogenesis and glioblastoma multiforme progression," Am J Pathol. 2013 Oct;183(4):1293-1305). Because type IV collagen plays a supportive role in tumor angiogenesis and glioblastoma progression, coal tar products are expected to exhibit antiangiogenic effects and slow progression by inhibiting type IV collagen binding to malignant cells within glioblastoma tumors.

[0144] Liposomes, microspheres, and drug-embedding polymers are viable drug carriers for the composition.

[0145] Solutions of 2% or less of coal tar USP (the source of the composition and the purified source) are considered safe by the FDA for transdermal delivery. See the Creosote Toxicology Profile found on the website of the Agency for Toxic Substances and Disease Registry.

[0146] Example 5 Treatment using a low-concentration composition derived from coal tar

[0147] A patient was treated with several early-stage basal cell carcinomas on the left forehead with topical application of a 0.3% composition of Example 4 in DiPG / alcohol solution twice daily for 12 days, which resulted in the shrinkage of the early-stage basal cell carcinomas, as shown in Figure 8A (before treatment) and Figure 8B (after treatment). The present invention includes the following aspects. (1) 1. A method for treating basal cell carcinoma, comprising administering to a patient in need thereof a therapeutically effective amount of a coal tar product. (2) The method according to (1), wherein the coal tar product is present in a pharmaceutical composition. (3) The method according to (2), wherein the pharmaceutical composition is applied topically to the basal cell carcinoma. (4) 3. The method of claim 3, wherein the topical application to the basal cell carcinoma is by a unit dose dispensing device, a needle, a microneedle, a needle-free injection device, a pre-filled applicator, an injection pad, a saturated wipe, an adhesive bandage or tab, a cream, a gel, an ointment, or a petrolatum-based ointment. (5) The method according to (3), wherein the coal tar product is coal tar USP. (6) The coal tar product Hydrocarbons wt% Phenanthrene 29.3 Fluoranthene 12.6 Anthracene 10.3 Biphenyl 9.5 Pyrene 9.1 Fluorene 7.7 Naphthalene 5.7 Carbazole 4.7 Dibenzofuran 4.5 2-Methylnaphthalene 1.8 Chrysene 1.2 Benz(a)anthracene 1.1 1-methylnaphthalene 0.9 Acenaphthene 0.6 Indene 0.6 Quinoline 0.4 Total 100% The method according to (3), (7) The method according to (3), wherein the coal tar product is coal tar ointment USP. (8) The method of (3), wherein the coal tar product is Coal Tar Topical Solution, USP. (9) The pharmaceutical composition comprises: Castor oil 20-30% Denatured alcohol 20-30% Coal Tar USP 0.05-2% Xanthan gum 1-3% Wintergreen oil 0.025% Deionized water 40-55% The method according to (3), (10) The pharmaceutical composition comprises: Castor oil 25% Denatured alcohol 25% Coal Tar USP 2% Xanthan gum 1.6% Wintergreen oil 0.025% Deionized water 46.375% The method according to (3), (11) The pharmaceutical composition comprises: 12% acetic acid aqueous solution 20-35% Grape seed oil 65-80% Coal Tar USP 0.5-2.5% The method according to (3), (12) The pharmaceutical composition comprises: 12% acetic acid aqueous solution 27.7% Grape seed oil 70.6% Coal Tar USP 1.7% The method according to (3), (13) The pharmaceutical composition comprises: Coal tar 50-250g Polysorbate 80 40-60g Alcohol, enough to make 1000ml The method according to (3), (14) The pharmaceutical composition comprises: 200g coal tar Polysorbate 80 50g Alcohol, enough to make 1000ml The method according to (3), (15) The pharmaceutical composition comprises: Hydrocarbons wt% Phenanthrene 29.3 Fluoranthene 12.6 Anthracene 10.3 Biphenyl 9.5 Pyrene 9.1 Fluorene 7.7 Naphthalene 5.7 Carbazole 4.7 Dibenzofuran 4.5 2-Methylnaphthalene 1.8 Chrysene 1.2 Benz(a)anthracene 1.1 1-methylnaphthalene 0.9 Acenaphthene 0.6 Indene 0.6 Quinoline 0.4 Total 100% The method according to (3), comprising a 1.27% w / w DMSO solution of a hydrocarbon mixture defined as: (16) 3. The method of claim 2, further comprising administering to the patient at least one additional treatment for basal cell carcinoma selected from the group consisting of surgical excision, cryosurgery, curettage and electrocoagulation, electrosurgery, topical chemotherapy, radiation, electronic skin surface brachytherapy, laser therapy, and Mohs surgery, or a combination thereof. (17) The method of (16), wherein the further treatment for basal cell carcinoma is Mohs surgery. (18) The method of (16), wherein the further treatment for basal cell carcinoma is topical chemotherapy with 5-fluorouracil or imiquimod. (19) 1. A method for preventing basal cell carcinoma, comprising administering a therapeutically effective amount of a coal tar product to a patient previously treated for basal cell carcinoma. (20) 19. The method of claim 18, wherein the coal tar product is administered to an area of ​​the patient's skin where basal cell carcinoma previously appeared and was treated, and the method prevents recurrence of the previously treated basal cell carcinoma.

Claims

1. A composition for treating glioblastoma (GBM), comprising a therapeutically effective amount of a coal tar product.

2. The composition of claim 1 , wherein the coal tar product is present in a pharmaceutical composition.

3. 3. The composition of claim 2, wherein the pharmaceutical composition is adapted to be administered locally or by injection using a unit dose dispensing device, a needle, a microneedle, a needle-free injection device, a pre-filled applicator to a GBM tumor or to the lining of the surgical cavity of a tumor after surgical resection.

4. 3. The composition of claim 2, wherein the coal tar product is delivered intravenously, orally, intranasally, or internally using liposomes, microneedle patches, transdermal patches, microspheres, drug-embedded polymers, polymer nanoparticles, nanocrystals, or polylactic acid scaffolds.

5. 3. The composition of claim 2, wherein the coal tar product is used before, after, or concurrently with a pharmaceutical alkylating agent and / or angiogenesis inhibitor treatment.

6. the pharmaceutical alkylating agent is temozolomide, carmustine, lomustine and / or cisplatin; and / or The composition of claim 5 , wherein the angiogenesis inhibitor is bevacizumab.

7. 3. The composition of claim 2, wherein the coal tar product is used before, after, or concurrently with radiation therapy.

8. 3. The composition of claim 2, wherein the coal tar product is used in combination with robotic stereotactic radiosurgery, immunomodulators, biologics including antibody drug conjugates, radiosensitizers, boron neutron capture therapy, or gene therapy.

9. 9. The composition of claim 8, wherein the radiosensitizer is temozolid.

10. Treatment of GBM inhibits the ability of neoplastic cells to recycle glutathione and thioredoxin, which scavenge excess reactive oxygen species (ROS), thereby preventing the reduction of NADPH. The composition of claim 2, comprising administering the coal tar product to glioblastoma and / or cells.

11. 3. The composition of claim 2, wherein the composition is a coal tar topical solution United States Pharmacopeia (USP) and the coal tar product is USP grade coal tar.

12. 3. The composition of claim 2, wherein the coal tar product is used in combination with a diluent or solvent.

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