Prodrugs for the Treatment of Cancer

Abstract

The embodiments include, among others, prodrug compounds that can be used to treat diseases such as cancer. The prodrug compounds may include an active agent component such as a cyclic monoterpene. The compounds may also include a prodrug component such as cholecalciferol or retinoic acid. Advantages of prodrug compounds include increased solubility, increased half-life, increased stability, increased lipophilicity, improved targeting (e.g., to tumor cells) and / or increased permeability / permeability across the blood-brain barrier.

Description

[Technical field]

[0001] This application claims priority to U.S. Provisional Patent Application No. 63 / 329,272, filed April 8, 2022. The contents of the aforementioned application are incorporated herein by reference. FIELD OF THEINVENTION

[0002] The present invention relates generally to small molecule therapeutics, and more specifically to prodrug compounds with high bioavailability and anti-neoplastic activity. [Background technology]

[0003] Cancer can be defined as a group of diseases involving abnormal cell growth that invades or spreads to other parts of the body. Despite technological advances, cancer continues to be a major cause of death and immense suffering. Cancer is associated with several factors including smoking, obesity, poor diet, lack of physical activity and excessive consumption of alcohol. Other factors include exposure to certain infections, ionizing radiation and environmental pollutants. Certain cancers are associated with infections such as Helicobacter pylori, Hepatitis B, Hepatitis C, Human Papillomavirus infection, Epstein-Barr Virus and Human Immunodeficiency Virus (HIV). Cancer is the second leading cause of death in the United States.

[0004] Cancer patients often have limited treatment options. Traditional cancer treatments are directed at removing cancerous tissue and preventing its spread. Despite advances in research, these treatments have remained relatively unchanged in recent decades. Treatments may include a combination of surgery, radiation therapy, chemotherapy and targeted therapy, hormonal therapy, and palliative care. Treatments are usually pursued based on the type, location, and grade of cancer, as well as the patient's health and preferences. However, these options are limited. They may be ineffective, especially if the cancer has metastasized.

[0005] Cancer cells divide more rapidly than most normal cells, so they may be more sensitive to chemotherapy. However, chemotherapy also attacks other cells in the body, particularly rapidly dividing cells such as blood cells and cells lining the mouth, stomach and intestines. Radiation therapy and chemotherapy usually cause multiple side effects, especially epithelial cell damage. Therefore, there is a need for improved drugs and methods for the treatment of cancer that are more targeted and have fewer harmful side effects.

[0006] Recent efforts have been directed towards small molecule drugs. Perillyl alcohol (PA) is a monoterpene that has been used orally for the treatment of systemic cancer. Perillyl alcohol is a metabolite of limonene, which is itself formed from geranyl pyrophosphate in the mevalonate pathway. Conversion of limonene to perillyl alcohol is achieved via hydroxylation by enzymes belonging to the cytochrome P450 protein superfamily. Perillyl alcohol can be further metabolized to perillaldehyde (perillyl aldehyde) and perillic acid.

[0007] Published in vitro studies have demonstrated that perillyl alcohol (PA) and limonene can both induce apoptosis in cancer cells. Furthermore, under certain conditions, these compounds can restore cancer cell identity without adversely affecting healthy cells in cell culture populations. However, PA and limonene are not used in clinical settings and patient care due to their poor bioavailability and ADME (absorption, distribution, metabolism and excretion) issues. When taken orally, the compounds have negative effects on mucosal tissues and generally have short half-lives. Common side effects include nausea, diarrhea and abdominal pain.

[0008] Due to the shortcomings of the use of PA as described above, there is a need for improved formulations and methods of administering compounds. Such formulations and methods must improve their bioavailability and ADME. The embodiments of the present invention meet these needs and provide related additional advantages as outlined below. Summary of the Invention

[0009] Aspects of the present disclosure teach particular benefits in construction and use that result in exemplary advantages described below.

[0010] The present disclosure solves the above problems by providing prodrugs of perillyl alcohol (PA), limonene, perillic acid, perillyl alcohol acetate, perillic acid methyl ester, perillyl alcohol isobutyrate, perillic acid ethyl ester, perillyl alcohol pivaloate, perillic acid isopropyl ester, perillyl perilliate, perillyl carbonate, and / or other monocyclic terpenes. In some embodiments, the prodrugs can be used to treat diseases such as cancer. In some embodiments, the prodrugs can cross the blood-brain barrier. In some embodiments, the prodrug has one or more of increased solubility, increased half-life, increased stability, increased lipophilicity, improved targeting (e.g., to tumor cells), metabolic inactivation / metabolic elimination, improved patient compliance, and increased permeability / permeability across the blood-brain barrier.

[0011] Prodrugs can increase the bioavailability and improve the ADME (absorption, distribution, metabolism and excretion) of drugs / agents such as monocyclic terpenes.

[0012] The present disclosure also relates to methods for the chemical synthesis of prodrugs. In some embodiments, the prodrugs include cholecalciferol / vitamin D, retinoic acid, N-methyl perillic acid, tyrosine, and / or valproic acid.

[0013] In some embodiments, the prodrug protects the mucosa from the effects of the drug / agent. In some embodiments, the prodrug allows targeted delivery to tumor cells and the drug / agent induces apoptosis of the tumor cells. In some embodiments, the prodrug is capable of crossing the blood-brain barrier.

[0014] Thus, some embodiments include small molecule therapeutics that include an active agent (e.g., a monocyclic terpene) and a prodrug moiety. Therapeutic amounts of the compositions can be administered to treat diseases such as cancer.

[0015] Some embodiments include a therapeutic agent comprising perillic acid and cholecalciferol.Therapeutic amounts of the composition can be administered to treat diseases such as cancer.

[0016] Some embodiments include a therapeutic agent comprising limonene and cholecalciferol. A therapeutic amount of the therapeutic agent can be administered to treat a disease, such as cancer.

[0017] Some embodiments include a therapeutic agent comprising limonene, PA, perillic acid and cholecalciferol. Therapeutic amounts of the composition can be administered to treat a disease, such as cancer.

[0018] Some embodiments include a therapeutic agent comprising PA, limonene and cholecalciferol. Therapeutic amounts of the composition can be administered to treat a disease, such as cancer.

[0019] Some embodiments include a treatment that includes PA, retinoic acid, and cholecalciferol.Therapeutic amounts of the composition can be administered to treat a disease, such as cancer.

[0020] Some embodiments include a therapeutic agent comprising PA and retinoic acid.Therapeutic amounts of the composition can be administered to treat a disease, such as cancer.

[0021] Some embodiments include a therapeutic agent comprising perillic acid and retinoic acid.Therapeutic amounts of the composition can be administered to treat diseases such as cancer.

[0022] Some embodiments include a therapeutic agent comprising limonene and retinoic acid. A therapeutic amount of the composition can be administered to treat a disease, such as cancer.

[0023] Some embodiments include a therapeutic agent comprising limonene, PA, perillic acid and retinoic acid. Therapeutic amounts of the composition can be administered to treat diseases such as cancer.

[0024] Some embodiments include a therapeutic agent comprising PA, limonene and retinoic acid. Therapeutic amounts of the composition can be administered to treat a disease, such as cancer.

[0025] Some embodiments include a therapeutic agent comprising one or more of perillyl alcohol, perillic acid, perillyl alcohol acetate, perillic acid methyl ester, perillyl alcohol isobutyrate, perillic acid ethyl ester, perillyl alcohol pivaloate, perillic acid isopropyl ester, perillyl perillate, and perillyl carbonate. The compound can enter the target cell via passive transport.

[0026] Some embodiments include a prodrug that uses active transport to enter a target cell. The prodrug may include N-methyl perillic acid, tyrosine, valproic acid, retinoic acid, or vitamin D.

[0027] In some embodiments, the compounds described herein are administered to treat one or more of leukemia, lung cancer, breast cancer, colon cancer, colorectal cancer, prostate cancer, and renal cell carcinoma.

[0028] Some embodiments also include a method of treating cancer, such as glioblastoma, with chemotherapy, in which cells are treated with an effective amount of a monoterpene derivative and then exposed to chemotherapy. The monoterpene derivative treatment can be before, during, and / or after chemotherapy.

[0029] In some embodiments, the compounds described herein are administered to treat conditions such as infections, gallstones, cholecystitis, gastroesophageal reflux disease (GERD), and cholangitis.

[0030] In some embodiments, the compounds described herein are administered to restore the cellular identity of glioblastoma and / or astrocytoma cells.

[0031] In some embodiments, the compounds described herein are administered to increase apoptosis in glioblastomas and / or astrocytomas.

[0032] In some embodiments, the compounds described herein are administered to maintain healthy neuronal and astroglial homeostasis.

[0033] In some embodiments, the compounds described herein are administered to treat Parkinson's disease by removing amyloid plaques in brain tissue.

[0034] Some embodiments also include methods of treating diseases. The methods may include combining a drug / agent (e.g., limonene, PA, and / or perillic acid) with another molecule (e.g., cholecalciferol or retinoic acid) to generate a prodrug with higher bioavailability and / or improved ADME (absorption, distribution, metabolism, and excretion). Therapeutic amounts of the therapeutic agent may be administered to treat diseases such as cancer.

[0035] Other features and advantages of aspects of the present invention will become apparent from the following more detailed description, taken in conjunction with the accompanying drawings, which illustrate, by way of example, the principles of the invention. [Brief description of the drawings]

[0036] The accompanying drawings illustrate embodiments of the present invention.

[0037] [Figure 1A] The chemical structures of isomers of perillyl alcohol (PA) are shown.

[0038] [Figure 1B] 1 shows the stepwise oxidation of limonene to perillic acid.

[0039] [Diagram 2] 1 shows the chemical structures of cholecalciferol and retinoic acid.

[0040] [Diagram 3] Illustrates the stepwise biosynthesis of cholecalciferol (vitamin D3).

[0041] [Figure 4] 1 shows chemical structures of active transport prodrugs according to some embodiments.

[0042] [Diagram 5] 1 shows chemical structures of passive transport prodrugs according to some embodiments.

[0043] Reference herein to "one embodiment" or "an embodiment" means that a particular feature, structure, or characteristic described in connection with that embodiment is included in at least one embodiment of the disclosure. The phrases "in one embodiment" or "in an embodiment" in various places in this specification do not necessarily all refer to the same embodiment or embodiment, or to mutually exclusive, separate, or alternative embodiments of other embodiments. Furthermore, various features are described that may be exhibited by some embodiments but not by others. Similarly, various requirements are described that may be requirements for some embodiments but not for others. The terms embodiment and aspect may be used interchangeably in certain instances.

[0044] The terms used herein generally have their usual meaning in the art, in the context of this disclosure, and in the specific context in which each term is used.Specific terms used in the description of this disclosure are discussed below or elsewhere in this specification, providing additional guidance to practitioners regarding the description of this disclosure.It will be understood that the same thing can be stated in more than one way.

[0045] Thus, alternative terms and synonyms may be used for any one or more of the terms discussed herein. There is no special significance to whether a term is detailed or discussed herein. Synonyms for certain terms are provided. The description of one or more synonyms does not exclude the use of other synonyms. The use of examples anywhere in this specification, including examples of any term discussed herein, is for illustrative purposes only and is not intended to further limit the scope and meaning of the disclosure or any exemplified term. Similarly, the disclosure is not limited to the various embodiments presented herein.

[0046] Without intending to further limit the scope of the present disclosure, the following describes the instruments, devices, methods and their related results according to the embodiments of the present disclosure. Please note that headings or subheadings may be used in the examples for the convenience of the reader, but do not limit the scope of the present disclosure. Unless otherwise specified, all technical and scientific terms used herein generally have the same meaning as those understood by those skilled in the art to which this disclosure belongs. In case of conflict, the present document, including definitions, shall prevail.

[0047] The term "tumor" refers to a disease caused or resulting from inappropriately high levels of cell division, inappropriately low levels of apoptosis, or both. For example, cancer is an example of a tumor. Examples of cancer include, but are not limited to, leukemia (e.g., acute leukemia, acute lymphocytic leukemia, acute myeloid leukemia, acute myeloblastic leukemia, acute promyelocytic leukemia, acute myelomonocytic leukemia, acute monocytic leukemia, acute erythroleukemia, chronic leukemia, chronic myelogenous leukemia, chronic lymphocytic leukemia), polycythemia vera, lymphoma (e.g., Hodgkin's disease and non-Hodgkin's disease), Waldenstrom's macroglobulinemia, heavy chain disease, and solid tumors such as sarcomas and carcinomas (e.g., fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, chordoma, angiosarcoma, endothelial sarcoma, lymphangiosarcoma, lymphoma ... These include intraductal sarcoma, synovium, mesothelioma, Ewing's tumor, leiomyosarcoma, rhabdomyosarcoma, colon cancer, pancreatic cancer, breast cancer, ovarian cancer, prostate cancer, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, sweat gland carcinoma, sebaceous gland carcinoma, papillary carcinoma, papillary adenocarcinoma, cystadenocarcinoma, medullary carcinoma, bronchogenic carcinoma, renal cell carcinoma, hepatoma, cholangiocarcinoma, choriocarcinoma, seminoma, embryonal carcinoma, Wilms' tumor, cervical cancer, uterine cancer, testicular cancer, lung cancer, small cell lung carcinoma, bladder carcinoma, epithelial carcinoma, glioma, astrocytoma, medulloblastoma, craniopharyngioma, ependymoma, pinealoma, hemangioblastoma, acoustic neuroma, oligodendroglioma, schwannoma, meningioma, melanoma, neuroblastoma, and retinoblastoma. Lymphoproliferative disorders are also considered to be proliferative disorders.

[0048] The term "glioma" refers to a type of tumor that arises beginning in the glial cells of the brain or spinal cord. Gliomas comprise approximately 30% of all brain and central nervous system tumors and 80% of all malignant brain tumors.

[0049] The term "glioblastoma" refers to an aggressive type of cancer that can occur in the brain or spinal cord. Glioblastomas form from cells called astrocytes, which support nerve cells. Glioblastomas can occur at any age, but tend to occur more often in older people. Initially, signs and symptoms of glioblastoma are nonspecific. They may include headaches, personality changes, nausea, and symptoms similar to those of a stroke. Symptoms often worsen rapidly and may progress to loss of consciousness. The cause of most cases of glioblastoma is unknown. Uncommon risk factors include genetic disorders such as neurofibromatosis and Li-Fraumeni syndrome, as well as previous radiation therapy. Glioblastomas represent 15% of all brain tumors. They can begin in normal brain cells or develop from pre-existing low-grade astrocytomas. Diagnosis is typically made by a combination of CT scans, MRI scans, and tissue biopsies. Treatment usually involves surgery, followed by chemotherapy and radiation therapy. The drug temozolomide is often used as part of chemotherapy. High-dose steroids may also be used to help reduce swelling and decrease symptoms. Surgical removal of the tumor is associated with increased survival, but only for a few months.

[0050] The term "astrocytoma" refers to a type of brain tumor. They begin in a specific type of glial cell in the brain, a star-shaped brain cell called an astrocyte. This type of tumor does not usually spread outside the brain and spinal cord, and does not usually affect other organs. Astrocytomas are the most common gliomas and can occur in most parts of the brain, and occasionally the spinal cord. Within astrocytomas, two broad classes are generally recognized, which share various characteristics, including (a) narrow areas of infiltration that are often clearly delineated on diagnostic images (predominantly non-invasive tumors; e.g., pilocytic astrocytoma, subependymal giant cell astrocytoma, pleomorphic xanthoastrocytoma), but (b) diffuse areas of infiltration that share various characteristics, including being able to arise anywhere in the central nervous system, but are more prevalent in the brain hemispheres (e.g., high-grade astrocytoma, anaplastic astrocytoma, glioblastoma); they usually arise in adults and have an inherent tendency to progress to a more aggressive form. People can develop astrocytomas at any age. Low-grade types are more often found in children or young adults, while high-grade types are more common in adults. Basilar astrocytomas are more common in young people and account for about 75% of neuroepithelial tumors.

[0051] The term "cell identity" can be defined by the expression or activity of certain genes in its DNA and the resulting production of certain proteins. The increase in biological complexity is made possible by the ability of cells to differentiate and achieve a distinct "identity" in systems that reflect morphological or functional differences from precursor cells. This identity is defined primarily in terms of cell type and cell state. The precise definition of these terms remains elusive: cell types have historically been described by observing reproducible functional differences in vivo or in vitro (often together with the expression of a set of marker genes), whereas cell state refers to dynamic responsive changes that modify the phenotype and function of the cell, but not significant changes that result in the acquisition of a new cell type.

[0052] The term "blood-brain barrier" or "BBB" refers to a highly selective semi-permeable boundary of endothelial cells that prevents solutes in circulating blood from crossing nonselectively into the extracellular fluid of the central nervous system where neurons reside. The blood-brain barrier is formed by endothelial cells of the capillary walls, the foot processes of astrocytes that encase the capillaries, and pericytes embedded in the capillary basement membrane. This system allows the passage of some small molecules by passive diffusion, as well as the selective active transport of various nutrients, ions, organic anions, and macromolecules such as glucose and amino acids that are crucial for neuronal function.

[0053] The term "perillic alcohol", "PA" or "POH" refers to a naturally occurring monoterpene. It is also identified as [4-(prop-1-en-2-yl)cyclohex-1-en-1-yl]methanol) (i.e., IUPA name). PA and its precursor limonene are monocyclic terpenes of natural origin that can be derived from the mevalonate pathway in plants. PA has also shown some antitumor activity in laboratory and animal studies. Human clinical trials were inconclusive due to adverse side effects. PA can be found in the essential oils of various plants such as lavender, lemongrass, sage, and peppermint. It has many manufacturing, household, and medical applications.

[0054] The term "perillic acid" refers to the metabolite / conjugate acid of perillic alcohol. Perillic acid is an alpha, beta unsaturated monocarboxylic acid and a cyclohexene carboxylic acid. It has a role as an antitumor drug, human metabolite and mouse metabolite.

[0055] The term "limonene" refers to a colorless liquid aliphatic hydrocarbon classified as a cyclic monoterpene. It is the major component in citrus peel oil. It is also identified as 1-methyl-4-(prop-1-en-2-yl)cyclohex-1-ene (i.e., IUPA name).

[0056] The term "cholecalciferol" or "vitamin D3" refers to an analog of vitamin D. It is naturally synthesized in the skin, where it functions as a prohormone and is converted to calcitriol. In the liver, it is converted to calcifediol (25-hydroxyvitamin D), which is then converted to calcitriol (1,25-dihydroxyvitamin D) in the kidneys. One of its actions is to increase calcium uptake by the intestine.

[0057] The term "prodrug" refers to a derivative of a known direct acting drug, which has enhanced delivery properties and therapeutic value compared to the drug, and which is converted to the active drug by enzymatic or chemical processes.

[0058] The term "terpene" refers to a compound of the formula (C5H8) n Terpenes refers to a class of compounds having the formula: 1. Terpenes include over 30,000 compounds and are primarily produced by plants, especially conifers. Terpenes can be further classified by the number of carbon atoms (e.g., monoterpenes (C 10 ), sesquiterpenes (C 15 ), diterpenes (C 20 ), etc. Terpenes comprise a diverse group of naturally occurring compounds. They are mostly found in plants and form the major constituents of plant-derived essential oils. Terpenes have a wide range of medical uses, among which antiplasmodial activity is notable as its mechanism of action is similar to commonly used antimalarial drugs (i.e., chloroquine). Monoterpenes have been particularly widely studied for their antiviral properties. With the modern era seeing an increase in the incidence of cancer and diabetes, terpenes also have the potential to serve as anticancer and antidiabetic agents.

[0059] The term "monoterpene" refers to compounds that contain two isoprene units and have the molecular formula C, such as perillyl alcohol. 10 H 16Monoterpenes refer to a class of terpenes having the formula: Monoterpenes may be linear (i.e., acyclic) or may contain rings (i.e., cyclic). Monoterpenes can be modified by oxidation or rearrangement to produce monoterpenoids. Examples of monoterpenes and monoterpenoids include geranyl pyrophosphate, ocimene, myrcene, geraniol, citral, citronellal, linalool, limonene, terpinene, phellandrene, and terpinolene.

[0060] The term "retinoic acid" (used herein for brevity as all-trans retinoic acid) is a metabolite of vitamin A1 (all-trans retinol) that mediates the functions of vitamin A1 required for growth and development. All-trans retinoic acid is required in chordates, which includes all higher animals from fish to humans. All-trans retinoic acid (ATRA) is the predominant retinoic acid present, while isomers such as 13-cis- and 9-cis-retinoic acid are also present at much lower levels in mammals.

[0061] The term "mevalonate pathway" refers to a metabolic pathway that plays an important role in multiple cellular processes by synthesizing sterol isoprenoids, such as cholesterol, and non-sterol isoprenoids, such as dolichol, heme-A, isopentenyl tRNA, and ubiquinone.

[0062] The term "linker" refers to a functional group that covalently bonds two or more moieties in a compound or substance. For example, a linker can serve to covalently bond a prodrug moiety to an active agent.

[0063] The term "alkyl" refers to a straight or branched chain saturated aliphatic radical having the indicated number of carbon atoms. Alkyl can be any number of carbons, e.g., C 1-2 , C 1-3 , C 1-4 , C 1-5 , C 1-6 , C 1-7 , C 1-8 , C 1-9 , C 1-10 , C2-3 , C 2-4 , C 2-5 , C 2-6 , C 3-4 , C 3-5 , C 3-6 , C 4-5 , C 4-6 and C 5-6 For example, C 1-6 Alkyl includes, but is not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, t-butyl, pentyl, isopentyl, hexyl. Alkyl also refers to alkyl groups having up to 30 carbon atoms, such as, but not limited to, heptyl, octyl, nonyl, decyl, etc. Alkyl groups can be substituted or unsubstituted. "Substituted alkyl" groups can be substituted with one or more groups selected from halo, hydroxy, amino, oxo (=O), alkylamino, amido, acyl, nitro, cyano, and alkoxy. The term "alkylene" refers to a divalent alkyl radical.

[0064] The term "heteroalkyl" refers to an alkyl group, as described herein, in which one or more carbon atoms are optionally and independently replaced with a heteroatom selected from N, O, and S. The term "heteroalkylene" refers to a divalent heteroalkyl radical.

[0065] The term "amino" refers to the moiety -NR3, where each R group is hydrogen or alkyl. The amino moiety can be ionized to form the ammonium cation.

[0066] The term "hydroxy" refers to the moiety --OH.

[0067] The term "carboxy" refers to the moiety -C(O)OH. The carboxy moiety can be ionized to form the corresponding carboxylate anion.

[0068] The term "amide" refers to the moiety -NRC(O)R or -C(O)NR2, where each R group is hydrogen or alkyl.

[0069] The term "nitro" refers to the moiety --NO.

[0070] The term "oxo" refers to an oxygen atom that is double bonded to a compound (ie, O=).

[0071] As used herein, the term "formulation" refers to a combination of a prodrug composition disclosed herein and an excipient that can be administered for therapeutic use. Formulations can include other agents as needed, such as, for example, water, emulsions, buffers, and preservatives.

[0072] The term "passive transport" refers to a type of membrane transport that does not require energy to move substances across the cell membrane. The four main types of passive transport are simple diffusion, facilitated diffusion, filtration, and / or osmosis. Passive transport follows Fick's first and second laws of thermodynamics.

[0073] The term "active transport" refers to the movement of molecules across a cell membrane from an area of ​​low concentration to an area of ​​high concentration (i.e., movement against a concentration gradient). Unlike passive transport, which uses the kinetic energy and natural entropy of the molecule moving along the gradient, active transport uses cellular energy to move molecules against a gradient, polar repulsion, or other resistance. Active transport is usually associated with the accumulation of high concentrations of molecules needed by cells, such as ions, glucose, and amino acids. Specialized transmembrane proteins recognize and move substances across the membrane that would not otherwise occur because the phospholipid bilayer of the membrane is impermeable to the substance being moved, or because the substance moves against the direction of its concentration gradient. There are two types of active transport: primary active transport and secondary active transport. In primary active transport, the proteins involved are pumps that use chemical energy, usually in the form of ATP. Secondary active transport uses potential energy, usually obtained by exploiting an electrochemical gradient.

[0074] The term "administration" refers to the introduction of a predetermined amount of a substance into a patient by a specific suitable method. The compositions disclosed herein can be administered via any of the common routes, such as, but not limited to, intraperitoneal, intravenous, intramuscular, subcutaneous, intradermal, oral, topical, intranasal, pulmonary, or rectal administration, as long as they can reach the target tissue. However, since peptides are digested when administered orally, the active ingredients of compositions for oral administration should be coated or formulated to protect against degradation in the stomach.

[0075] Where applicable, the term "about" or "generally" as used herein and in the appended claims means a tolerance of ±20% unless otherwise indicated. Where applicable, the term "substantially" as used herein and in the appended claims means a tolerance of ±10% unless otherwise indicated. It should be understood that not all uses of the above terms are necessarily quantifiable such that a reference range can be applied.

[0076] The terms "medicament", "active agent" or "active ingredient" refer to a substance, compound, or molecule that is biologically active or that induces a biological or physiological effect in a subject to which it is administered. In other words, an "active agent" or "active ingredient" refers to the component or components of a composition to which all or part of the effect of the composition is due. The active agent may be the primary active agent, or in other words the component of the composition to which all or part of the effect of the composition is due. The active agent may be a secondary agent, or in other words the component of the composition to which additional parts of the composition and / or other effects are due.

[0077] The term "bioavailability" refers to the proportion of the administered dose of unchanged drug that reaches the systemic circulation. For example, when a drug is administered intravenously, its bioavailability is 100%. However, when a drug is administered via other routes (e.g., orally), its bioavailability is usually reduced due to incomplete absorption and the first-pass effect. Bioavailability is one of the essential tools in pharmacokinetics, since it must be taken into account when calculating dosage for non-intravenous administration routes. In one embodiment, the bioavailability of an agent is increased by converting it into a prodrug.

[0078] The term "pharmaceutical composition" is intended to include the combination of an active agent (i.e., a prodrug therapeutic agent) with an inert or active carrier in a sterile composition suitable for in vitro, in vivo or ex vivo diagnostic or therapeutic use. In one aspect, the pharmaceutical composition is substantially free of endotoxin or is non-toxic to a recipient at the dosage or concentration employed.

[0079] The term "pharmaceutically acceptable salt" refers to an acid or base salt generally regarded in the art as suitable for use in contact with the tissues of humans or animals without undue toxicity, irritation, allergic response, or other problems or complications. Such salts include inorganic or organic acid salts of basic residues such as amines, as well as alkali or organic salts of acidic residues such as carboxylic acids. Specific pharmaceutical salts include, but are not limited to, alkanoic acids such as hydrochloric acid, phosphoric acid, hydrobromic acid, malic acid, glycolic acid, fumaric acid, sulfuric acid, sulfamic acid, sulfanilic acid, formic acid, toluenesulfonic acid, methanesulfonic acid, benzenesulfonic acid, ethanedisulfonic acid, 2-hydroxyethylsulfonic acid, nitric acid, benzoic acid, 2-acetoxybenzoic acid, citric acid, tartaric acid, lactic acid, stearic acid, salicylic acid, glutamic acid, ascorbic acid, pamoic acid, succinic acid, fumaric acid, maleic acid, propionic acid, hydroxymaleic acid, hydroiodic acid, phenylacetic acid, acetic acid, HOOC-(CH2) n-COOH (n=0-4) and the like. Similarly, pharma-ceutically acceptable cations include, but are not limited to, sodium, potassium, calcium, aluminum, and ammonium. In general, pharma-ceutically acceptable acid or base salts can be synthesized from a parent compound that contains a basic or acidic moiety by any conventional chemical method. For example, such salts can be prepared by reacting the free acid or base form of these compounds with a stoichiometric amount of the appropriate base or acid in a suitable solvent.

[0080] The term "effective amount" refers to the amount of a desired chemical composition or a specified component sufficient to achieve a desired biological and / or therapeutic result. The desired result may be the alleviation or amelioration of the signs, symptoms or causes of a disease, or any other desired change in a biological system. If the desired result is a therapeutic response, the effective amount will vary depending on, but is not limited to, the specific disease or condition being treated or alleviated, the age, sex and weight of the subject being treated, the dosage schedule of the formulation, the severity of the condition, the method of administration, etc. These factors can be easily determined by those skilled in the art.

[0081] In one embodiment, the "subject" of diagnosis or treatment is a prokaryotic or eukaryotic cell, tissue culture, tissue or animal, e.g., a mammal, including a human. Non-human animals subject to diagnosis or treatment include, for example, monkeys, mice, dogs, lagomorphs such as rabbits, farm animals, sport animals, and pets.

[0082] As used herein, the terms "treating," "treatment," and the like refer to, but are not limited to, obtaining a desired pharmacological and physiological effect. The effect may be prophylactic in that it completely or partially prevents a disorder or its signs or symptoms, and / or it may be therapeutic in that it improves the symptoms of a disease or infection, or partially or completely cures a disorder and / or adverse effects resulting from a disorder.

[0083] All numerical designations, including ranges, such as pH, temperature, time, and molecular weight, should be understood as approximate values ​​according to common practice in the art.As used herein, the term "about" can imply a variation of (+) or (-) 1%, 5% or 10% of the indicated amount, as the context requires.It should be understood, although not always explicitly stated, that the reagents described herein are merely exemplary, and their equivalents are known in the art.

[0084] Many known and useful compounds and the like can be found in Remington's Pharmaceutical Sciences (13th Ed), Mack Publishing Company, Easton, PA, a standard text for various types of administration. As used herein, the term "formulation" refers to a combination of at least one active ingredient with one or more other ingredients, also commonly referred to as excipients, which may be independently active or inactive. The term "formulation" may or may not refer to a pharma- ceutically acceptable composition for administration to humans or animals, and may include compositions that are intermediates useful for storage or research purposes.

[0085] In addition to humans, patients and subjects of the methods of the invention include veterinary subjects, and suitable formulations for these subjects also apply. Such subjects include farm animals and pets, as well as sport animals such as horses, greyhounds, and the like.

[0086] For purposes herein, the formulations may be administered by one or more of the following routes: percutaneous, intranasal, subcutaneous, intravenous, intraperitoneal or lymphatic, including intramuscular, subcutaneous or intradermal laminar injection with or without a needle. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0087] Perillyl alcohol (PA) and other cyclic monoterpenes have demonstrated antineoplastic activity in cell and animal models. The mode of action of PA in programmed cell death of cancer cells is under investigation. However, studies have shown that PA can increase mannose-6-phosphate and insulin-like growth factor II receptors. In addition, treatment of cell lines with PA has been demonstrated to increase tissue growth factor beta receptor and BAK, a proapoptotic Bcl-2 family member. PA exposure has also been shown to decrease RAS protein prenylation, decrease ubiquinone synthesis, and induce phase I and phase II detoxification systems.

[0088] Another proposed mechanism of action of PA in cancer cell apoptosis involves the modulation of CDC42 gene expression, including enzymatic interaction with rho GTPases and pausing of spindle fiber formation. In particular, the dynamics between CDC42 and the response proteins γ-H2AX and p-Chk1 have been proposed to be altered in the presence of these compounds. There is also evidence suggesting that increased arrest through the G2 / M checkpoint may affect the relative expression levels of the response proteins γ-H2AX and p-Chk1. Although additional studies are required to confirm the exact mode of action of PA in cancer cell apoptosis, the conversion of PA, limonene and related compounds into prodrugs represents a novel strategy for the treatment of cancer. However, the compounds have been ineffective in human models due to poor bioavailability and ADME (absorption, distribution, metabolism and excretion) issues.

[0089] The structures of (R)-(+)PA and (S)-(-)PA are shown in Figure 1A. In nature, limonene is formed from geranyl pyrophosphate via the neryl carbocation or its equivalent. The final step involves the loss of a proton from the cation to form an alkene. The stepwise oxidation of limonene to perillic acid is shown in Figure 1B.

[0090] A prodrug is a drug or compound that is metabolized (i.e., converted in the body) into a pharmacologically active drug after administration. Instead of administering a drug directly, the corresponding prodrug can be used to improve the way the drug is absorbed, distributed, metabolized, and excreted (ADME). It can be considered that about 10% of all drugs sold worldwide are prodrugs. For example, aspirin was originally synthesized in the 19th century with the aim of producing a prodrug of salicylic acid that was acceptable when taken orally.

[0091] At least 30 prodrugs have been approved by the FDA since 2008. Prodrugs can be classified into two major types based on the manner in which the body converts the prodrug into the final active drug form. Type I prodrugs are bioactivated inside the cell (i.e., intracellularly). Examples include antiviral nucleoside analogs, which must be phosphorylated, and lipid-lowering statins. Type II prodrugs are bioactivated outside the cell (i.e., extracellularly), such as in the digestive fluids or in the body's circulatory system. Examples of Type II prodrugs include salicin, and certain antibody-targeted, gene-targeted, or virus-targeted enzyme prodrugs used in chemotherapy or immunotherapy. Either type can be further classified into subtypes based on factors such as whether the site of bioactivation within the cell is also the site of therapeutic action (Type 1), or whether bioactivation occurs in the digestive fluids or in the circulatory system (Type 2).

[0092] The present invention overcomes the potential dangers inherent in the prior art by providing novel compositions and methods for use in the treatment of diseases such as cancer. Specifically, the present invention provides cyclic monoterpenes as prodrug compositions. As prodrugs, bioavailability and ADME issues are improved. Conjugation of cyclic monoterpenes can also increase the lipophilicity of the compound. This can increase the penetration of the conjugate through the blood-brain barrier. Furthermore, smaller drug doses can be administered to achieve the desired effect while minimizing toxicity.

[0093] In some embodiments, the prodrugs described herein can target specific tissues, such as tumors. The compounds can be used to treat diseases, such as cancer. In other embodiments, the disease is an infection, Parkinson's disease (PD), gallstones, cholecystitis, or cholangitis.

[0094] In some embodiments, one or more monoterpenes are conjugated to a prodrug moiety such as cholecalciferol / vitamin D, retinoic acid, N-methylperillic acid, tyrosine and / or valproic acid. The molecules can be conjugated via an ester bond. In other embodiments, a linker molecule is used to form a covalent bond. Table 1 lists some drugs, their respective prodrug moieties and transporters. [Table 1]

[0095] Cholecalciferol is one of the five forms of vitamin D (i.e., vitamin D3). It is naturally synthesized in the skin, where it functions as a prohormone and is converted to calcitriol. Cholecalciferol is synthesized by the body and functions as a prehormone. Cholecalciferol is converted to its active form, calcitriol, by two reactions: first in the liver and second in the kidney, the action of which is mediated by the vitamin D receptor. This receptor regulates the synthesis of hundreds of enzymes and is present in virtually every cell of the body.

[0096] Retinoids are a class of compounds that contain four isoprenoid units in their molecular structure. Examples of retinoids include retinol (vitamin A), retinal, retiferol, tretinoin (all-trans retinoic acid, e.g., retinoic acid, retin A), isotretinoin, alitretinoin (9-cis-retinoic acid), etretinate, acitretin, tazarotene, bexarotene, and adapalene. Retinoids and retinoid-related compounds have important and diverse functions. Retinoic acid is a metabolite of vitamin A1 (all-trans retinol) and mediates the functions of vitamin A1, which are necessary for growth and development. All-trans retinoic acid (ATRA) is the predominant retinoic acid present, but isomers such as 13-cis- and 9-cis-retinoic acid also exist at fairly low levels in mammals.

[0097] Tyrosine is a non-essential amino acid that the body makes from another amino acid called phenylalanine. It is an essential component in the production of several important brain chemicals called neurotransmitters, including epinephrine, norepinephrine, and dopamine. LAT1 or SLC7A5 is a major nutrient transport protein involved in the transport of large neutral aromatic or branched amino acids from the extracellular fluid into cells. These include many essential amino acids such as phenylalanine, leucine, isoleucine, valine, tryptophan, histidine, and methionine. Tyrosine is a LAT1 substrate that has a phenolic hydroxyl group that can undergo conjugation with a variety of structurally different drugs, providing a biodegradable linkage.

[0098] Valproic acid is a branched short-chain fatty acid and the 2-n-propyl derivative of valeric acid. Prodrugs of valproic acid include propyl valproic acid (P-VPA), butyl valproic acid (B-VPA, isobutyl valproic acid (IB-VPA), isoamyl valproic acid (IA-VPA), and hexyl valproic acid (H-VPA). Due to the rapid conversion of the prodrug to the parent drug, the concentration of VPA in plasma after administration of the prodrug peaks soon after administration (i.e., at 6 to 26 minutes). Valproic acid (or sodium valproate) is commonly used for the treatment of epilepsy and bipolar disorder, as well as to prevent migraines. Active Transport Prodrugs

[0099] There are two major modes of transport of molecules across biological membranes: passive and active transport. Passive transport (e.g., diffusion) occurs along a concentration gradient from a higher concentration to a lower concentration. This mode of transport does not require energy. In contrast, active transport is an energy-driven process in which membrane proteins transport molecules through cells. Active transport can be classified as primary or secondary based on how energy is coupled to fuel these mechanisms.

[0100] In some embodiments, the prodrugs described herein are actively transported into target cells: a transmembrane protein recognizes the prodrug (or a portion of the prodrug) and can translocate it across the membrane by utilizing an energy source.

[0101] The chemical structures of some active transport prodrugs, their transport proteins and metabolites are shown in FIG. 4. N-methylperillic acid can be transported by FAH. The metabolites produced are perillic acid and methylamine. Similarly, tyrosine can be conjugated to perillic acid to generate a prodrug. Compounds can be transported into target cells by LAT1. Valproic acid can be conjugated to perillic acid to generate a prodrug. Compounds can be transported into target cells by MCT1. Retinoic acid can be conjugated to perillic acid to generate a prodrug. Compounds can be transported into target cells by protein carriers. Additionally, vitamin D can be conjugated to perillic acid to generate a prodrug that can be transported into target cells by protein carriers. Passive Transport Prodrugs

[0102] In some embodiments, the prodrugs described herein are passively transported into target cells.Prodrugs that can enter target cells via passive transport are shown in Figure 5, and include, for example, perillyl alcohol, perillyl acid, perillyl alcohol acetate, perillyl acid methyl ester, perillyl alcohol isobutyrate, perillyl acid ethyl ester, perillyl alcohol pivaloate, perillyl acid isopropyl ester, perillyl perillate, and perillyl carbonate. Treatment

[0103] Provided herein are methods of treating, preventing, or ameliorating a disease, disorder, condition, or a symptom thereof or a condition associated therewith. Preferred, but non-limiting, embodiments are directed to methods of treating, preventing, inhibiting, or ameliorating a disease, disorder, condition, or a symptom thereof as described below.

[0104] The present invention provides a method of treating a disease, such as cancer, in a subject, comprising administering to the subject one or more compounds or salts thereof described herein, or pharmaceutical compositions thereof. In some embodiments, the subject is in need of such treatment. In some embodiments, the compound is administered as a prodrug. Examples of cancer include melanoma, endometrial, lung, hematopoietic / lymphoid, ovarian, cervical, soft tissue sarcoma, urinary tract, pancreatic, thyroid, renal, glioblastoma, and breast cancer. In some embodiments, the cancer is not a B-cell proliferative cancer. In some embodiments, the cancer is not multiple myeloma.

[0105] In any of the embodiments, one or more cancer therapies (e.g., chemotherapy, radiation therapy, immunotherapy, surgery or hormonal therapy) can be further co-administered with the medicament of the present invention. In one embodiment, the chemotherapy reagent is an alkylating agent: nitrogen mustard, nitrosourea, tetrazine, aziridine, cisplatin and derivatives, and non-classical alkylating agents. Nitrogen mustards include mechlorethamine, cyclophosphamide, melphalan, chlorambucil, ifosfamide and busulfan. Nitrosoureas include N-nitroso-N-methylurea (MNU), lomustine (CCNU) and semustine (MeCCNU), fotemustine and streptozotocin. Tetrazines include dacarbazine, mitozolomide and temozolomide. Aziridines include thiotepa, mitomycin and diaziquone (AZQ). Cisplatin and derivatives include cisplatin, carboplatin and oxaliplatin. In one embodiment, the chemotherapeutic agent is an antimetabolite: antifolates (e.g., methotrexate), fluoropyrimidines (e.g., fluorouracil and capecitabine), deoxynucleoside analogs and thiopurines. In another embodiment, the chemotherapeutic agent is an anti-microtubule agent, such as a vinca alkaloid (e.g., vincristine and vinblastine) and a taxane (e.g., paclitaxel and docetaxel). In another embodiment, the chemotherapeutic agent is a topoisomerase inhibitor or a cytotoxic antibiotic, such as doxorubicin, mitoxantrone, bleomycin, actinomycin, and mitomycin. Administration of prodrug drugs

[0106] To prepare a pharmaceutical composition, one or more monoterpene (or sesquiterpene) derivatives can be mixed with pharma- ceutically acceptable carriers, adjuvants and / or excipients according to conventional compounding techniques. Pharmaceutically acceptable carriers that can be used in the present compositions include any of the standard pharmaceutical carriers, such as phosphate buffered saline, water, and emulsions, such as oil / water or water / oil emulsions, and various types of wetting agents. The compositions can further include solid pharmaceutical excipients, such as starch, cellulose, talc, glucose, lactose, sucrose, gelatin, malt, rice, flour, silica gel, magnesium stearate, sodium stearate, glycerol monostearate, glycerol monostearate, sodium chloride, and the like. Liquid and semi-solid excipients can be, for example, glycerol, propylene glycol, water, ethanol, and various oils, including oils of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil, and the like. Liquid carriers, particularly injectable solutions, include water, saline, aqueous dextrose and glycols. The compositions may also contain stabilizers and preservatives.

[0107] It is understood that the present invention encompasses the use of stereoisomers, diastereomers and optical stereoisomers of the compounds of the present invention, and mixtures thereof, if applicable.Furthermore, it is understood that stereoisomers, diastereomers and optical stereoisomers of the compounds of the present invention, and mixtures thereof, are within the scope of the present invention.As a non-limiting example, the mixture may be racemic, or the mixture may contain an unequal ratio of one particular stereoisomer to other stereoisomers.Furthermore, the compounds may be provided as substantially pure stereoisomers, diastereomers and optical stereoisomers (e.g., epimers).

[0108] The compounds described herein may be asymmetric (e.g., have one or more stereocenters). All stereoisomers, such as enantiomers and diastereomers, are intended to be included within the scope of the present invention unless otherwise indicated. The compounds containing asymmetrically substituted carbon atoms can be separated as optically active or racemic forms. Methods for preparing optically active forms from optically active starting materials are known in the art, for example, by separation of racemic mixtures or stereoselective synthesis. Many geometric isomers of olefins, C=N double bonds, and the like can also be present in the compounds described herein, and all such stable isomers are contemplated in the present invention. Cis and trans geometric isomers of the compounds are also included within the scope of the present invention and can be separated as a mixture of isomers or separated isomeric forms. If a compound is capable of stereoisomerism, all such isomers are contemplated.

[0109] Compounds may also include tautomeric forms. Tautomeric forms result from the exchange of a single bond with an adjacent double bond with the concomitant migration of a proton. Tautomeric forms include prototropic tautomers, which are isomeric protonation states with the same empirical formula and total charge. Examples of prototropic tautomers include, but are not limited to, ketone-enol pairs, amide-imidic acid pairs, lactam-lactim pairs, amide-imidic acid pairs, enamine-imine pairs, and cyclic forms in which protons occupy two or more positions in a heterocyclic ring system, including, but not limited to, 1H- and 3H-imidazole, 1H-, 2H- and 4H-1,2,4-triazole, 1H- and 2H-isoindole, and 1H- and 2H-pyrazole. Tautomeric forms may be in equilibrium or sterically fixed into one form by appropriate substitution.

[0110] The compounds also include hydrates and solvates, as well as anhydrous and non-solvated forms. The compounds also include all isotopes of atoms occurring in the intermediates or final compounds. Isotopes include those atoms having the same atomic number but different mass numbers. For example, isotopes of hydrogen include tritium and deuterium.

[0111] In some embodiments, the compound or its salt is substantially isolated. Partial isolation can include, for example, compositions enriched with the compound of the present invention. Substantial isolation can include compositions containing at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 97%, or at least about 99% by weight of the compound of the present invention or its salt. Methods for isolating compounds and their salts are routine in the art.

[0112] One or more compounds described herein may be administered by any method known in the art, including, for example, intranasal, oral, transdermal, ophthalmic, intraperitoneal, inhalation, intravenous, ICV, intracisternal injection or infusion, subcutaneous, implant, vaginal, sublingual, urethral (e.g., urethral suppository), subcutaneous, intramuscular, intravenous, rectal, sublingual, mucosal, ophthalmic, spinal, intrathecal, intraarticular, intraarterial, subarachnoid, bronchial, and lymphatic administration. Topical formulations may be in the form of gels, ointments, creams, aerosols, and the like. Intranasal formulations may be delivered as sprays or drops. Prodrug forms may be administered by transdermal patches or iontophoresis. Formulations for inhalation may be delivered using a nebulizer or similar device. The compositions may take the form of tablets, pills, capsules, semisolids, powders, sustained release formulations, solutions, suspensions, elixirs, aerosols, or any other suitable compositions.

[0113] In another aspect, certain embodiments are directed to a sustained release drug delivery platform that releases the therapeutic compounds disclosed and made as formulations described herein for a period of time including, but not limited to, about 3 days after administration, about 7 days after administration, about 10 days after administration, about 15 days after administration, about 20 days after administration, about 25 days after administration, about 30 days after administration, about 45 days after administration, about 60 days after administration, about 75 days after administration, or about 90 days after administration. In other aspects of this embodiment, the sustained release drug delivery platform releases the therapeutic compounds disclosed herein at a substantially first order release rate for a period of time including, but not limited to, at least 3 days after administration, at least 7 days after administration, at least 10 days after administration, at least 15 days after administration, at least 20 days after administration, at least 25 days after administration, at least 30 days after administration, at least 45 days after administration, at least 60 days after administration, at least 75 days after administration, or at least 90 days after administration.

[0114] In an embodiment, the disease is cancer.Cancer may include one or more of lung cancer, breast cancer, colon cancer, midline carcinoma, mesenchymal tumor, liver tumor, neoplasm, neuroendocrine tumor, adrenal cancer, precancerous cancer, eosinophilic leukemia, acute leukemia, acute lymphoblastic leukemia, acute megakaryocytic leukemia, acute monocytic leukemia, acute promyelocytic leukemia, adenocarcinoma, adenocarcinomatous carcinoma, adenoma, squamous cell carcinoma, adult T-cell leukemia / lymphoma, high-grade NK-cell leukemia, AIDS-related lymphoma, alveolar rhabdomyosarcoma, alveolar soft tissue sarcoma, B-cell chronic lymphocytic leukemia, B-cell lymphocytic leukemia, and B-cell lymphoma. The present invention also relates to the treatment of cancer of the following cancer types: cell carcinoma, cholangiocarcinoma, bladder cancer, blastoma, bone cancer, Brenner's tumor, Brown's tumor, Burkitt's lymphoma, brain cancer, carcinoma, renal neoplasm, renal cell tumor, cytoskeletal craniopharyngioma, cutaneous T-cell lymphoma, cervical cancer, colorectal cancer, Degos disease, connective tissue small round cell tumor, diffuse large B-cell lymphoma, endometrial lymphoma, follicular lymphoma, follicular thyroid cancer, ganglion transection, gastric cancer, stomach cancer, The present invention also relates to a method of treating a cancer selected from the group consisting of endometrial cancer, glioblastoma multiforme, glioma / glioblastoma, pancreatic cancer, hepatocellular carcinoma, hepatosplenic T-cell lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, aggressive carcinoma, papillary carcinoma, gallbladder cancer, gastric cancer, hairy cell leukemia, hemangioblastoma, head and neck cancer, lymphoma, acute lymphoblastic leukemia, chronic lymphocytic leukemia, liver cancer, small cell lung cancer, non-small cell lung cancer, MALT lymphoma, malignant fibrous histiocytoma, malignant peripheral neuropathy tumor, malignant triton tumor, mantle cell lymphoma, marginal zone B-cell lymphoma, mast cell leukemia, tumor, breast cancer, metastatic breast cancer, mixed Mullerian tumor, mucinous tumor, and breast cancer.The present invention relates to a method for treating neuroblastoma, tumor, multiple myeloma, muscle tissue neoplasm, fungal sarcoma, myxoid liposarcoma, myxoma, myxoid sarcoma, pituitary tumor, pituitary adenoma, pituitary adenoma, pituitary adenoma, papillary thyroid carcinoma, pineal neoplasm, pineal tumor, lymphocytic lymphoma, primary exudative lymphoma, primary effusion lymphoma, primary peritoneal carcinoma, prostate carcinoma, pancreatic carcinoma, parietal cell carcinoma, thyroid cancer ... The present invention relates to the use of a compound of formula I or a pharmacologic agent, such as a medicament for the treatment or prevention of a neurodegenerative disease selected from the group consisting of myeloma, cystic leukemia, myeloma, ovarian cancer, thyroid cancer, transitional cell carcinoma, squamous cell carcinoma, small cell carcinoma, gastric cancer, T-cell lymphoma, synovial sarcoma, lymphoma, testicular cancer, ovarian cancer, thyroid cancer, transitional cell carcinoma, laryngeal cancer, urothelial carcinoma, genitourinary cancer, uveal melanoma, uterine cancer, wart cancer, visual pathway glioma, vulvar cancer, vaginal cancer, leukemia, and Wilms' tumor.

[0115] Another aspect of the present application relates to a method of treating a cell proliferative disorder, the method comprising administering to a subject in need thereof an effective amount of an agent according to the present disclosure.

[0116] Any suitable route or method of administration can be used to provide a patient with a therapeutically or prophylactically effective amount of the agent. Exemplary routes and modes of administration include parenteral (e.g., intravenous, intraarterial, intramuscular, subcutaneous, intratumoral), oral, topical (nasal, transdermal, intradermal or intraocular), mucosal (e.g., nasal, sublingual, buccal, rectal, vaginal), inhalation, intranodal, intraspinal, intracranial, intraperitoneal, intratracheal, intravesical, intrathecal, intraintestinal, intrapulmonary, intranodal, intracavity, intraorbital, intraarticular and transurethral, ​​as well as local delivery via catheter or stent.

[0117] Pharmaceutical compositions containing agents according to the present disclosure may be formulated in any pharma- ceutically acceptable carrier or excipient. As used herein, the term "pharma-ceutically acceptable carrier" includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like, that are physiologically compatible. Pharmaceutical compositions may include suitable solid or gel phase carriers or excipients. Exemplary carriers or excipients include calcium carbonate, calcium phosphate, various sugars, starches, cellulose derivatives, gelatin, and polymers such as polyethylene glycols. Examples of pharma-ceutically acceptable carriers include one or more of water, saline, phosphate buffered saline, dextrose, glycerol, ethanol, and the like, and combinations thereof. In many cases, it will be preferable to include an isotonic agent in the composition, for example, sugars, polyalcohols such as mannitol, sorbitol, or sodium chloride. Pharmaceutically acceptable carriers may further include minor amounts of auxiliary substances that enhance the shelf life or effectiveness of the therapeutic agent, such as wetting or emulsifying agents, preservatives, or buffers.

[0118] In some embodiments, the compositions described herein are intended to be used in the treatment of a variety of cancers, including fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteosarcoma, chordoma, malignant fibrous histiocytoma, angiosarcoma, hemangiosarcoma, lymphangiosarcoma, mesothelioma, leukemia, aleukemic leukemia, plasmacytoma; rare malignancies, multiple myeloma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, malignant tumors, leiomyosarcoma, rhabdomyosarcoma, squamous cell carcinoma, epidermoid carcinoma, malignant skin adnexal tumors, adenocarcinoma, hepatocellular carcinoma, renal cell carcinoma, renal cell carcinoma, cholangiocarcinoma, transitional cell carcinoma, choriocarcinoma, seminocarcinoma, cholangiocarcinoma, transitional cell carcinoma, chorio ... In some embodiments, the compound may be used in combination with other therapeutic agents as a treatment for one or more of the following: glioma, germ cell carcinoma, glioma, grades I-III, anaplastic; glioblastoma multiforme (grade IV), neuroblastoma, medulloblastoma, malignant meningioma, malignant meningioma, malignant schwannoma, neurofibrosarcoma, parathyroid carcinoma, medullary carcinoma of the thyroid, bronchial carcinoid, oat cell carcinoma, pheochromocytoma, islet cell carcinoma, malignant carcinoid, malignant paraganglioma, melanoma, malignant schwannoma, Merkel cell neoplasm, cystosarcoma phyllodes, and / or Wilms' tumor.

[0119] The therapeutic agent in the pharmaceutical composition may be formulated in a "therapeutically effective amount" or a "prophylactically effective amount". A "therapeutically effective amount" refers to an amount effective at the dosages and for the time periods necessary to achieve the desired therapeutic result. The therapeutically effective amount of the recombinant vector may vary depending on the condition being treated, the severity and course of the condition, the method of administration, whether the antibody or agent is administered for prophylactic or therapeutic purposes, the bioavailability of the particular agent, the ability of the agent to induce the desired response in the individual, previous treatments, the age, weight, and sex of the patient, the patient's clinical history and response to the agent, the type of agent used, the discretion of the attending physician, and the like. A therapeutically effective amount is also an amount in which any toxic or harmful effects of the recombinant vector are outweighed by the therapeutically beneficial effects. A "prophylactically effective amount" refers to an amount effective at the dosages and for the time periods necessary to achieve the desired prophylactic result.

[0120] As a general proposition, a therapeutically or prophylactically effective amount of an agent will be administered in the range of about 1 ng / kg body weight / day to about 100 mg / kg body weight / day, whether administered in single or multiple doses.In certain embodiments, each agent is administered at a concentration of about 1 ng / kg body weight / day to about 10 mg / kg body weight / day, about 1 ng / kg body weight / day to about 1 mg / kg body weight / day, about 1 ng / kg body weight / day to about 100 g / kg body weight / day, about 1 ng / kg body weight / day to about 10 g / kg body weight / day, about 1 ng / kg body weight / day to about 1 g / kg body weight / day, about 1 ng / kg body weight / day to about 100 ng / kg body weight / day, about 1 ng / kg body weight / day to about 10 ng / kg body weight / day, about 10 ng / kg body weight / day to about 100 mg / kg body weight / day, or about 10 ng / kg body weight / day to about 10 mg / kg body weight / day, about 10ng / kg body weight / day to about 1mg / kg body weight / day, about 10ng / kg body weight / day to about 10mg / kg body weight / day, about 10ng / kg body weight / day to about 1mg / kg body weight / day, 10ng / kg body weight / day to about 100ng / kg body weight / day, about 100ng / kg body weight / day to about 100mg / kg body weight / day, about 100ng / kg body weight / day to about 10mg / kg body weight / day, about 100ng / kg body weight / day to about 10mg / kg body weight / day, about 100ng / kg body weight / day to about 1mg / kg body weight / day, about 100ng / kg body weight / day to about 100mg / kg body weight / day, about 100ng / kg body weight / day to about 10mg / kg body weight / day, about 100ng / kg body weight / day to about 1mg / kg body weight / day, about 1mg / kg body weight / day to about 100mg / kg body weight / day, about 1mg / kg body weight / day to about 10mg / kg body weight / day, about 1mg / kg body weight / day to about 1mg / kg body weight / day, about 1mg / kg body weight / day to about 100mg / kg body weight / day, about 1mg / kg body weight / day to about 10mg / kg body weight / day, about 10mg / kg body weight / day to about 100mg / kg body weight / day, about 10mg / kg body weight / day to about 100mg / kg body weight / day It is administered in the range of about 10 mg / kg body weight / day, about 10 mg / kg body weight / day to about 1 mg / kg body weight / day, about 10 mg / kg body weight / day to about 100 mg / kg body weight / day, about 100 mg / kg body weight / day to about 100 mg / kg body weight / day, about 100 mg / kg body weight / day to about 10 mg / kg body weight / day, about 100 mg / kg body weight / day to about 1 mg / kg body weight / day, about 1 mg / kg body weight / day to about 100 mg / kg body weight / day, about 1 mg / kg body weight / day to about 10 mg / kg body weight / day, about 10 mg / kg body weight / day to about 100 mg / kg body weight / day.

[0121] In other embodiments, the agent is administered at a dose of 200 g to 500 g every three days, or at a dose of 25 mg / kg body weight every three days.

[0122] In other embodiments, each agent is administered in an amount of about 10 ng to about 100 ng per individual administration, about 10 ng to about 1 g per individual administration, about 10 ng to about 10 g per individual administration, about 10 ng to about 100 mg per individual administration, about 10 ng to about 1 mg per individual administration, about 10 ng to about 10 mg per individual administration, about 10 ng to about 100 mg per individual administration, about 10 ng to about 1000 mg per individual administration, about 10 ng to about 10,000 mg per individual administration, about 100 ng to about 1 mg per individual administration, about 100 ng to about 10 ... about 100 ng to about 100 mg per dose, about 100 ng to about 1 mg per individual dose, about 100 ng to about 10 mg per individual dose, about 100 ng to about 100 mg per individual dose, about 100 ng to about 1000 mg per injection, about 100 ng to about 10,000 mg per individual dose, about 1 mg to about 10 mg per individual dose, about 1 mg to about 100 mg per individual dose, about 1 mg to about 5 mg per individual dose, about 1 mg to about 10 mg per individual dose, about 1 mg to about 100 mg per individual dose, about 1 mg to about 100 mg per individual dose, about 1 mg per administration to about 10,000 mg per individual administration, about 10 mg to about 100 mg per individual administration, about 10 mg to about 1 mg per individual administration, about 10 mg to about 50 mg per individual administration, about 10 mg to about 100 mg per individual administration, about 10 mg to about 1000 mg per individual administration, about 10 mg to about 10,000 mg per individual administration, about 100 mg to about 1 mg per individual administration, about 100 mg to about 10 mg per individual administration, about 100 mg to about 500 mg per individual administration, about 100 mg to about 1000 mg per individual administration about 100 mg to about 10,000 mg per individual administration, about 1 mg to about 10 mg per individual administration, about 1 mg to about 100 mg per individual administration, about 1 mg to about 1000 mg per individual administration, about 1 mg to about 10,000 mg per individual administration, about 10 mg to about 100 mg per individual administration, about 10 mg to about 1000 mg per individual administration, about 10 mg to about 10,000 mg per individual administration, about 100 mg to about 1000 mg per individual administration, about 100 mg to about 5,000 mg per individual administration, and about 1000 mg to about 10,000 mg per individual administration.The agents may be administered daily, every 2, 3, 4, 5, 6, or 7 days, or every 1, 2, 3, or 4 weeks.

[0123] In other embodiments, each agent is administered in an amount of from about 10 ng to about 100 ng per injection, from about 10 ng to about 1 g per injection, from about 10 ng to about 10 g per injection, from about 10 ng to about 100 mg per injection, from about 10 ng to about 1 mg per injection, from about 10 ng to about 10 mg per injection, from about 10 ng to about 100 mg per injection, from about 10 ng to about 1000 mg per injection, from about 10 ng to about 10,000 mg per injection, from about 100 ng to about 1 mg per injection, from about 100 ng to about 10 mg per injection, about 100 ng to about 100 mg per injection, about 100 ng to about 1 mg per injection, about 100 ng to about 10 mg per injection, about 100 ng to about 100 mg per injection, about 100 ng to about 1000 mg per injection, about 100 ng to about 10,000 mg per injection, about 1 mg to about 10 mg per injection, about 1 mg to about 100 mg per injection, about 1 mg to about 5 mg per injection, about 1 mg to about 10 mg per injection, about 1 mg to about 100 mg per injection, about 1 mg to about 100 mg per injection, about 1 mg to about 1000 mg per injection, about 1 mg to about 10,000 mg per injection, about 10 mg to about 100 mg per injection, about 10 mg to about 1 mg per injection, about 10 mg to about 50 mg per injection, about 10 mg to about 100 mg per injection, about 10 mg to about 1000 mg per injection, about 10 mg to about 10,000 mg per injection, about 100 mg to about 1 mg per injection, about 100 mg to about 10 mg per injection, about 100 mg to about 500 mg per injection, about 100 mg to about 1000 mg per injection, about 100 mg to about 10,000 mg per injection, about 1 mg to about 10 mg per injection, about 1 mg to about 100 mg per injection, about 1 mg to about 1000 mg per injection, about 1 mg to about 10,000 mg per injection, about 10 mg to about 100 mg per injection, about 10 mg to about 1000 mg per injection, about 10 mg to about 10,000 mg per injection, about 100 mg to about 1000 mg per injection, about 10 mg to about 10,000 mg per injection, about 100 mg to about 1000 mg per injection, about 100 mg to about 5,000 mg per injection, and about 1000 mg to about 10,000 mg per injection. The agent may be administered hourly, every 2 hours, every 3 hours, every 90 minutes, every 2 hours, every 3 hours, every 4 hours, twice a day, three times a day, three times a day, four times a day, five times a day, six times a day, seven times a day, eight times a day, every 2, 3, 4, 5, 6, or 7 days, or every 1, 2, 3, or 4 weeks.

[0124] In other specific embodiments, the amount of the agent is administered in dosages of 0.0006 mg / day, 0.001 mg / day, 0.003 mg / day, 0.006 mg / day, 0.01 mg / day, 0.03 mg / day, 0.06 mg / day, 0.1 mg / day, 0.3 mg / day, 0.6 mg / day, 1 mg / day, 3 mg / day, 6 mg / day, 10 mg / day, 30 mg / day, 60 mg / day, 100 mg / day, 300 mg / day, 600 mg / day, 1000 mg / day, 2000 mg / day, 5000 mg / day, or 10,000 mg / day. As expected, the dosage will depend on the condition, size, age, and medical condition of the patient.

[0125] In other aspects of this embodiment, the pharmaceutical compositions disclosed herein reduce tumor size by, e.g., at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, or at least 95%. In yet another aspect of this embodiment, the pharmaceutical compositions disclosed herein reduce tumor size by, for example, about 5% to about 100%, about 10% to about 100%, about 20% to about 100%, about 30% to about 100%, about 40% to about 100%, about 50% to about 100%, about 60% to about 100%, about 70% to about 100%, about 80% to about 100%, about 10% to about 90%, about 20% to about 90%, about 30% to about 100%, or about 40% to about 100%. about 90%, about 40% to about 90%, about 50% to about 90%, about 60% to about 90%, about 70% to about 90%, about 10% to about 80%, about 20% to about 80%, about 30% to about 80%, about 40% to about 80%, about 50% to about 80%, or about 60% to about 80%, about 10% to about 70%, about 20% to about 70%, about 30% to about 70%, about 40% to about 70%, or about 50% to about 70%.

[0126] The pharmaceutical composition disclosed herein is sufficient to allow for routine administration to individual.In some aspects of this embodiment, the pharmaceutical composition disclosed herein can be, for example, at least 5mg, at least 10mg, at least 15mg, at least 20mg, at least 25mg, at least 30mg, at least 35mg, at least 40mg, at least 45mg, at least 50mg, at least 55mg, at least 60mg, at least 65mg, at least 70mg, at least 75mg, at least 80mg, at least 85mg, at least 90mg, at least 95mg, or at least 100mg pharmaceutical composition. In other aspects of this embodiment, the pharmaceutical compositions disclosed herein can be, for example, at least 5 mg, at least 10 mg, at least 20 mg, at least 25 mg, at least 50 mg, at least 75 mg, at least 100 mg, at least 200 mg, at least 300 mg, at least 400 mg, at least 500 mg, at least 600 mg, at least 700 mg, at least 800 mg, at least 900 mg, at least 1,000 mg, at least 1,100 mg, at least 1,200 mg, at least 1,300 mg, at least 1,400 mg, or at least 1,500 mg of a pharmaceutical composition. In yet another aspect of this embodiment, the pharmaceutical compositions disclosed herein can be in the range of, for example, about 5 mg to about 100 mg, about 10 mg to about 100 mg, about 50 mg to about 150 mg, about 100 mg to about 250 mg, about 150 mg to about 350 mg, about 250 mg to about 500 mg, about 350 mg to about 600 mg, about 500 mg to about 750 mg, about 600 mg to about 900 mg, about 750 mg to about 1,000 mg, about 850 mg to about 1,200 mg, or about 1,000 mg to about 1,500 mg.In yet another aspect of this embodiment, the pharmaceutical composition disclosed herein may be administered in an amount of, for example, about 10 mg to about 250 mg, about 10 mg to about 500 mg, about 10 mg to about 750 mg, about 10 mg to about 1,000 mg, about 10 mg to about 1,500 mg, about 50 mg to about 250 mg, about 50 mg to about 500 mg, about 50 mg to about 750 mg, about 50 mg to about 1,000 mg, about 50 mg to about 1,500 mg, about 10 ... The amount of the active ingredient may be in the range of about 5 mg to about 250 mg, about 100 mg to about 500 mg, about 100 mg to about 750 mg, about 100 mg to about 1,000 mg, about 100 mg to about 1,500 mg, about 200 mg to about 500 mg, about 200 mg to about 750 mg, about 200 mg to about 1,000 mg, about 200 mg to about 1,500 mg, about 5 mg to about 1,500 mg, about 5 mg to about 1,000 mg, or about 5 mg to about 250 mg.

[0127] The pharmaceutical compositions disclosed herein may include a sufficient amount of a solvent, emulsion, or other diluent to dissolve the pharmaceutical compositions disclosed herein. In other aspects of this embodiment, the pharmaceutical compositions disclosed herein may include a solvent, emulsion, or diluent in an amount of, for example, less than about 90% (v / v), less than about 80% (v / v), less than about 70% (v / v), less than about 65% (v / v), less than about 60% (v / v), less than about 55% (v / v), less than about 50% (v / v), less than about 45% (v / v), less than about 40% (v / v), less than about 35% (v / v), less than about 30% (v / v), less than about 25% (v / v), less than about 20% (v / v), less than about 15% (v / v), less than about 10% (v / v), less than about 5% (v / v), or less than about 1% (v / v). In other aspects of this embodiment, the pharmaceutical compositions disclosed herein may contain a solvent, emulsion or other diluent in an amount of, for example, about 1% (v / v) to 90% (v / v), about 1% (v / v) to 70% (v / v), about 1% (v / v) to 60% (v / v), about 1% (v / v) to 50% (v / v), about 1% (v / v) to 40% (v / v), about 1% (v / v) to 5 ... )~30%(v / v), approx. 1%(v / v)~20%(v / v), approx. 1%(v / v)~10%(v / v), approx. 2%(v / v)~50%(v / v), approx. 2%(v / v) ~40%(v / v), approx. 2%(v / v)~30%(v / v), approx. 2%(v / v)~20%(v / v), approx. 2%(v / v)~10%(v / v), approx. 4%(v / v)~ 50%(v / v), approx. 4%(v / v)~40%(v / v), approx. 4%(v / v)~30%(v / v), approx. 4%(v / v)~20%(v / v), approx. 4%(v / v)~1 0%(v / v), approx. 6%(v / v)~50%(v / v), approx. 6%(v / v)~40%(v / v), approx. 6%(v / v)~30%(v / v), approx. 6%(v / v)~20 % (v / v), about 6% (v / v) to 10% (v / v), about 8% (v / v) to 50% (v / v), about 8% (v / v) to 40% (v / v), about 8% (v / v) to 30% (v / v), about 8% (v / v) to 20% (v / v), about 8% (v / v) to 15% (v / v), or about 8% (v / v) to 12% (v / v).

[0128] The final concentration of the pharmaceutical composition disclosed herein can be any desired concentration.In one aspect of this embodiment, the final concentration of the pharmaceutical composition can be a therapeutically effective amount.In another aspect of this embodiment, the final concentration of the pharmaceutical composition in the pharmaceutical composition can be, for example, at least 0.00001mg / mL, at least 0.0001mg / mL, at least 0.001mg / mL, at least 0.01mg / mL, at least 0.1mg / mL, at least 1mg / mL, at least 10mg / mL, at least 25mg / mL, at least 50mg / mL, at least 100mg / mL, at least 200mg / mL, at least 500mg / mL, at least 700mg / mL, at least 1,000mg / mL, or at least 1,200mg / mL. In other aspects of this embodiment, the concentration of the pharmaceutical composition disclosed herein in the liquid formulation can be, for example, up to 1,000 mg / mL, up to 1,100 mg / mL, up to 1,200 mg / mL, up to 1,300 mg / mL, up to 1,400 mg / mL, up to 1,500 mg / mL, up to 2,000 mg / mL, up to 2,000 mg / mL, or up to 3,000 mg / mL. In other aspects of this embodiment, the final concentration of the pharmaceutical composition can be, for example, about 0.00001 mg / mL to about 3,000 mg / mL, about 0.0001 mg / mL to about 3,000 mg / mL, about 0.01 mg / mL to about 3,000 mg / mL, about 0.1mg / mL to approx. 3,000mg / mL, approx. 1mg / mL to approx. 3,000mg / mL, approx. 250mg / mL to approx. 3,000mg / mL, approx. 500mg / mL to approx. 3,000mg / mL, approx. 750mg / mL to approx. 3,000mg / mL, approx. 1,000m g / mL ~ approx. 3,000 mg / mL, approx. 100 mg / mL ~ approx. 2,000 mg / mL, approx. 250 mg / mL ~ approx. 2,000 mg / mL, approx. 500 mg / mL ~ approx. 2,000 mg / mL, approx. 750 mg / mL ~ approx. 2,000 mg / mL, approx. 1,000 m g / mL~about 2,000mg / mL, about 100mg / mL~about 1,500mg / mL, about 250mg / mL~about 1,500mg / mL, about 500mg / mL~about 1,500mg / mL, about 750mg / mL~about 1,500mg / mL, about 1,000m g / mL ~ approx. 1,500 mg / mL, approx. 100 mg / mL ~ approx. 1,200 mg / mL, approx. 250 mg / mL ~ approx. 1,200 mg / mL, approx. 500 mg / mL ~ approx. 1,200 mg / mL, approx. 750 mg / mL ~ approx. 1,200 mg / mL, approx. 1,000 m g / mL~about 1,200mg / mL, about 100mg / mL~about 1,000mg / mL, about 250mg / mL~about 1,000mg / mL, about 500mg / mL~about 1,000mg / mL, about 750mg / mL~about 1,000mg / mL, about 100mg / mL mL ~ approx. 750 mg / mL, approx. 250 mg / mL ~ approx. 750 mg / mL, approx. 500 mg / mL ~ approx. 750 mg / mL, approx. 100 mg / mL ~ approx. 500 mg / mL, approx. 250 mg / mL ~ approx. 500 mg / mL, approx. 0.00001 mg / mL ~ approx. 0.00 The concentration of the glycerol in the solution may range from about 0.01 mg / mL, about 0.00001 mg / mL to about 0.001 mg / mL, about 0.00001 mg / mL to about 0.01 mg / mL, about 0.00001 mg / mL to about 0.1 mg / mL, about 0.00001 mg / mL to about 1 mg / mL, about 0.001 mg / mL to about 0.01 mg / mL, about 0.001 mg / mL to about 0.1 mg / mL, about 0.001 mg / mL to about 1 mg / mL, about 0.001 mg / mL to about 10 mg / mL, or about 0.001 mg / mL to about 100 mg / mL.

[0129] Some embodiments herein disclose, in part, the treatment of individuals suffering from cancer. As used herein, the term "treat" refers to reducing or eliminating the clinical symptoms of cancer in an individual, or delaying or preventing the onset of the clinical symptoms of cancer in an individual. For example, the term "treat" can mean, but is not limited to, reducing the symptoms of a condition that characterizes cancer, such as, but not limited to, tumor size, by at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90% at least 95%, or at least 100%. The actual symptoms associated with cancer are well known and can be determined by those skilled in the art, taking into account various factors, including but not limited to, the site of the cancer, the cause of the cancer, the severity of the cancer, and / or the tissue or organ affected by the cancer. One of ordinary skill in the art will know the appropriate symptoms or indicators associated with a particular type of cancer and how to determine whether an individual is a candidate for the treatments disclosed herein.

[0130] In another aspect, the pharmaceutical compositions disclosed herein reduce the severity of symptoms of a cancer-related disorder. In some aspects of this embodiment, the pharmaceutical compositions disclosed herein reduce the severity of symptoms of a cancer-related disorder, for example, by at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, or at least 95%. In other aspects of this embodiment, the pharmaceutical compositions disclosed herein can reduce or improve the severity of symptoms of a cancer-related disorder by, for example, about 10% to about 100%, about 20% to about 100%, about 30% to about 100%, about 40% to about 100%, about 50% to about 100%, about 60% to about 100%, about 70% to about 100%, about 80% to about 100%, about 10% to about 90%, about 20% to about 9 ... about 90%, about 40% to about 90%, about 50% to about 90%, about 60% to about 90%, about 70% to about 90%, about 10% to about 80%, about 20% to about 80%, about 30% to about 80%, about 40% to about 80%, about 50% to about 80%, about 60% to about 80%, about 10% to about 70%, about 20% to about 70%, about 30% to about 70%, about 40% to about 70%, or about 50% to about 70%.

[0131] In some aspects of this embodiment, a therapeutically effective amount of a pharmaceutical composition disclosed herein reduces a symptom associated with cancer by, for example, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 100%. In other aspects of this embodiment, a therapeutically effective amount of a pharmaceutical composition disclosed herein reduces a symptom associated with cancer by, for example, up to 10%, up to 15%, up to 20%, up to 25%, up to 30%, up to 35%, up to 40%, up to 45%, up to 50%, up to 55%, up to 60%, up to 65%, up to 70%, up to 75%, up to 80%, up to 85%, up to 90%, up to 95%, or up to 100%. In yet other aspects of this embodiment, a therapeutically effective amount of a pharmaceutical composition disclosed herein reduces a symptom associated with cancer by, for example, about 10% to about 100%, about 10% to about 90%, about 10% to about 80%, about 10% to about 70%, about 10% to about 60%, about 10% to about 50%, about 10% to about 40%, about 20% to about 100%, about 20% to about 90%, about 20% to about 80%, about 20% to about 20%, about 20% to about 60%, about 20% to about 50%, about 20% to about 40%, about 30% to about 100%, about 30% to about 90%, about 30% to about 80%, about 30% to about 70%, about 30% to about 60%, or about 30% to about 50%.

[0132] In yet another aspect of this embodiment, the therapeutically effective amount of the pharmaceutical composition disclosed herein is typically in the range of about 0.001 mg / kg / day to about 100 mg / kg / day. In some aspects of this embodiment, the effective amount of the pharmaceutical composition disclosed herein can be, for example, at least 0.001 mg / kg / day, at least 0.01 mg / kg / day, at least 0.1 mg / kg / day, at least 1.0 mg / kg / day, at least 5.0 mg / kg / day, at least 10 mg / kg / day, at least 15 mg / kg / day, at least 20 mg / kg / day, at least 25 mg / kg / day, at least 30 mg / kg / day, at least 35 mg / kg / day, at least 40 mg / kg / day, at least 45 mg / kg / day, or at least 50 mg / kg / day. In other aspects of this embodiment, an effective amount of the pharmaceutical composition disclosed herein can be, for example, from about 0.001 mg / kg / day to about 10 mg / kg / day, from about 0.001 mg / kg / day to about 15 mg / kg / day, from about 0.001 mg / kg / day to about 20 mg / kg / day, from about 0.001 mg / kg / day to about 25 mg / kg / day, from about 0.001 mg / kg / day to about 30 mg / kg / day, It may be in the range of about 0.001 mg / kg / day to about 35 mg / kg / day, about 0.001 mg / kg / day to about 40 mg / kg / day, about 0.001 mg / kg / day to about 45 mg / kg / day, about 0.001 mg / kg / day to about 50 mg / kg / day, about 0.001 mg / kg / day to about 75 mg / kg / day, or about 0.001 mg / kg / day to about 100 mg / kg / day. In yet other aspects of this embodiment, an effective amount of a pharmaceutical composition disclosed herein can be in the range of, for example, about 0.01 mg / kg / day to about 10 mg / kg / day, about 0.01 mg / kg / day to about 15 mg / kg / day, about 0.01 mg / kg / day to about 20 mg / kg / day, about 0.01 mg / kg / day to about 25 mg / kg / day, about 0.01 mg / kg / day to about 30 mg / kg / day, about 0.01 mg / kg / day to about 35 mg / kg / day, about 0.01 mg / kg / day to about 40 mg / kg / day, about 0.01 mg / kg / day to about 45 mg / kg / day, about 0.01 mg / kg / day to about 50 mg / kg / day, about 0.01 mg / kg / day to about 75 mg / kg / day, or about 0.01 mg / kg / day to about 100 mg / kg / day.In yet other aspects of this embodiment, an effective amount of a pharmaceutical composition disclosed herein can be in the range of, for example, about 0.1 mg / kg / day to about 10 mg / kg / day, about 0.1 mg / kg / day to about 15 mg / kg / day, about 0.1 mg / kg / day to about 20 mg / kg / day, about 0.1 mg / kg / day to about 25 mg / kg / day, about 0.1 mg / kg / day to about 30 mg / kg / day, about 0.1 mg / kg / day to about 35 mg / kg / day, about 0.1 mg / kg / day to about 40 mg / kg / day, about 0.1 mg / kg / day to about 45 mg / kg / day, about 0.1 mg / kg / day to about 50 mg / kg / day, about 0.1 mg / kg / day to about 75 mg / kg / day, or about 0.1 mg / kg / day to about 100 mg / kg / day.

[0133] The dosage may be a single dose or a cumulative dose (sequential administration), which can be easily determined by one skilled in the art. For example, the treatment of cancer may include only one administration of an effective amount of the pharmaceutical composition disclosed herein. Alternatively, the treatment of cancer may include multiple administrations of an effective amount of the pharmaceutical composition administered over a range of time periods, such as once a day, twice a day, three times a day, once every few days, or once a week. The timing of administration may vary from individual to individual, depending on factors such as the severity of the individual's symptoms. For example, an effective amount of the pharmaceutical composition disclosed herein may be administered to an individual once a day for an indefinite period of time, or until the individual no longer requires further treatment. One skilled in the art will recognize that an individual's condition can be monitored throughout the course of treatment, and the effective amount of the pharmaceutical composition disclosed herein administered can be adjusted accordingly.

[0134] In one embodiment, the cancer therapeutics disclosed herein are capable of reducing the number of cancer cells or tumor size in an individual afflicted with cancer by, e.g., at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, or at least 95% compared to a patient not receiving the same treatment. In other aspects of this embodiment, the cancer therapeutic agent reduces the number of cancer cells or tumor size in an individual suffering from cancer, for example, by about 10% to about 100%, about 20% to about 100%, about 30% to about 100%, about 40% to about 100%, about 50% to about 100%, about 60% to about 100%, about 70% to about 100%, about 80% to about 100%, about 10% to about 90%, about 20% to about 90%, or about 10% to about 100%. %, about 30% to about 90%, about 40% to about 90%, about 50% to about 90%, about 60% to about 90%, about 70% to about 90%, about 10% to about 80%, about 20% to about 80%, about 30% to about 80%, about 40% to about 80%, about 50% to about 80%, or about 60% to about 80%, about 10% to about 70%, about 20% to about 70%, about 30% to about 70%, about 40% to about 70%, or about 50% to about 70%.

[0135] In further embodiments, the cancer therapeutics and derivatives thereof have a half-life of 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, 18 hours, 19 hours, 20 hours, 21 hours, 22 hours, 23 hours, 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 1 week, 2 weeks, 3 weeks, 4 weeks, 1 month, 2 months, 3 months, 4 months or more.

[0136] In some embodiments, the cancer medicament is administered for 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, or more. In further embodiments, administration is suspended for 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, or more.

[0137] In some aspects of this embodiment, a therapeutically effective amount of a cancer therapeutic agent disclosed herein reduces or maintains an individual's cancer cell population and / or tumor cell size by, for example, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 100%. In other aspects of this embodiment, a therapeutically effective amount of a cancer therapeutic agent disclosed herein reduces or maintains cancer cell population and / or tumor cell size, for example, by up to 10%, up to 15%, up to 20%, up to 25%, up to 30%, up to 35%, up to 40%, up to 45%, up to 50%, up to 55%, up to 60%, up to 65%, up to 70%, up to 75%, up to 80%, up to 85%, up to 90%, up to 95%, or up to 100%. In yet other aspects of this embodiment, a therapeutically effective amount of a cancer therapeutic agent disclosed herein reduces or maintains a cancer cell population and / or tumor cell size by, for example, about 10% to about 100%, about 10% to about 90%, about 10% to about 80%, about 10% to about 70%, about 10% to about 60%, about 10% to about 50%, about 10% to about 40%, about 20% to about 100%, about 20% to about 90%, about 20% to about 80%, about 20% to about 20%, about 20% to about 60%, about 20% to about 50%, about 20% to about 40%, about 30% to about 100%, about 30% to about 90%, about 30% to about 80%, about 30% to about 70%, about 30% to about 60%, or about 30% to about 50%.

[0138] The pharmaceutical composition or cancer therapeutic agent is administered to an individual. The individual is typically a human, but may be an animal, including but not limited to, dogs, cats, birds, cattle, horses, sheep, goats, reptiles, and other animals, whether domesticated or not. Typically, any individual who is a candidate for treatment is a candidate with some form of cancer, whether the cancer is benign or malignant, whether tumor, solid or otherwise, whether the cancer cells are present in a tumor or some other form of cancer. The most common types of cancer include but are not limited to bladder cancer, breast cancer, colon and rectal cancer, endometrial cancer, kidney cancer, renal cancer, leukemia, lung cancer, melanoma, non-Hodgkin's lymphoma, pancreatic cancer, prostate cancer, stomach cancer, and thyroid cancer. Preoperative evaluation typically includes a routine medical history and physical examination, in addition to a thorough informed consent that discloses all the associated risks and benefits of the procedure.

[0139] In one aspect, the pharmaceutical compositions disclosed herein reduce symptoms of a cancer-related disorder (e.g., tumor size and / or number of tumor cells). In some aspects of this embodiment, the pharmaceutical compositions disclosed herein reduce symptoms of a cancer-related disorder, e.g., by at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, or at least 95%. In other aspects of this embodiment, any of the pharmaceutical compositions disclosed herein can be used to alleviate symptoms of a cancer-related disorder, for example, by about 10% to about 100%, about 20% to about 100%, about 30% to about 100%, about 40% to about 100%, about 50% to about 100%, about 60% to about 100%, about 70% to about 100%, about 80% to about 100%, about 10% to about 90%, about 20% to about 9 ... about 90%, about 40% to about 90%, about 50% to about 90%, about 60% to about 90%, about 70% to about 90%, about 10% to about 80%, about 20% to about 80%, about 30% to about 80%, about 40% to about 80%, about 50% to about 80%, about 60% to about 80%, about 10% to about 70%, about 20% to about 70%, about 30% to about 70%, about 40% to about 70%, or about 50% to about 70%.

[0140] In one embodiment, the pharmaceutical compositions disclosed herein reduce symptoms of a disorder associated with a disease (e.g., infection, Parkinson's disease (PD), gallstones, cholecystitis, or cholangitis). In some embodiments, the pharmaceutical compositions disclosed herein reduce symptoms of a disorder associated with a disease, e.g., by at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, or at least 95%. In other aspects of this embodiment, any of the pharmaceutical compositions disclosed herein can be used to alleviate symptoms of a disease-related disorder by, for example, about 10% to about 100%, about 20% to about 100%, about 30% to about 100%, about 40% to about 100%, about 50% to about 100%, about 60% to about 100%, about 70% to about 100%, about 80% to about 100%, about 10% to about 90%, about 20% to about 9 ...10% to about 100%, about 10% to about 100%, about 10% to about 100%, about 10% to about 100%, about 10% to about 100%, about 10% to about 100%, about 10% to about 100%, about 10% about 90%, about 40% to about 90%, about 50% to about 90%, about 60% to about 90%, about 70% to about 90%, about 10% to about 80%, about 20% to about 80%, about 30% to about 80%, about 40% to about 80%, about 50% to about 80%, about 60% to about 80%, about 10% to about 70%, about 20% to about 70%, about 30% to about 70%, about 40% to about 70%, or about 50% to about 70%.

[0141] In another aspect, the pharmaceutical compositions disclosed herein reduce the frequency of symptoms of a cancer-related disorder suffered over a period of time. In some aspects of this embodiment, the pharmaceutical compositions disclosed herein reduce the frequency of symptoms of a cancer-related disorder (e.g., tumor size, etc.) by, for example, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, or at least 95%. In other aspects of this embodiment, the pharmaceutical compositions disclosed herein may be used to reduce the frequency of symptoms of a cancer-related disorder suffered over a given period of time, for example, by about 10% to about 100%, about 20% to about 100%, about 30% to about 100%, about 40% to about 100%, about 50% to about 100%, about 60% to about 100%, about 70% to about 100%, about 80% to about 100%, about 10% to about 90%, about 20% to about 90%, or about 10% to about 10%. , about 30% to about 90%, about 40% to about 90%, about 50% to about 90%, about 60% to about 90%, about 70% to about 90%, about 10% to about 80%, about 20% to about 80%, about 30% to about 80%, about 40% to about 80%, about 50% to about 80%, about 60% to about 80%, about 10% to about 70%, about 20% to about 70%, about 30% to about 70%, about 40% to about 70%, or about 50% to about 70%.

[0142] In some embodiments, the prodrug is capable of crossing the blood-brain barrier, in some embodiments, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, or at least 95% of the prodrug crosses the blood-brain barrier.

[0143] In some embodiments, the prodrug increases the half-life of a small molecule active agent administered to a subject, hi some embodiments, the half-life is increased by at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, or at least 95% compared to the unconjugated active agent.

[0144] As mentioned above, other therapeutic agents can be used, if desired, in conjunction with those provided in the above compositions. The amount of active ingredient that can be combined with the carrier materials to produce a single dosage form will vary depending on the host being treated, the nature of the disease, disorder, or condition, and the nature of the active ingredient.

[0145] It is understood that the specific dosage level for a particular patient will vary depending on a variety of factors, such as the activity of the particular active agent, the age, weight, general health, sex, and diet of the patient, the time of administration, the route of administration, the rate of excretion, possible drug combinations, the severity of the particular condition being treated, etc. Those skilled in the art will recognize the variability of such factors and will be able to establish specific dosage levels using no more than routine experimentation.

[0146] Pharmacokinetic parameters, such as bioavailability, absorption rate, apparent volume of distribution, unbound fraction, total clearance, percent unchanged excretion, first-pass metabolism, elimination rate constant, half-life, and mean residence time, can be determined by methods well known in the art.

[0147] If desired, other therapeutic agents can be used in conjunction with those provided in the above compositions. The amount of active ingredient that can be combined with the carrier materials to produce a single dosage form will vary depending on the host being treated, the nature of the disease, disorder, or condition, and the nature of the active ingredient.

[0148] It is understood that the specific dosage level for a particular patient will vary depending on a variety of factors, such as the activity of the particular active agent, the age, weight, general health, sex, and diet of the patient, the time of administration, the route of administration, the rate of excretion, possible drug combinations, the severity of the particular condition being treated, etc. Those skilled in the art will recognize the variability of such factors and will be able to establish specific dosage levels using no more than routine experimentation.

[0149] Pharmacokinetic parameters, such as bioavailability, absorption rate, apparent volume of distribution, unbound fraction, total clearance, percent unchanged excretion, first-pass metabolism, elimination rate constant, half-life, and mean residence time, can be determined by methods well known in the art.

[0150] The dosage may be a single dose or a cumulative dose (sequential administration), which may be easily determined by one skilled in the art. The prodrug formulation of the present invention may be administered to a subject 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 or more times. For example, the treatment of a disease may include a one-time administration of an effective amount of the prodrug formulation disclosed herein. Alternatively, the treatment of a disease may include multiple administrations of an effective amount of the prodrug formulation administered over a range of periods, such as once a day, twice a day, three times a day, once every few days, or once a week. The timing of administration may vary from individual to individual, depending on factors such as the severity of the individual's symptoms. For example, an effective amount of the prodrug formulation disclosed herein may be administered to an individual once a day for an indeterminate period of time, or until the individual no longer requires treatment. One skilled in the art will recognize that an individual's condition can be monitored throughout the course of treatment, and the effective amount of the prodrug formulation disclosed herein administered can be adjusted accordingly. In one embodiment, the prodrug formulation disclosed herein can reduce the time to resolution of disease symptoms in an individual suffering from a disease, for example, by at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, or at least 95%, compared to a patient not receiving the same therapeutic agent.

[0151] The appropriate effective amount of the prodrug formulation disclosed herein to be administered to an individual can be determined by those skilled in the art by considering factors including, but not limited to, the individual's improvement based on one or more clinical symptoms, and / or physiological indicators related to the improvement of muscle movement, pain reduction and / or general health, the patient's specific characteristics, medical history and risk factors, such as age, weight, general health, etc., or any combination thereof. Furthermore, when using repeated administration of a prodrug delivery formulation, the effective amount of the prodrug delivery formulation further depends on factors including, but not limited to, administration frequency, the half-life of the prodrug delivery formulation, or any combination thereof. It is known to those skilled in the art that the effective amount of the prodrug delivery formulation disclosed herein can be estimated from in vitro assays and in vivo administration tests using animal models before administration to humans or animals.

[0152] Considering the different efficiencies of various administration routes, a wide variation in the required effective amount is expected. For example, oral administration of the prodrug formulations disclosed herein is expected to generally require a higher dosage level than administration by inhalation. Similarly, systemic administration of the prodrug formulations disclosed herein is expected to require a higher dosage level than local administration. These dosage level variations can be adjusted using standard empirical routines for optimization that are well known to those skilled in the art. The exact therapeutically effective dosage level and pattern are preferably determined by the attending physician, taking into account the factors identified above. Those skilled in the art will understand that the condition of an individual can be monitored throughout the course of treatment, and the effective amount of the therapeutic agent disclosed herein administered can be adjusted accordingly.

[0153] Some embodiments herein disclose, in part, the reduction or alleviation of symptoms of a disease, such as muscle spasms or pain, in an individual. As used herein, the term "treat" refers to the reduction of tumor size, number and / or area. For example, the term "treat" can mean reducing tumor size, for example, by at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90% at least 95%, or at least 100%. Those skilled in the art will know the appropriate symptoms or indicators associated with a disease, such as cancer, and know how to determine whether an individual is a candidate for the treatments disclosed herein. Working Example

[0154] The following non-limiting examples are provided for illustrative purposes only, to facilitate a more complete understanding of the representative embodiments currently contemplated.These examples are intended to be merely a subset of all possible situations in which the components of the formulation can be combined.Therefore, these examples should not be construed as limiting any of the embodiments described herein, including the types and amounts of the components of the formulation, and / or the embodiments related to the method and its use. Example 1 Conjugation of perillyl alcohol with cholecalciferol

[0155] In this example, perillyl alcohol (PA) is conjugated to cholecalciferol. Molecules can be conjugated via an ester bond using methods known in the art. Example 2 Conjugated perillyl alcohol for the treatment of glioblastoma

[0156] In this example, a patient is seeking treatment for glioblastoma. A medical professional suggests that the patient try perillyl alcohol (PA). PA is orally administered to the patient as a prodrug. Specifically, PA is conjugated to cholecalciferol.

[0157] Prodrug formulations exhibit several advantages, including increased stability, increased solubility and increased lipophilicity. The formulations also allow selective targeting to tumor cells and permeability across the blood-brain barrier.

[0158] Medical professionals monitor tumor size during the course of treatment. In this example, therapeutic amounts of the prodrug formulation are administered daily for six weeks. Example 3 Conjugation of perillyl alcohol to retinoic acid.

[0159] In this example, perillyl alcohol (PA) is conjugated to retinoic acid. Molecules can be conjugated via an ester bond using methods known in the art. Example 4 Conjugated perillyl alcohol for the treatment of glioblastoma

[0160] In this example, a patient is seeking treatment for glioblastoma. A medical professional suggests that the patient try perillyl alcohol (PA). PA is orally administered to the patient as a prodrug. Specifically, PA is conjugated to retinoic acid.

[0161] Prodrug formulations exhibit several advantages, including increased stability, increased solubility and increased lipophilicity. The formulations also allow selective targeting to tumor cells and permeability across the blood-brain barrier.

[0162] Medical professionals monitor tumor size during the course of treatment. In this example, therapeutic amounts of the prodrug formulation are administered daily for six weeks.

[0163] In one embodiment, the dose of the composition can be administered daily, twice weekly, every other week, or monthly. The treatment period can be one week, two weeks, one month, two months, four months, six months, eight months, one year, or more. The initial dose can be higher than the maintenance dose. In one embodiment, the dose is at least 0.01 mg / kg, at least 0.25 mg / kg, at least 0.3 mg / kg, at least 0.5 mg / kg, at least 0.75 mg / kg, at least 1 mg / kg, at least 2 mg / kg, at least 3 mg / kg, at least 4 mg / kg, at least 5 mg / kg, at least 6 mg / kg, at least 7 mg / kg, at least 8 mg / kg, at least 9 mg / kg, at least 10 mg / kg, at least 15 mg / kg, at least 20 mg / kg, at least 25 mg / kg, or at least 30 mg / kg administered weekly. In one embodiment, the weekly dose can be up to 1.5 mg / kg, up to 2 mg / kg, up to 2.5 mg / kg, up to 3 mg / kg, up to 4 mg / kg, up to 5 mg / kg, up to 6 mg / kg, up to 7 mg / kg, up to 8 mg / kg, up to 9 mg / kg, up to 10 mg / kg, up to 15 mg / kg, up to 20 mg / kg, up to 25 mg / kg, or up to 30 mg / kg. In certain aspects, the weekly dose can range from 5 mg / kg to 20 mg / kg. In alternative aspects, the weekly dose can range from 10 mg / kg to 15 mg / kg.

[0164] This specification also provides pharmaceutical compositions for administering to subjects.The pharmaceutical compositions disclosed herein can further comprise pharmaceutically acceptable carriers, excipients or diluents.As used herein, the term "pharmaceutically acceptable" means that the composition is sufficient to achieve therapeutic effect without harmful side effects, and can be easily determined according to the type of disease, the age, weight, health condition, sex and drug sensitivity of the patient, the route of administration, the mode of administration, the frequency of administration, the duration of treatment, the drugs used in combination or simultaneously with the compositions disclosed herein, and other factors known in medicine.

[0165] The pharmaceutical composition comprising the prodrug disclosed herein may further comprise a pharmaceutically acceptable carrier.For oral administration, the carrier may comprise, but is not limited to, a binder, a lubricant, a disintegrant, an excipient, a solubilizer, a dispersant, a stabilizer, a suspending agent, a coloring agent, and / or a flavoring agent.For injectable preparations, the carrier may comprise a buffer, a preservative, an analgesic, a solubilizer, an isotonic agent, and a stabilizer.For topical administration preparations, the carrier may comprise a base, an excipient, a lubricant, and a preservative.

[0166] The composition of the present disclosure can be combined with the above-mentioned pharmaceutically acceptable carrier and formulated into various dosage forms.For example, for oral administration, pharmaceutical composition can be formulated into tablets, troches, capsules, elixirs, suspensions, syrups or wafers.For injectable formulations, pharmaceutical composition can be formulated into ampoules or into multi-dose containers as single dosage forms.Pharmaceutical composition can also be formulated into solutions, suspensions, tablets, pills, capsules and long-acting formulations.

[0167] On the other hand, examples of suitable carriers, excipients and diluents for pharmaceutical preparations include, but are not limited to, lactose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, gum arabic, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methylcellulose, microcrystalline cellulose, polyvinylpyrrolidone, water, methylhydroxybenzoic acid, propylhydroxybenzoic acid, talc, magnesium stearate and mineral oil.In addition, pharmaceutical preparations may further include fillers, anticoagulants, lubricants, humectants, flavorings and preservatives.

[0168] Furthermore, the pharmaceutical compositions disclosed herein may have any formulation selected from the group consisting of tablets, pills, powders, granules, capsules, suspensions, oral liquids, emulsions, syrups, sterile aqueous solutions, non-aqueous solvents, lyophilized formulations, and suppositories.

[0169] The compositions are formulated into a unitary dosage form suitable for the patient's body, preferably formulated into preparations useful for peptide drugs by methods typical in the pharmaceutical art to be administered by oral or parenteral routes, including, but not limited to, via dermal, intravenous, intramuscular, intraarterial, intramedullary, intraspinal, intraventricular, pulmonary, inhalation, transdermal, subcutaneous, intraperitoneal, intranasal, intracolonic, topical, sublingual, vaginal, or rectal administration.

[0170] The composition can be used by mixing with various pharma- ceutically acceptable carriers, such as physiological saline or organic solvents.To increase stability or absorptivity, carbohydrates such as glucose, sucrose, or dextran, antioxidants such as ascorbic acid or glutathione, chelating agents, low molecular weight proteins, or other stabilizers can be used.

[0171] The dosage and frequency of administration of the pharmaceutical compositions disclosed herein will be determined by the type of active ingredient, along with various factors such as the disease being treated, the route of administration, the age, sex, and weight of the patient, and the severity of the disease.

[0172] The total effective dose of the compositions disclosed herein may be administered to the patient in a single dose or may be administered over an extended period of time in multiple doses according to a split treatment protocol. In the pharmaceutical compositions disclosed herein, the content of the active ingredient may vary depending on the severity of the disease. Preferably, the total daily dose of the peptides disclosed herein may be about 0.0001 μg to about 500 mg / (1 kg of patient body weight). However, the effective dose of the peptide is determined by taking into consideration various factors including the age, body weight, health condition, sex, disease severity, diet, and secretion rate of the patient, in addition to the administration route and treatment frequency of the pharmaceutical composition. Taking this into consideration, a person skilled in the art can easily determine an effective dose suitable for a particular use of the pharmaceutical compositions disclosed herein. The pharmaceutical compositions disclosed herein are not particularly limited in formulation, and in route and mode of administration, as long as they show a suitable effect.

[0173] In addition, the pharmaceutical compositions may be administered alone or in combination or concurrently with other pharmaceutical agents that exhibit prophylactic or therapeutic efficacy.

[0174] In yet another aspect, the present specification provides a method for preventing or treating cancer, an infectious disease, or a neurodegenerative disease, the method comprising the step of administering the chimeric protein or a pharmaceutical composition comprising the same to a subject.

[0175] Given the teachings and guidance provided herein, one of skill in the art will understand that the formulations described herein may be equally applicable to many types of biopharmaceuticals, including those exemplified, as well as others known in the art. Given the teachings and guidance provided herein, one of skill in the art will also understand that, for example, the selection of the type and / or amount of one or more excipients, surfactants, and / or optional ingredients may be based on chemical and functional compatibility with the formulated biopharmaceutical and / or method of administration, as well as other chemical, functional, physiological, and / or medical factors known in the art. For example, non-reducing sugars exhibit favorable excipient properties compared to reducing sugars when used with polypeptide biopharmaceuticals. Thus, exemplary formulations are further exemplified herein in the context of polypeptide biopharmaceuticals. However, the scope of applicability, chemical and physical properties, considerations, and methodologies applied to polypeptide biopharmaceuticals may be applied to biopharmaceuticals other than polypeptide biopharmaceuticals as well.

[0176] In various embodiments, the formulations may include, but are not limited to, a combination of bioactive agents (e.g., viruses, proteins, antibodies, peptides, etc., as described herein) in the formulation. For example, the formulations described herein may include a single bioactive agent to treat one or more conditions, including, but not limited to, a disease. The formulations disclosed herein may also include, in one embodiment, two or more different bioactive agents for single or multiple conditions, including, but not limited to, two or more different bioactive agents. The use of multiple bioactive agents in the formulation may, for example, be directed to the same or different indications. Similarly, in another embodiment, multiple bioactive agents in the formulation may be used, for example, to treat both a pathology and one or more side effects caused by a primary treatment. In further embodiments, multiple bioactive agents may also be included in the formulations described herein to achieve different medical purposes, including, but not limited to, simultaneous treatment and monitoring the progression of a pathology. In additional embodiments, multiple, combination therapies, such as those exemplified herein, as well as other combinations known in the art, are particularly useful for patient compliance, since a single composition may be sufficient for some or all of the suggested treatments and / or diagnoses. Those skilled in the art will be aware of the bioactive agents that can be mixed for a wide range of combination therapy.Similarly, in various embodiments, formulations can be used with small molecules and with one or more small molecule pharmaceuticals and with the combination of one or more bioactive agents.Thus, in various embodiments, formulations are provided that include 1, 2, 3, 4, 5, or 6 or more different bioactive agents, as well as one or more bioactive agents combined with one or more small molecule pharmaceuticals.

[0177] In various embodiments, the formulation may include one or more preservatives and / or additives known in the art. Similarly, the formulation may be further formulated into various known delivery formulations, including, but not limited to, in one embodiment. For example, in one embodiment, the formulation may include surfactants, adjuvants, biodegradable polymers, hydrogels, and the like, and such optional components, their chemical and functional properties are known in the art. Similarly, formulations that promote rapid, sustained or delayed release of bioactive agents after administration are also known in the art. The formulations described may be produced to include these or other formulation components known in the art.

[0178] The composition may therefore be administered as a single dose or as two or more doses (which may or may not contain the same amount of the desired molecule), over time, as a supplement or continuous infusion, via an implanted device or catheter. Further refinement of the appropriate dosage is routinely performed by those skilled in the art and is within the scope of routinely performed work by those skilled in the art. The appropriate dosage may be confirmed by the use of appropriate dose-response data. In various embodiments, the bioactive agent in the formulation described herein may be administered to a patient for an extended period of time, for example, but not limited to, chronic administration for chronic conditions. The composition may be a solid, semi-solid or aerosol, and the pharmaceutical composition is formulated as a tablet, gel tab, lozenge, orally dissolving strip, capsule, syrup, oral suspension, emulsion, granule, sprinkle or pellet.

[0179] In one embodiment, for oral, rectal, vaginal, parenteral, pulmonary, sublingual, and / or intranasal delivery formulations, tablets can be made by compression or molding, optionally with one or more auxiliary ingredients or additives.In some embodiments, compressed tablets are prepared, for example, by compressing the active ingredient in a free-flowing form, such as powder or granules, in a suitable tablet press, optionally mixed with a binder (e.g., but not limited to, povidone, gelatin, hydroxypropylmethylcellulose), a lubricant, an inert diluent, a preservative, a disintegrant (e.g., but not limited to, sodium starch glycolate, cross-linked povidone, cross-linked sodium carboxymethylcellulose), and / or a surfactant or dispersant.

[0180] In one embodiment, molded tablets are prepared by molding a mixture of powdered compounds moistened with an inert liquid diluent, for example, but not limited to, in a suitable tablet press. In some embodiments, the tablets may be optionally coated or scored, and may be formulated to provide delayed and controlled release of the active ingredient, for example, but not limited to, using various ratios of hydroxypropylmethylcellulose to provide a desired release profile. In some embodiments, the tablets may be optionally provided with a coating, for example, but not limited to, a thin film, sugar coating, or enteric coating, to provide release in parts of the intestine other than the stomach. In some embodiments, the processes, equipment, and contract manufacturers for tablet and capsule manufacturing are well known in the art.

[0181] In one embodiment, the capsule formulation can utilize either hard or soft capsules, including, but not limited to, gelatin capsules or vegetable capsules, such as those made from hydroxymethylpropylcellulose (HMPC). In some embodiments, the type of capsule is a gelatin capsule. In some embodiments, the capsule can be filled using a capsule filler, such as, but not limited to, those available from Miranda International, or from a supplier employing capsule manufacturing techniques well known in the industry, such as those described in detail in Pharmaceutical Capules, 2.sup.nd Ed., F.Podczeck and B.Jones, 2004. In some embodiments, the capsule formulation can be made using a contract manufacturing facility, such as, but not limited to, the Chao Center for Industrial Pharmacy & Contract Manufacturing, located at Purdue Research Park.

[0182] Packaging and administration devices may be determined by a variety of considerations, including, but not limited to, the volume of material to be administered, storage conditions, whether administration is by a skilled health practitioner or self-administration by the patient, the administration schedule, the geopolitical environment (e.g., exposure to extreme temperature conditions in the case of developing countries), and other practical considerations.

[0183] Also described herein is a method of treating a subject in need thereof, comprising administering to the subject an effective amount of a formulation disclosed herein. The therapeutically effective amount or dose of the formulation depends on the disease or condition of the subject and the actual clinical setting.

[0184] The formulations described herein can be used for the manufacture of medicaments and can be used for the treatment of humans and other animals by administration in accordance with conventional procedures.

[0185] Also provided herein are combinatorial approaches to develop suitable virus formulations using combinations of amino acids. These methods are useful for developing stable liquid or lyophilized formulations, and in particular, pharmaceutical virus formulations.

[0186] Compositions according to embodiments described herein have desired properties, such as desired solubility, viscosity, syringeability and stability. Lyophilizates according to embodiments described herein also have desired properties, such as desired recovery, stability and reconstitution.

[0187] In some embodiments, the pH of the pharmaceutical formulation is at least about 3.5, 3.75, 4, 4.25, 4.5, 4.75, 5, 5.25, 5.5, 5.75, 6, 6.25, 6.5, 6.75, 7, 7.25, 7.5, 7.75, 8, 8.25, 8.5, 8.75, or 9.

[0188] In one embodiment, the pH of the pharmaceutical formulation is about 3 to about 9, about 4 to about 9, about 5 to about 9, about 6 to about 8, about 6 to about 7, about 6 to about 9, about 5 to about 6, about 5 to about 7, about 5 to about 8, about 4 to about 9, about 4 to about 8, about 4 to about 7, about 4 to about 6, about 4 to about 5, about 3 to about 8, about 3 to about 7, about 3 to about 6, about 3 to about 5, about 3 to about 4, about 7 to about 8, about 7 to about 9, or about 7 to about 10.

[0189] Certain embodiments of the present invention are described herein, including the best mode for carrying out the invention known to the inventors. Of course, variations on the embodiments described herein will become apparent to those skilled in the art upon reading the foregoing description. The inventors anticipate that those skilled in the art will adopt such modifications as necessary, and the inventors intend for the invention to be practiced in ways other than those specifically described herein. Accordingly, the present invention includes all modifications and equivalents of the subject matter recited in the claims appended hereto as permitted by applicable law. Moreover, any combination of the above-described embodiments in all possible variations thereof is encompassed in this application unless otherwise indicated herein or otherwise clearly contradicted by the context.

[0190] Grouping of alternative embodiments, elements, or steps of the invention should not be construed as limiting the invention. Each group member may be referenced and claimed individually or in any combination with other group members disclosed herein. It is anticipated that one or more members of a group may be included in or deleted from a group for reasons of convenience and / or patentability. When any such inclusion or deletion occurs, the specification shall be deemed to be amended to include groups that meet the recitation requirements of all Markush groups used in the appended claims.

[0191] Unless otherwise indicated, all numbers expressing properties, items, amounts, parameters, properties, periods, etc. used in the specification and claims should be understood in all instances as being modified by the word "about". As used herein, the term "about" means that such suitable properties, items, amounts, parameters, properties, periods encompass a range of plus or minus 10% higher or lower than the value of the indicated property, item, amount, parameter, property, period. Thus, unless otherwise indicated, the numerical parameters set forth in the specification and the appended claims are approximations that may vary. To be conservative, and without attempting to limit the application of the doctrine of equivalents to the scope of the claims, each numerical indication should be construed, at the very least, in light of the number of reported significant digits and by applying ordinary rounding techniques. Notwithstanding that the numerical ranges and values ​​setting forth the broad scope of the invention are approximations, the numerical ranges and values ​​set forth in the specific examples are reported as precisely as possible. However, any numerical range and value inherently contains certain errors necessarily resulting from the standard deviation found in their respective testing measurements. The recitation of ranges of values ​​herein is merely intended to serve as a shorthand method of referring individually to each separate value falling within the range, and unless otherwise stated herein, each separate value of a numerical range is incorporated into the specification as if it were individually set forth herein.

[0192] Specific embodiments disclosed herein may be further limited in the claims using the words "consisting of" or "consisting essentially of." The transitional term "consisting of," when used in a claim, excludes any element, step, or ingredient not expressly stated in the claim, whether as filed or added by amendment. The transitional term "consisting essentially of" limits the claim to those materials or steps expressly stated and those materials or steps that do not materially affect the underlying novel characteristics. Embodiments of the invention so claimed are essentially or explicitly described and enabled herein.

[0193] Grouping of alternative embodiments, elements, or steps of the invention should not be construed as limiting the invention. Each group member may be referenced and claimed individually or in any combination with other group members disclosed herein. It is anticipated that one or more members of a group may be included in or deleted from a group for reasons of convenience and / or patentability. When any such inclusion or deletion occurs, the specification shall be deemed to be amended to include groups that meet the recitation requirements of all Markush groups used in the appended claims.

[0194] All patents, patent publications, and other publications mentioned or identified herein are individually and expressly incorporated herein by reference in their entirety, for example to describe and disclose the compositions and methods described in such publications and that can be used in connection with the present invention. These publications are provided solely for their disclosure prior to the filing date of this application. Nothing in this regard should be construed as an admission that the inventors are not entitled to antedate such disclosure by virtue of prior invention or for any other reason. Any dates or representations as to the contents of these documents are based on the information available to the applicants and do not constitute any admission as to the accuracy of the dates or contents of these documents.

[0195] Finally, although aspects of the present specification are emphasized by reference to specific embodiments, it should be understood that those skilled in the art will readily recognize that these disclosed embodiments are merely illustrative of the principles of the subject matter disclosed herein. Therefore, it should be understood that the disclosed subject matter is in no way limited to the specific methods, protocols, and / or reagents, etc. described herein. Thus, various modifications or alterations to the disclosed subject matter or alternative configurations of the disclosed subject matter can be made in accordance with the teachings of the present specification without departing from the spirit of the present specification. Finally, the terms used in the present specification are for the purpose of describing only specific embodiments and are not intended to limit the scope of the present invention. The scope of the present invention is defined only by the claims. Therefore, the present invention is not limited to the exact forms shown and described.

Claims

1. A prodrug consisting of perillyl alcohol and cholecalciferol, a pharma- ceutically acceptable salt, solvate, tautomer, isomer or deuterated analog thereof.

2. 13. A method for treating a disease comprising administering to a subject a therapeutic amount of the prodrug of claim 1.

3. The method of claim 2, wherein the disease is cancer or Parkinson's disease.

4. 4. The method of claim 3, wherein the cancer is astrocytoma, lung cancer, non-small cell lung cancer, mesothelioma, brain cancer, glioblastoma, skin cancer, or melanoma.

5. A prodrug consisting of perillic acid and cholecalciferol, a pharma- ceutically acceptable salt, solvate, tautomer, isomer or deuterated analogue thereof.

6. 6. A method of treating a disease comprising administering to a subject a therapeutic amount of the prodrug of claim 5.

7. The method of claim 6, wherein the disease is cancer or Parkinson's disease.

8. 8. The method of claim 7, wherein the cancer is astrocytoma, lung cancer, non-small cell lung cancer, mesothelioma, brain cancer, glioblastoma, skin cancer, or melanoma.

9. A prodrug consisting of limonene and cholecalciferol, a pharma- ceutically acceptable salt, solvate, tautomer, isomer or deuterated analogue thereof.

10. 10. A method of treating a disease comprising administering to a subject a therapeutic amount of the prodrug of claim 9.

11. The method of claim 10, wherein the disease is cancer or Parkinson's disease.

12. 12. The method of claim 11, wherein the cancer is astrocytoma, lung cancer, non-small cell lung cancer, mesothelioma, brain cancer, glioblastoma, skin cancer, or melanoma.

13. Prodrugs consisting of limonene, perillyl alcohol, perillic acid and cholecalciferol, pharma- ceutically acceptable salts, solvates, tautomers, isomers or deuterated analogs thereof.

14. 14. A method of treating a disease comprising administering to a subject a therapeutic amount of the prodrug of claim 13.

15. 15. The method of claim 14, wherein the disease is cancer or Parkinson's disease.

16. 16. The method of claim 15, wherein the cancer is astrocytoma, lung cancer, non-small cell lung cancer, mesothelioma, brain cancer, glioblastoma, skin cancer, or melanoma.

17. Prodrugs consisting of perillyl alcohol, limonene and cholecalciferol, pharma- ceutically acceptable salts, solvates, tautomers, isomers or deuterated analogs thereof.

18. 20. A method of treating a disease comprising administering to a subject a therapeutic amount of the prodrug of claim 17.

19. 19. The method of claim 18, wherein the disease is cancer or Parkinson's disease.

20. 20. The method of claim 19, wherein the cancer is astrocytoma, lung cancer, non-small cell lung cancer, mesothelioma, brain cancer, glioblastoma, skin cancer, or melanoma.

21. Prodrugs consisting of perillyl alcohol, cholecalciferol and retinoic acid, pharma- ceutically acceptable salts, solvates, tautomers, isomers or deuterated analogs thereof.

22. 22. A method of treating a disease comprising administering to a subject a therapeutic amount of the prodrug of claim 21.

23. 23. The method of claim 22, wherein the disease is cancer or Parkinson's disease.

24. 24. The method of claim 23, wherein the cancer is astrocytoma, lung cancer, non-small cell lung cancer, mesothelioma, brain cancer, glioblastoma, skin cancer, or melanoma.

25. A prodrug consisting of perillyl alcohol and retinoic acid, a pharma- ceutically acceptable salt, solvate, tautomer, isomer or deuterated analog thereof.

26. 26. A method of treating a disease comprising administering to a subject a therapeutic amount of the prodrug of claim 25.

27. 27. The method of claim 26, wherein the disease is cancer or Parkinson's disease.

28. 28. The method of claim 27, wherein the cancer is astrocytoma, lung cancer, non-small cell lung cancer, mesothelioma, brain cancer, glioblastoma, skin cancer, or melanoma.

29. Prodrugs consisting of perillic acid and retinoic acid, pharma- ceutically acceptable salts, solvates, tautomers, isomers or deuterated analogs thereof.

30. 30. A method of treating a disease comprising administering to a subject a therapeutic amount of the prodrug of claim 29.

31. 31. The method of claim 30, wherein the disease is cancer or Parkinson's disease.

32. 32. The method of claim 31, wherein the cancer is astrocytoma, lung cancer, non-small cell lung cancer, mesothelioma, brain cancer, glioblastoma, skin cancer, or melanoma.

33. A prodrug consisting of limonene and retinoic acid, a pharma- ceutically acceptable salt, solvate, tautomer, isomer or deuterated analog thereof.

34. 34. A method of treating a disease comprising administering to a subject a therapeutic amount of the prodrug of claim 33.

35. 35. The method of claim 34, wherein the disease is cancer or Parkinson's disease.

36. 36. The method of claim 35, wherein the cancer is astrocytoma, lung cancer, non-small cell lung cancer, mesothelioma, brain cancer, glioblastoma, skin cancer, or melanoma.

37. Prodrugs consisting of limonene, perillyl alcohol, perillic acid and retinoic acid, pharma- ceutically acceptable salts, solvates, tautomers, isomers or deuterated analogs thereof.

38. 40. A method of treating a disease comprising administering to a subject a therapeutic amount of the prodrug of claim 37.

39. 39. The method of claim 38, wherein the disease is cancer or Parkinson's disease.

40. 40. The method of claim 39, wherein the cancer is astrocytoma, lung cancer, non-small cell lung cancer, mesothelioma, brain cancer, glioblastoma, skin cancer, or melanoma.

41. A prodrug consisting of perillyl alcohol, limonene and retinoic acid, a pharma- ceutically acceptable salt, solvate, tautomer, isomer or deuterated analog thereof.

42. 42. A method of treating a disease comprising administering to a subject a therapeutic amount of the prodrug of claim 41.

43. 43. The method of claim 42, wherein the disease is cancer or Parkinson's disease.

44. 44. The method of claim 43, wherein the cancer is astrocytoma, lung cancer, non-small cell lung cancer, mesothelioma, brain cancer, glioblastoma, skin cancer, or melanoma.

45. A prodrug consisting of perillyl carbonate, a pharma- ceutically acceptable salt, solvate, tautomer, isomer or deuterated analog thereof.

46. 46. ​​A method of treating a disease comprising administering to a subject a therapeutic amount of the prodrug of claim 45.

47. 47. The method of claim 46, wherein the disease is cancer or Parkinson's disease.

48. 48. The method of claim 47, wherein the cancer is astrocytoma, lung cancer, non-small cell lung cancer, mesothelioma, brain cancer, glioblastoma, skin cancer, or melanoma.

49. A prodrug consisting of perillyl N-methylamide, a pharma- ceutically acceptable salt, solvate, tautomer, isomer or deuterated analog thereof.

50. 50. A method of treating a disease comprising administering to a subject a therapeutic amount of the prodrug of claim 49.

51. 51. The method of claim 50, wherein the disease is cancer or Parkinson's disease.

52. 52. The method of claim 51, wherein the cancer is astrocytoma, lung cancer, non-small cell lung cancer, mesothelioma, brain cancer, glioblastoma, skin cancer, or melanoma.

53. A prodrug consisting of valproic acid, a pharma- ceutically acceptable salt, solvate, tautomer, isomer or deuterated analogue thereof.

54. 54. A method of treating a disease comprising administering to a subject a therapeutic amount of the prodrug of claim 53.

55. 55. The method of claim 54, wherein the disease is cancer or Parkinson's disease.

56. 56. The method of claim 55, wherein the cancer is astrocytoma, lung cancer, non-small cell lung cancer, mesothelioma, brain cancer, glioblastoma, skin cancer, or melanoma.

57. 1. A method of treating cancer in a subject, comprising administering a compound consisting of an active agent and a prodrug moiety, wherein the active agent is a cyclic monoterpene.

58. 58. The method of claim 57, wherein the cyclic monoterpene is perillyl alcohol, limonene, perillic acid, perillyl alcohol acetate, perillic acid methyl ester, perillyl alcohol isobutyrate, perillic acid ethyl ester, perillyl alcohol pivaloate, perillic acid isopropyl ester, perillyl perrylate, or perillyl carbonate.

59. 58. The method of claim 57, wherein the prodrug moiety is cholecalciferol / vitamin D, retinoic acid, N-methylperillic acid, tyrosine, or valproic acid.

60. 58. The method of claim 57, wherein the cancer is astrocytoma, lung cancer, non-small cell lung cancer, mesothelioma, brain cancer, glioblastoma, skin cancer, or melanoma.

61. 58. The method of claim 57, further comprising a second cancer therapy, wherein the second cancer therapy is selected from chemotherapy, radiation therapy, immunotherapy, surgery, and hormonal therapy.

62. A method for treating Parkinson's disease in a subject, comprising administering a compound consisting of an active agent and a prodrug moiety, wherein the active agent is a cyclic monoterpene.

63. 63. The method of claim 62, wherein the cyclic monoterpene is perillyl alcohol, limonene, perillic acid, perillyl alcohol acetate, perillic acid methyl ester, perillyl alcohol isobutyrate, perillic acid ethyl ester, perillyl alcohol pivaloate, perillic acid isopropyl ester, perillyl perrylate or perillyl carbonate.

64. 63. The method of claim 62, wherein the prodrug moiety is cholecalciferol / vitamin D, retinoic acid, N-methylperillic acid, tyrosine, or valproic acid.

65. 1. A method of treating a condition in a subject, comprising administering a compound consisting of an active agent and a prodrug moiety, wherein the active agent is a cyclic monoterpene, and the condition is one or more of an infection, gallstones, cholecystitis, gastroesophageal reflux disease (GERD), and cholangitis.

66. 66. The method of claim 65, wherein the cyclic monoterpene is perillyl alcohol, limonene, perillic acid, perillyl alcohol acetate, perillic acid methyl ester, perillyl alcohol isobutyrate, perillic acid ethyl ester, perillyl alcohol pivaloate, perillic acid isopropyl ester, perillyl perillate, or perillyl carbonate.

67. 66. The method of claim 65, wherein the prodrug moiety is cholecalciferol / vitamin D, retinoic acid, N-methylperillic acid, tyrosine, or valproic acid.

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