Methods to make the blood-brain barrier permeable

Abstract

This invention provides a method for administering a therapeutic agent to the central nervous system of a mammal. [Solution] A method for administering a therapeutic agent to the central nervous system of a mammal, comprising administering a monoterpene before or simultaneously with the therapeutic agent.

Description

[Technical Field]

[0001] This invention uses monoterpenes or sesquiterpenes to make the blood-brain barrier permeable. Regarding what to do. [Background technology]

[0002] The blood-brain barrier (BBB) ​​is the barrier between blood, interstitial fluid (IF), and cerebrospinal fluid (CSF) of the brain. It is a continuous boundary. The blood-brain barrier (BBB) ​​is a layer of endothelial cells, which are the endothelium of brain capillaries. It is composed of these components and is effective against the intrusion of high and low molecular weight serum components into brain tissue. It acts as a barrier. Limiting the entry of such substances into the brain and CSF is the brain hair This is due to the unique structure of the endothelium of the vascular tissue. In other organs, the cells of the endothelial layer are interwoven with gaps that penetrate the layer. They have piping and channels between them, but the anatomical tight junctions between their cells Brain hairs are unique in terms of their characteristics and the rarity of their endothelial cells, which are often found in other endotheliums. Such channels do not exist in the endothelium of vascular microclavia.

[0003] In a normal (healthy) state, only substances that can cross the blood-brain barrier (BBB) ​​can enter the brain. Such substances tend to be relatively hydrophobic (lipid-like). Hydrophilic (water-soluble) The substance has little to no effect on permeating the blood-brain barrier (BBB). Substances with low permeability include molecules as large as albumin, as well as sodium. The entire range of molecules, including even the smallest ions, as well as chemotherapeutic agents, drugs, and diagnostic imaging compounds. This includes proteins with potential therapeutic applications. Some therapeutic agents permeate the blood-brain barrier. It has a sufficient degree of lipid solubility, but most drugs (e.g., penicillin) and others Because therapeutically useful substances have limited lipid solubility, they cannot adequately penetrate the blood-brain barrier (BBB). It is not possible. This low permeability of the BBB by many potentially useful drugs is due to the brain tissue and C This imposes strict limitations on the treatment of SF disorders. Therefore, it "opens" the BBB and treats brain damage. Although it is known to be effective in diagnosis, it cannot cross the blood-brain barrier on its own. Develop products and methods that enable access to brain tissue and CSF using drugs that cannot be used otherwise. Doing so is of clinical importance.

[0004] Malignant gliomas, the most common form of central nervous system (CNS) cancer, are now essentially ineffective. It is considered curable. Among the various malignant gliomas, malignant astrocytoma (Grade II) I) and glioblastoma multiforme (GBM, grade IV) are characterized by their invasive growth, and The prognosis is particularly poor due to resistance to currently available treatments. Current status of malignant gliomas The standard treatment consists of surgery, ionizing radiation, and chemotherapy. Despite recent advances in medicine... However, no significant improvement in the prognosis of malignant gliomas has been observed over the past 50 years. (Wen et al.) al.Malignant gliomas in adults. New trailer and J Med. 359:492-507,2008.Stupp et al.R adiotherapy plus concomitant and adjuvan t temozolomide for glioblastoma. New trailer and J Med. 352:987-996, 2005. The main reason for the poor prognosis of malignant gliomas is the difficulty in delivering sufficient amounts of chemotherapy drugs to the brain. The difficulty lies in the fact that drug access to the brain is restricted by the blood-brain barrier (BBB). The final drug concentration is further reduced by first-pass metabolism in the liver and urinary excretion. Therefore, for tumor resection, stereotactic infusion of antitumor drugs, or convection-enhanced delivery of drugs In many cases, invasive procedures such as catheter placement are required.

[0005] Intranasal drug delivery bypasses the blood-brain barrier, enabling rapid and direct delivery of drugs to the central nervous system (CNS). It provides a standard non-invasive treatment. The drug administered intranasally reaches the brain parenchymal tissue, spinal cord and / or It reaches the cerebrospinal fluid (CSF) within minutes. In addition to delivery via the olfactory tract and trigeminal nerve. Animal studies have shown that therapeutic drugs are delivered systemically via the nasal vascular system. hizume et al.New therapeutic approach fo r brain tumors: intranasal delivery of te Lomerase inhibitor GRN163 Neuro-oncology 10:112-120,2008.Thorne et al.Delivery o f insulin-like growth factor-1 to the ra t brain and spinal cord along olfactory and trigeminal pathways following intra Asal administration. Neuroscience 127:481 -496, 2004. Intranasal delivery of therapeutic agents is used, for example, in lung cancer, prostate cancer (prostat e cancer), breast cancer, hematopoietic cancer and ovarian cancer (o It provides systemic methods for treating other types of cancer, such as varian cancer. It is possible.

[0006] Despite decades of attempts, curative immunotherapy for cancer remains extremely difficult to achieve because its basic principle lies in the antigen recognition ability mediated by either antibodies or T cells (via T cell receptors) (Cousin-Frankel, Science (2013 ) 342:1432). Antibody-based immunotherapy is widely used for cancer when target antigens are upregulated in tumor cells compared to normal cells (e.g., Her-2 in Her-2 amplified breast cancer), or when tumor cells express antigens that can be recognized by antibodies or antibody-toxin conjugates (e.g., rituximab against CD20) (Base lga et al., Annals Oncology (2001) 12:S35). Clinical trials using antibody-based immunotherapy have shown improved survival rates in a limited number of cancer types (usually when combined with standard chemotherapy), but these effects often come with significant concerns regarding safety and efficacy (Cousin-Frankel Cancer, Science (2013) 342:1432). Effective T cell therapy for cancer is even more difficult to achieve clinically (Schm itt et al., Hum. Gene Ther. (2009) 20(11):12 40). Effective T cell therapy for cancer depends on T cells that bind to antigens on cancer cells with high affinity. Chimeric antigen receptor T cells (CAR T cells) are widely used to recognize cell surface antigens with both high affinity and specificity without the need for auxiliary recognition molecules such as HLA antigens that "present" peptides

[0007] Because receptors are "exchanged" with antigen-binding heavy and light chains, HLA co-molecule is essential. The need disappears. Recombinant CAR T receptors fuse with the signaling domain and bind to the target antigen. When combined, they activate T cells.

[0008] Periryl alcohol (POH), a natural monoterpene, is known to be associated with CNS cancer and breast cancer (bre). Effective against various cancers, including AST cancer, pancreatic cancer, lung cancer, melanoma, and colon cancer. It is suggested to be a suitable drug. Gould, M. Cancer chemopr event and therapy by monoterpenes.Env iron Health Perspect.1997,105(Suppl 4):9 77-979. Hybrid molecules containing both periryl alcohol and retinoids, Prepared to enhance apoptosis-inducing activity. Das et al. Design and synthesis of potential new apoptosis agents:hybrid compounds containing peri llyl alcohol and new constrained retinoi ds.Tetrahedron Letters 2010,51,1462-1466 . Cancers such as malignant gliomas, as well as other brain diseases such as Parkinson's disease and Alzheimer's disease. In the treatment of disorders, it is still necessary to make the blood-brain barrier permeable in order to deliver various therapeutic agents. It exists as such. [Prior art documents] [Non-patent literature]

[0009] [Non-Patent Document 1] Wen et al.Malignant gliomas in adults.New England J Med.359:492-507,2008 [Non-licensed document 2] Stupp et al. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. New England J Med. 352:987-996, 2005 [Non-licensed document 3] Hashizume et al. New therapeutic approach for brain tumors: intranasal delivery of telomerase inhibitor GRN163. Neuro-oncology 10:112-120, 2008

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[0010] The present invention provides a method for administering a therapeutic agent to the central nervous system of a mammal (e.g., a human). The method includes administering a monoterpene before, after, or simultaneously with the therapeutic agent.

[0011] The central nervous system can be the brain.

[0012] The monoterpene can be periryl alcohol.

[0013] Monoterpenes (e.g., periryl alcohol) can be administered intra-arterially (e.g., by injection into an artery). It may be administered into the vascular system of mammals. Monoterpenes (e.g., periryl alcohol) It is administered by inhalation, intranasal administration, oral administration, or intravenous administration. It may be administered via injection, subcutaneously, or intramuscularly.

[0014] Monoterpenes (e.g., periryl alcohol) are present in doses of approximately 0.050 mg / kg body weight to approximately 5 It may be administered in doses within the range of 00 mg / kg body weight.

[0015] Monoterpenes (e.g., periryl alcohol) are released approximately 0.2 minutes after the therapeutic agent is administered. It may be administered 60 minutes prior, or approximately 1 to 15 minutes prior.

[0016] Monoterpenes and therapeutic agents may be administered separately.

[0017] The monoterpene and the therapeutic agent may be administered simultaneously. In one embodiment, the monoterpene and Therapeutic agents are administered together in a pharmaceutical composition (e.g., a solution).

[0018] The therapeutic agent may be a chemotherapeutic agent. A non-limiting example of a chemotherapeutic agent is DNA alkylation. Agents, topoisomerase inhibitors, endoplasmic reticulum stress inducers, platinum compounds, antimetabolites, enzyme inhibitors Examples include harmful agents, receptor antagonists, therapeutic antibodies, and combinations thereof.

[0019] The chemotherapy agents include dimethylcelecoxib (DMC), irinotecan (CPT-11), and te It may be mozolomid or rolipram.

[0020] The therapeutic agent may be an antibody or an antibody fragment.

[0021] The therapeutic agent may be immune cells that express chimeric antigen receptors. The immune cells are T cells. That's fine. In one embodiment, the therapeutic agent is CAR-T cells.

[0022] Mammals can develop cancers, such as tumors of the nervous system (e.g., glioblastoma).

[0023] The method may further include a step of treating a mammal with radiation. [Brief explanation of the drawing]

[0024] [Figure 1]Schematic diagrams of the Lym-1 CAR structure and the CD19 (FMC 63) CAR structure are shown. [Figure 2A] Figure 2A shows the accumulation of human CAR T cells in brain tumors. Immunohistochemical (IHC) staining for detection of human CAR T cell permeability in the brain and the formed tumor (GL261 mouse glioma). Human-derived CD3-positive cells were identified using the primary antibody, anti-human CD3 antibody (CD3ε(D7A6E(trademark))XP(registered trademark) Rabbit mAb (#85061)) (Cell Signaling, Boston, MA). [Figure 2B] This shows CD3 expression on cultured human CAR T cells. [Figure 2C] This shows CD3 staining in a normal C57 BL / 6 brain section. [Figure 2D] This shows CD3 expression in the brains of GL261 mice with gliomas after administration of Lym-1 human CAR T cells by intravenous (IV) injection. [Figure 2E] This shows CD3 expression in the brains of GL261 mice with gliomas after intravenous injection of Lym-1 human CAR T cells following an IC injection of 3% NEO100. [Figure 2F] This shows CD3 expression in the brains of GL261 mice with gliomas after administration of anti-CD19 human CAR T cells by intravenous (IV) injection. [Figure 2G] This shows CD3 expression in the brains of GL261 mice with gliomas after intravenous injection of anti-CD19 human CAR T cells following an IC injection of 3% NEO100. [Figure 2H] This shows a comparison of CD3-positive cells from a normal brain region and a GL261 tumor. [Figure 3] This shows the survival rate in C57 BL / 6 mice carrying the syngeneic GBM (GL261) gene, reflecting the efficacy of anti-mouse PD-1 antibody-mediated therapy, in the absence or presence of periryl alcohol. [Figure 4A] Figure 4A shows an in vitro tight junction model of the blood-brain barrier. [Figure 4B]Figure 4B shows that as the concentration increases, the permeability of the fluorescently labeled antibody into the upper chamber is enhanced. [Figure 4C] Figure 4C shows the decrease in TEER after administration of NEO100 at a concentration of 2 mM. [Figure 4D] Figure 4D shows the recovery time of TEER after administration of NEO100. [Figure 5A] This shows intracardiac injection (IC) of a mixture of NEO100 (various concentrations) and 2% Evans Blue (EB). [Figure 5B] This shows EB permeability to the brain after NEO100 is administered by IC (intracardiac injection) or IV injection. [Figure 6] This shows that NEO100 destroyed tight junctions in the brain. [Figure 7] This demonstrates NEO100-mediated dopamine delivery across a damaged blood-brain barrier. [Figure 8] This shows the measurement of the opening and closing time of the BBB (Ballpoint of Barrier). [Figure 9] This demonstrates anti-mouse IgG antibody delivery in the absence or presence of periryl alcohol. [Figure 10] This demonstrates the delivery of anti-PD-1 antibodies in the absence or presence of periryl alcohol. [Figure 11] This shows Kaplan-Meier survival curves after NEO100-mediated human CAR T cell (Lym-1 CAR) delivery in NSG mice treated with intracranial Raji lymphoma xenografts.

[0025] As used herein, the term "NEO100" refers to periryl alcohol. [Modes for carrying out the invention]

[0026] The present invention relates to monoterpenes or sesquiterpenes or derivatives thereof (e.g., peri Isoperilyl alcohol, also known as POH, isoperiryl alcohol, or periryl alcohol derivative. A method is provided to make the blood-brain barrier permeable using a conductor. Therefore, monoterp Using ions or sesquiterpenes, deliver at least one therapeutic agent across the blood-brain barrier (BBB). It is possible.

[0027] Monoterpenes (or sesquiterpenes) are present in concentrations of over 98.5% (w / w) and approximately 99.0%. It may have a purity of over (w / w) or approximately over 99.5% (w / w).

[0028] Monoterpenes (or sesquiterpenes) are used in the presence of (one or more) therapeutic agents or Monoterpenes (or sesquiterpenes) may be incorporated into pharmaceutical compositions in the absence of other substances. Approximately 0.01% (w / w) to approximately 100% (w / w), approximately 0.1% (w / w) to approximately 80% (w / w), approximately 1% (w / w) to approximately 70% (w / w), approximately 10% (w / w) to approximately 60% (w / w), approximately 1% (w / w) to approximately 10% (w / w), approximately 1% (w / w) to approximately 5% (w / w), Approximately 1% (w / w) to approximately 3% (w / w), approximately 3% (w / w) to approximately 10% (w / w), or approximately It exists in amounts ranging from 0.1% (w / w) to approximately 20% (w / w).

[0029] Monoterpenes (e.g., periryl alcohol) are present in doses of approximately 0.050 mg / kg body weight to approximately 5 It may be administered in doses within the range of 00 mg / kg body weight. For other ranges, approximately 0.1 mg / kg g ~ approx. 100mg / kg, approx. 1mg / kg ~ approx. 50mg / kg, approx. 5mg / kg ~ approx. 25 It contains mg / kg and approximately 10 mg / kg to 15 mg / kg.

[0030] Monoterpenes or sesquiterpenes are, but are not limited to, chemotherapeutic agents and immunotherapeutic agents. Immunomodulators, immunomodulators, antibodies (e.g., monoclonal antibodies), immune cells (e.g., CAR- T cells, vaccines, antibody-drug conjugates, antiviral agents, anti-inflammatory agents, antibacterial agents, antimicrobial agents Used in combination with at least one therapeutic agent, including antibiotics and combinations thereof. obtain.

[0031] Anticancer agents that can be used in combination with purified monoterpenes or sesquiterpenes are: The following effects are observed on cancer cells or targets: namely, cell death; decreased cell proliferation; and reduction of cell number. Decrease; inhibition of cell proliferation; apoptosis; necrosis; cell death by division; cell cycle arrest; reduction in cell size. Reduced cell division; decreased cell viability; decreased cell metabolism; cell damage or cytotoxicity Indirect indicators of cell damage or cytotoxicity, such as tumor shrinkage; improvement of the survival rate of the subject. ; or the disappearance of markers associated with undesirable, unfavorable, or abnormal cell proliferation It may have one or more of the following defects. U.S. Patent Publication No. 20080275057.

[0032] The therapeutic agent can be dissolved in periryl alcohol. This composition is used to treat diseases such as cancer. It can be administered alone or in combination with radiation or another drug (e.g., a chemotherapy agent). It can be administered at any time.

[0033] In some embodiments, the drug is an antibody-drug conjugate. In some embodiments, the anti A body-drug conjugate consists of an antigen-binding fragment and a toxin or drug that induces cytotoxicity within the target cell. Includes. Toxins or drugs suitable for use in antibody-drug conjugates are well known in the art. This will be obvious to those skilled in the art. For example, Peters et al. Biosci. Re See p.(2015)35(4):e00225. In some embodiments, Antibody-drug conjugates contain a linker (e.g., a cleavable linker) that binds the antibody and drug molecules together. It may further contain peptide linkers such as -.

[0034] Treatment may be continuous, and monoterpenes (or sesquiterpenes) may be used (one or more). ) Administered before or after the administration of the therapeutic agent. Alternatively, monoterpenes (or sesquiterpenes) The pen and (one or more) therapeutic agents may be administered simultaneously.

[0035] Monoterpenes (or sesquiterpenes) and at least one therapeutic agent are used simultaneously, separately They may be administered individually or sequentially. They may have advantageously combined effects (e.g., It can produce additive or synergistic effects.

[0036] In the case of continuous administration, administer the monoterpene (or sesquiterpene) first (1 month Administer (or multiple) therapeutic agents, or administer (one or more) therapeutic agents first, then monotherapy. Administer terpenes (or sesquiterpenes). Monoterpenes (or sesquiterpenes) In embodiments in which the therapeutic agent and the monoterpene (or sesquiterpene) are administered separately The administration of (one or more) therapeutic agents may occur a few seconds, minutes, hours, days, or weeks before the administration of the therapeutic agent. Standing, or instead, taking (one or more) therapeutic agents for seconds, minutes, hours, or days. Alternatively, it can be done several weeks later. The time difference between non-simultaneous administrations may exceed one minute, for example. More precisely, at least 5 minutes, at least 10 minutes, at least 15 minutes, at least 30 minutes minutes, at least 45 minutes, at least 60 minutes, at least 2 hours, at least 3 hours, less At least 6 hours, at least 9 hours, at least 12 hours, at least 24 hours, and at least Also 36 hours or at least 48 hours, maximum 5 minutes, maximum 10 minutes, maximum 15 minutes, maximum 30 minutes, up to 45 minutes, up to 60 minutes, up to 2 hours, up to 3 hours, up to 6 hours, up to 9 hours, up to 12 hours, up to 24 hours, up to 36 hours or up to 48 hours, or less than 5 minutes, 10 Less than a minute, less than 15 minutes, less than 30 minutes, less than 45 minutes, less than 60 minutes, less than 2 hours, less than 3 hours, Less than 6 hours, less than 9 hours, less than 12 hours, less than 24 hours, less than 36 hours, or 48 hours The time between two or more drugs may be less than or more than 48 hours. Approximately 0.5 hours, approximately 1 hour, approximately 2 hours, approximately 3 hours, approximately 4 hours, approximately 6 hours, approximately 9 hours, approximately 1 Within 2 hours, approximately 15 hours, approximately 18 hours, approximately 24 hours, or approximately 36 hours, or between each other Approximately 1 day, approximately 2 days, approximately 3 days, approximately 4 days, approximately 5 days, approximately 6 days, approximately 7 days, approximately 8 days, approximately 9 days, approximately 10 days Within approximately 12 days, approximately 14 days, or approximately 2 weeks, approximately 3 weeks, approximately 4 weeks, approximately 5 weeks, It may be administered within approximately 6 weeks, 7 weeks, 8 weeks, 9 weeks, or 10 weeks. Depending on the circumstances, even longer intervals may be possible.

[0037] This disclosure also includes (i) at least one monoterpene (or sesquiterpene) and (ii) Provide a pharmaceutical composition comprising at least one therapeutic agent.

[0038] The route of administration can vary, including intra-arterial delivery, inhalation, intranasal delivery, oral delivery, transdermal delivery, intravenous delivery, subcutaneous delivery, and This may include intramuscular injection.

[0039] The present invention also provides a method for treating diseases such as cancer, comprising the step of delivering the composition to a patient. provide.

[0040] The composition of the present invention contains one or more types of monoterpenes (or sesquiterpenes). It is possible. Monoterpenes consist of two isoprene units, and their molecular formula is C10 H 16 possess It contains terpenes. Monoterpenes, even if linear (acyclic), contain rings. This is also fine. Monoterpenes produced by biochemical modifications such as oxidation or rearrangement of monoterpenes. Penoids, and pharmaceutically acceptable salts of monoterpenes or monoterpenoids, are also included in this invention. It is included in the light. Examples of monoterpenes and monoterpenoids include periryl alcohol (S (-) and R(+), geranyl pyrophosphate, ocimene, myrcene, geraniol, Citral, citronellol, citronellal, linalool, pinene, terpineol, Terpinene, limonene, terpinene, phellandrene, terpinolene, terpinene -4- All (or tea tree oil), pinene, terpineol, terpinene; menthol Derived from monocyclic terpenes such as thymol and carvocrol. Derived terpenoids such as p-cymene; camphor, borneol, and eucalyptus Examples include bicyclic monoterpenoids such as 'R'.

[0041] Monoterpenes can be distinguished by the structure of their carbon skeleton, and acyclic monoterpenes (for example, Myrcene, (Z)- and (E)-ocimene, linalool, geraniol, nerol, cy Tronnellol, Myrcenol, Geranial, Citral a, Neral, Citral b, (e.g., citronellal), monocyclic monoterpenes (e.g., limonene, terpinene, ferran) Dren, terpinolene, menthol, carveol, etc.), bicyclic monoterpenes (for example) , pinen, myrtenol, myrtenal, berbanool, berbano (verbanon) ), Pinot Carveol, Karen, Sabinen, Camphen, Tujien, etc.) and tri-ring mo It can be classified as a noterpene (e.g., tricyclene). Encyclopedia of Chemical Technology Fourth Edition, Volu See me 23, pages 834-835.

[0042] The sesquiterpene of the present invention consists of three isoprene units and has the molecular formula C 15 H 24 of It contains terpenes. Sesquiterpenes, even if linear (acyclic), do not contain rings. It may be produced by biochemical modifications such as oxidation or rearrangement of sesquiterpenes. Sesquiterpenoids are also included in the present invention. Examples of sesquiterpenes include farnesol. Examples include farnesal, farnesyl acid, and nerolidol.

[0043] Derivatives of monoterpenes (or sesquiterpenes) are, but are not limited to, mono Terpene (or sesquiterpene) esters, alcohols, aldehydes and ketones It contains. Monoterpene (or sesquiterpene) alcohols are esters, aldehydes. Alternatively, it can be derivatized with an acid.

[0044] The monoterpene (or sesquiterpene) alcohol esters of the present invention are inorganic acids or It can be derived from organic acids. Inorganic acids, however, include phosphoric acid and sulfuric acid. This includes acids and nitric acids. Organic acids include, but are not limited to, benzoic acid, fatty acids, and vinegar. This includes acids and carboxylic acids such as propionic acid. Monoterpenes (or sesquiterpenes) Examples of alcohol esters include, but are not limited to, carboxylic acid esters ( Palmitic acid esters, fatty acid esters (e.g., palmitic acid esters and linoleic acid esters) (Tel), acetate, propionate (or propanonoate), and formate), Phosphates, sulfates, and carbamates (e.g., N,N-dimethylaminocarbamates) Bonyl is one example. (Wikipedia - Ester. URL: http: / / en.) Search from wikipedia.org / wiki / Ester.

[0045] Specific examples of monoterpenes that can be used in the present invention include periryl alcohol (generally POH and (abbreviated). The periryl alcohol composition of the present invention is (S)-periryl alcohol , (R)-Periryl alcohol, or (S)-Periryl alcohol and (R)-Periryl It may contain a mixture with alcohol.

[0046] The terms "chimeric receptor," "chimeric antigen receptor," or "CAR" are distinguished throughout this text. Functional signaling domains (fu) derived from the following stimulating molecules are used without being utilized. (including an interceptual signaling domain) Antigen-binding domain, transmembrane domain and cytoplasmic signaling domain (referred to as " This refers to recombinant polypeptide constructs that contain an intracellular signaling domain (also known as an "intracellular signaling domain"). Lee et al., Clin. Cancer Res. (2012) 18(10): 2780;Jensen et al.,Immunol Rev.(2014)257 (1):127;www.cancer.gov / about-cancer / trea tment / research / car-t-cells. In one embodiment, the stimulating molecule is It is a zeta chain associated with the T cell receptor complex. In one embodiment, cytoplasmic signaling domain The signal is derived from one or more functional signals from at least one co-stimulatory molecule as defined below. It further contains a signaling domain. The co-stimulatory molecule also contains 4-1BB (i.e., CD137) ), CD27 and / or CD28, or fragments of these molecules. In this context, CARs are extracellular antigen recognition domains containing functional signaling domains derived from stimulating molecules. Chimeric fusion protein containing recognition domain, transmembrane domain and intracellular signaling domain It contains a substance. CAR has a functional signaling domain derived from the co-stimulatory molecule and the stimulatory molecule. Extracellular antigen recognition domain and transmembrane domain, including the derived functional signaling domain. and includes a chimeric fusion protein containing an intracellular signaling domain. Or, CA R is a functional signaling pathway derived from one or more co-stimulatory molecules. Extracellular antigen recognition domains including a main and a functional signaling domain derived from a stimulating molecule It contains a chimeric fusion protein that includes a transmembrane domain and an intracellular signaling domain. Hmm. CAR also has at least two co-stimulatory molecules derived from one or more (one or more) co-stimulatory molecules. It includes functional signaling domains derived from the stimulus molecule and functional signaling domains derived from the stimulus molecule. The cytoplasm contains an extracellular antigen recognition domain, a transmembrane domain, and an intracellular signaling domain. It may contain a MELLA fusion protein. The antigen-recognition portion of the CAR contains any antigen-binding antibody fragment. It is possible to do so. The antibody fragment consists of one or more CDRs, variable regions (or parts thereof), and constant regions. This may include a region (or a portion thereof), or any combination thereof.

[0047] As used herein, a chimeric receptor is a receptor that can be expressed on the surface of a host cell and binds to an antigen. This refers to unnatural molecules containing fragments. Generally, chimeric receptors are derived from fewer different molecules. Both contain two domains. Chimeric receptors, in addition to the antigen-binding fragments described herein, The hinge domain, transmembrane domain, at least one co-stimulatory domain and cytoplasmic domain It may further include one or more of the signaling domains. In some embodiments, The receptor consists of the N-terminus to the C-terminus, antigen-binding fragment, hinge domain, transmembrane domain and It contains a cytoplasmic signaling domain. In some embodiments, the chimeric receptor is less Each also contains one additional co-stimulatory domain.

[0048] In some embodiments, the chimeric receptor described herein comprises an antigen-binding fragment and a transmembrane receptor. It contains hinge domains that may be located between the main domains. An amino acid segment commonly found between two domains, contributing to protein flexibility. This may allow for the movement of one or both domains toward each other. Any amino acid that gives rise to such flexibility and mobility of antigen-binding fragments to the domain Acid sequences can be used.

[0049] Any of the chimeric receptors described herein are suitable for expression via conventional techniques. It can be introduced into disease cells. In some embodiments, immune cells are primary T cells or These are T cells such as primary T cell lines. Alternatively, immune cells are established NK cell lines (e.g., For example, NK cells such as NK-92 cells. In some embodiments, immune cells CD8 (CD8 + ) or CD8 and CD4 (CD8 + / CD4 + T expresses ) These are cells. In some embodiments, T cells are T cells from an established T cell line, for example. These are 293T cells or Jurcut cells.

[0050] In some embodiments, an immunosuppressant expressing any of the chimeric receptors described herein is used. Epidemic cells reduce the number of target cells (e.g., cancer cells) by at least 20%, for example, 50%, 80%. Reduce by %, 100%, 2x, 5x, 10x, 20x, 50x, 100x or more It is administered to the target in an effective amount for that purpose.

[0051] Cells administered to mammals (e.g., humans), such as immune cells (CAR T cells, etc.) A typical amount of this can be, for example, in the range of 1 million to 100 billion cells. However, Amounts below or above the exemplary range are also within the scope of this disclosure. For example, a day of cells The dosage is approximately 1 million to 50 billion cells (for example, approximately 5 million cells, approximately 25 million cells, approximately 500 million cells, about 1 billion cells, about 5 billion cells, about 20 billion cells, about 30 billion cells, about 400 billions of cells (or a range defined by any two of the aforementioned values), preferably about 10 00 million to approximately 100 billion cells (for example, approximately 20 million cells, approximately 30 million cells, approximately 40 million cells) million cells, approximately 60 million cells, approximately 70 million cells, approximately 80 million cells, approximately 90 million cells, Approximately 10 billion cells, approximately 25 billion cells, approximately 50 billion cells, approximately 75 billion cells, approximately 90 billion cells, (or a range defined by any two of the aforementioned values), more preferably about 100 million cells ~Approximately 50 billion cells (for example, approximately 120 million cells, approximately 250 million cells, approximately 350 million cells) million cells, approximately 450 million cells, approximately 650 million cells, approximately 800 million cells, approximately 900 million cells, Approximately 3 billion cells, approximately 30 billion cells, approximately 45 billion cells, or any two of the aforementioned values. (The range defined by) may be.

[0052] In one embodiment, a chimeric receptor (e.g., a nucleic acid encoding a chimeric receptor) is used by immune cells. It is introduced, and the target (e.g., human patients) receives an initial dose of immune cells expressing chimeric receptors. Or receive an initial dose. One or more doses of the drug (e.g., immune cells expressing chimeric receptors). Subsequent doses are given 15, 14, 13, 12, 11 days after the previous dose, and 1 Intervals of 0 days, 9 days, 8 days, 7 days, 6 days, 5 days, 4 days, 3 days, or 2 days later It may be provided to the patient in multiple doses, for example, two or three times per week. It can be administered for four or more doses. The target group is the amount of drug per week Multiple doses (e.g., immune cells expressing chimeric receptors) are administered, followed by one week. If no drug is administered, and the last dose is one or more additional doses of the drug (for example, expressing a chimeric receptor) Immune cells may be administered multiple times per week. Epidemic cells remain for 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks or longer. Alternatively, it may be administered every other day, three times a week.

[0053] In the context of this disclosure, the term "cure" is used as far as it relates to any of the disease conditions described herein. Words like "treat" and "treatment" are related to such a condition. To alleviate or reduce at least one related symptom, or to slow the progression of such a condition. Or, it means to reverse. Within the scope of the meaning of this disclosure, the term “to treat” also means To stop the onset, delay the onset (i.e., the period before the clinical symptoms of the disease), and / or This means reducing the risk of developing or worsening a disease. For example, cancer-related Therefore, the term "treat" means to eliminate or reduce the tumor burden on a patient, or to prevent metastasis. This can mean preventing, delaying, or inhibiting something.

[0054] The methods and compositions described herein, but not limited to, are used for brain tumors, lung cancer, Ear cancer, nose cancer and pharyngeal cancer, hematopoietic cancer, colon cancer, melanoma, pancreatic cancer, breast cancer (mammary cancer), prostate cancer, breast cancer cancer), ovarian cancer, basal cell carcinoma cell carcinoma), biliary tract cancer; bladder cancer; bone cancer; breast cancer cervical cancer; choriocarcinoma; colon cancer and rectal cancer rectum cancer; connective tissue cancer; digestive system cancer; endometrial cancer; esophageal cancer; eye cancer; head and neck cancer; gastric cancer; intraepithelial neoplasm; kidney cancer Eyes cancer; laryngeal cancer; liver cancer; fibroma, neuroblastoma; oral cancer (e.g., lip, tongue) , mouth and pharynx); ovarian cancer; pancreatic cancer; prostate cancer State cancer; retinoblastoma; rhabdomyosarcoma; rectal cancer cancer);renal cancer;respiratory system cancer;sarcoma;skin cancer cancer);stomach cancer;testicular cancer;thyroid cancer;uterine cancer It may be used to treat urinary tract cancers, as well as other carcinomas and sarcomas.

[0055] Carcinoma is a cancer of epithelial origin. This disclosure is limited to carcinomas that are intended to be treated using the method described herein. Although not the same as acinar carcinoma, lobular carcinoma, follicular carcinoma (adenocystic carcinoma, adenomyoepithelioma, cribriform carcinoma and round carcinoma). Also known as pilaroma, adenomatous carcinoma (carcinoma adenomatosum), Adenocarcinoma, adrenal cortical carcinoma, alveolar carcinoma, alveolar epithelial carcinoma (bronchiolar carcinoma, alveolar epithelioma and pulmonary adenomatosis) Also known as basal cell carcinoma, basal cell carcinoma carcinoma basocellulare (basalom cell carcinoma) a) Also known as basiloma or piloma carcinoma, basal cell carcinoid , basosquamous cell carcinoma, breast cancer (breast carcinoma), bronchoalveolar epithelial carcinoma, bronchiolar carcinoma, bronchogenic lung Cancer, cerebriform carcinoma, cholangiocarcinoma (bile duct cancer) Also known as cholangiocarcinoma, choriocarcinoma (chorionic carcinoma), Mucinous carcinoma (colloid carcinoma), comedonal carcinoma, endometrial cancer, cribriform carcinoma, armor-shaped carcinoma (carcinoma en cuirasse), skin cancer (carcinoma cuirasse), skin cancer (carcinoma en cuirasse) taneum), cylindrical carcinoma, cylindrical cell Cancer, ductal carcinoma, dural carcinoma, fetal carcinoma, medullary carcinoma phaloid carcinoma), epibulbar carcinoma noma), epidermoid carcinoma, epithelial adenoid carcinoma (carcinoma epithelial carcinoma) e adenoides), ulcerative carcinoma, fibrous carcinoma, gelatinous carcinoma (gelatinic carcinoma c arcinoma), colloid adenocarcinoma, giant cell carcinoma, giant cell (gigantocellula) re), adenocarcinoma, granulosa cell carcinoma, hematoid carcinoma, hematoid carcinoma a) Hepatocellular carcinoma (hepatocellular tumor, malignant) Hepatocellular carcinoma (also known as hepatocellular carcinoma), Haas Clear cell carcinoma, hyaline carcinoma, clear cell carcinoma of the kidney, infantile fetal carcinoma sexual cancer, carcinoma in situ, intraepidermal carcinoma, intraepithelial carcinoma (int raepithelial carcinoma, Krompecker carcinoma her's carcinoma), Kulchitzky cell carcinoma LL carcinoma, lenticular carcinoma ), lenticular carcinoma, lipo mammary carcinoma), lymphoid epithelial carcinoma, breast adenocarcinoma (carcinoma m astitoides, medullary carcinoma (carcinoma medullare), medullary carcinoma (medullary carcinoma), carcinoma mela nodes), melanotic carcinoma, mucinous carcinoma inous carcinoma), mucinous adenocarcinoma (carcinoma muciparu) m), carcinoma mucocellulare, mucoepidermoid carcinoma, Carcinoma mucosum, mucous carcinoma Myxomatous carcinoma, nasopharyngeal carcinoma, black carcinoma (carcinoma nigrum), oats cell carcinoma, carcinoma ossificans, osteoid carcinoma id carcinoma), ovarian carcinoma, papillary carcinoma periportal carcinoma, pre-invasive carcinoma, prostate cancer (prostate carcinoma), renal cell carcinoma of the kidney (renal adenocarcinoma, and high Also called hyperepoloid carcinoma. (to be discovered), preliminary cell carcinoma, sarcomatoid carcinoma (carcinoma sarcomatodes), Schneiderian carcinoma, scirrhous carcinoma, scrotal cancer , signet ring cell carcinoma, simple carcinoma, small cell carcinoma, solanoid carcinoma ma), spheroidal cell carcinoma, spindle cell carcinoma, cavernous carcinoma, squamous cell carcinoma, squamous cell carcinoma, striated cell carcinoma String carcinoma, angiodetic carcinoma elangiectaticum, carcinoma telan giectodes), transitional cell carcinoma, nodular carcinoma (carcinoma tuberosum) ), tuberous carcinoma, wart-like carcinoma, choriocarcinoma (carci This includes (noma vilosum). In a preferred embodiment, the method of the present disclosure is used for breast Patients with cancer of the cervix, ovaries, prostate, lungs, colon and rectum, pancreas, stomach, or kidneys. It is used to treat [condition].

[0056] Sarcomas are mesenchymal tumors that occur in bone and soft tissue. Various types of sarcomas are recognized. These include liposarcomas (including myxoid liposarcoma and pleomorphic liposarcoma), and leucomas. Myosarcoma, rhabdomyosarcoma, malignant peripheral nerve schwannoma (malignant schwannoma, neurofibrosarcoma or neurogenic Also called sarcoma), Ewing's tumor (Ewing's tumor of bone, extraosseous (i.e., outside of bone) Ewing's sarcoma, and primitive neuroectodermal tumors [PNET], synovial sarcoma, and angiosarcoma. (angiosarcoma), hemangiosarcoma, lymph Tubosarcoma, Kaposi's sarcoma, hemangioendothelioma, fibrosarcoma, tendonoid (also known as invasive fibromatosis), Dermatofibrosarcoma protuberans (DFSP), malignant fibrous histiocytoma (MFH), hemangioemyloidia, malignant hemisarcoma Lobar sarcoma, hydatidiform soft part sarcoma, epithelioid sarcoma, clear cell sarcoma, fibroplastic small cell tumor (desmoplume astic small cell tumor), gastrointestinal stromal tumor (GIST) (GI Also called stromal sarcoma, osteosarcoma (also called osteogenic sarcoma) (skeletal and extraskeletal) This includes chondrosarcoma.

[0057] In some embodiments, the cancer being treated may be a refractory cancer. In this case, "refractory cancer" is cancer that is resistant to prescribed standard treatment. Cancer may initially appear to respond to treatment (though it may recur later), or it may not respond at all to treatment. It may not always be necessary. Standard treatment varies depending on the type of cancer and the stage of its progression. The usual standard treatment is chemotherapy, or surgery, or radiation, or a combination thereof. It is possible. Those skilled in the art are aware of such standard treatments. Therefore, refractory cancer Subjects being treated in accordance with this disclosure have already been exposed to other treatments for those cancers. In some cases, cancer is likely to be refractory (for example, when analyzing cancer cells). (Considering the patient's medical history), the patient may not have yet been exposed to other treatments. Examples of sexually transmitted cancers, though not limited to them, include leukemia, melanoma, renal cell carcinoma, colon cancer, and liver cancer. Examples include hepatic liver cancer, pancreatic cancer, non-Hodgkin lymphoma, and lung cancer. ru.

[0058] Any of the immune cells expressing the chimeric receptor described herein may be used in a pharmaceutical composition. It can be administered in a pharmaceutically acceptable carrier or excipient.

[0059] The phrase "pharmaceutically acceptable" as used in relation to the compositions and / or cells of this disclosure. It is physiologically tolerable and, when administered to mammals (e.g., humans), does not cause unexpected side effects. This refers to molecular entities and other components of such compositions that do not typically undergo a reaction. Preferably As used herein, the term “pharmaceutically acceptable” means “pharmaceutically acceptable” or “pharmaceutically acceptable” in the context of federal or state governments. Approved by regulatory authorities for use in mammals, and more specifically in humans. This means that it is listed in the United States Pharmacopeia or other generally accepted pharmacopoeias. "Acceptable" means that the carrier is the active ingredient of the composition (e.g., nucleic acids, vectors, cells or therapeutic agents). Compatible with therapeutic antibodies and the composition (one or more) does not adversely affect the subject to which it is administered. This means that any of the pharmaceutical compositions and / or cells used in this method are frozen. A pharmaceutically acceptable carrier, excipient, or stabilizer in dry or aqueous form. It can include.

[0060] Pharmacochemically acceptable carriers including buffers are well known in the art, such as phosphates and cyto Acids and other organic acids; antioxidants including ascorbic acid and methionine; preservatives; low Molecular weight polypeptides; proteins such as serum albumin, gelatin, or immunoglobulins. ;amino acids;hydrophobic polymers;monosaccharides;disaccharides;and other carbohydrates;metal complexes;and It may contain a and / or nonionic surfactant. For example, Remington: The S Science and Practice of Pharmacy 20th Ed. (2000) Lippincott Williams and Wilkins,Ed. Please refer to .KEHoover.

[0061] Treatment kit Furthermore, within the scope of this disclosure are kits for using the drug / composition. The kit contains a first pharmaceutical composition comprising at least one monoterpene or sesquiterpene. A substance, a pharmaceutically acceptable carrier, and at least one therapeutic agent and a pharmaceutically acceptable carrier. It may include one or more containers containing a second pharmaceutical composition including a body. In another embodiment, a kit The compound comprises at least one monoterpene or sesquiterpene and at least one therapeutic agent. This may include one or more containers containing a pharmaceutical composition comprising a pharmaceutically acceptable carrier.

[0062] In some embodiments, the kit is used in any of the methods described herein. Instructions for achieving the intended activity for the target may be included. This may include a description of the administration of the first and second pharmaceutical compositions to the subject in order to achieve the desired result. The kit identifies suitable subjects for treatment based on whether the subject needs treatment. The description may further include an explanation of the selection process. In some embodiments, the description may include an explanation of the need for treatment. This includes an explanation of administering the pharmaceutical composition to the subject.

[0063] Instructions for the use of the pharmaceutical compositions described herein generally refer to the intended treatment. Includes information on dosage, administration schedule, and route of administration. The container contains unit dose information. This can be a bulk package (e.g., a multi-dose package) or a subunit dose. The instructions provided with the kit of this disclosure are typically written on the label or in the accompanying documentation. This is an instruction manual. The label or accompanying leaflet states that the pharmaceutical composition treats the disease or disorder of the subject. to delay the onset of the disease or disorder in question, and / or to treat the disease or disorder in question. This indicates that it is used to mitigate the problem.

[0064] The kits provided herein are in suitable packaging. Suitable packaging is limited to... This includes not just the product itself, but vials, bottles, jars, flexible packaging, etc. Inhalers, nasal inhalers, etc. Packaging for use in combination with specific devices such as administration devices or infusion devices is also intended. The kit may have a sterile access port (for example, the container may have an intravenous solution bag). (or it may be a vial with a stopper that can be pierced by a subcutaneous injection needle.) The container may also have a sterile access port.

[0065] The kit may provide additional components such as buffers and interpretation information. The container and any labels or accompanying statements on or attached to the container. This includes the document. In some embodiments, the present disclosure provides a product containing the contents of the above kit. To provide.

[0066] Periryl alcohol derivatives include periryl alcohol esters, periraldehyde, and di It contains hydroperylic acid and perylic acid. Derivatives of perillyl alcohol also include This may include oxidative and nucleophilic / electrophilic addition derivatives. (U.S. Patent Publication No. 200900314) No. 55. U.S. Patent Nos. 6,133,324 and 3,957,856.

[0067] The present invention also relates to a monoterpene (or sesquiterpene) and at least one therapeutic agent. It provides a method for treating diseases such as cancer or other neurological disorders using monoterpe. N (or sesquiterpenes) can be administered alone or in combination with other therapeutic agents. Noterpenes or sesquiterpenes can also be administered concurrently with therapeutic agents. Monoterpenes ( (or sesquiterpenes) can be administered in combination with therapeutic agents. The drugs can be administered simultaneously. Alternatively, they may be administered consecutively. Monoterpenes (or sesquiterpenes) are used in the administration of therapeutic agents. It can be administered before, during, or after administration.

[0068] Monoterpenes (or sesquiterpenes) are solvents used to deliver therapeutic agents to the lesion site. They can also be used as penetration enhancers. For example, monoterpenes (or sesquiterpenes) It can be used as a solvent or penetration enhancer for delivering chemotherapeutic agents to tumor cells. Noterpenes or sesquiterpenes are vaccines that can be delivered via any preferred route. It can also be used as a solvent.

[0069] This composition and method are for cancers of the nervous system, such as malignant gliomas (e.g., astrocytomas, malignant gliomas). astrocytoma, glioblastoma multiforme), retinoblastoma, pilocytic astrocytoma (grade I) Treatment of meningiomas, metastatic brain tumors, neuroblastomas, pituitary adenomas, skull base meningiomas, and skull base cancers It may be used in medical treatment. As used herein, the term “neurological tumor” means that the subject is a neurological tumor. This refers to a condition characterized by malignant proliferation of cells.

[0070] The cancers that can be treated by this composition and method are not limited to, Lung cancer, ear cancer, nose cancer and pharyngeal cancer, leukemia, colon cancer, melanoma, pancreatic cancer, breast cancer (mamma (Breakfast cancer), prostate cancer, breast cancer st cancer), hematopoietic cancer, ovarian cancer, basal cell Cancer (basal cell carcinoma), biliary tract cancer; bladder cancer; bone cancer; breast cancer (br east cancer; cervical cancer; choriocarcinoma; Bowel and rectum cancer; connective tissue cancer; digestive system cancer; endometrium Cancer; esophageal cancer; eye cancer; head and neck cancer; gastric cancer; intraepithelial neoplasm; Kidney cancer; Laryngeal cancer; Acute myeloid leukemia, acute lymphocytic leukemia leukemia including chronic myeloid leukemia and chronic lymphocytic leukemia; liver cancer; Hodgkin lymphoma and Lymphomas including non-Hodgkin lymphoma; myeloma; fibroma, neuroblastoma; oral cancer (for example, Lips, tongue, mouth and pharynx; ovarian cancer; pancreatic cancer; prostate cancer ( prostate cancer; retinoblastoma; rhabdomyosarcoma; rectal cancer cancer);renal cancer;respiratory system cancer;sarcoma;skin cancer(s) stomach cancer; testicular cancer; thyroid cancer; This includes uterine cancer; urinary tract cancers, as well as other carcinomas and sarcomas. (United States No. 7,601) No. 355.

[0071] The present invention also, without limitation, applies to primary degenerative neuropathy, such as Alzheimer's disease. - To treat CNS disorders, including Parkinson's disease, psychological disorders, psychosis, and depression. The present invention provides methods and compositions for this purpose.

[0072] This composition may be used in combination with radiotherapy.

[0073] This monoterpene or sesquiterpene is, but is not limited to, a chemotherapy agent, immunotherapy agent. Combined with at least one therapeutic agent, including a therapeutic agent and an antibody (e.g., a monoclonal antibody). They can be used together. They can be used in combination with refined monoterpenes or sesquiterpenes. The anticancer agents that may be used have the following effects on cancer cells or targets: namely, cell death; cells Decreased proliferation; decreased cell number; inhibition of cell proliferation; apoptosis; necrosis; cell death; cell cycle arrest Stoppage; decrease in cell size; decrease in cell division; decrease in cell viability; decrease in cell metabolism; cell damage. Alternatively, it can be used as a marker of cytotoxicity; an indirect indicator of cell damage or cytotoxicity, such as tumor shrinkage. ;Improvement of the survival rate of the target; or to prevent undesirable, unfavorable, or abnormal cell proliferation. It may have one or more of the following characteristics: loss of related markers. (U.S. Patent Publication No. 20080275) No. 057.

[0074] Furthermore, although not limited to monoterpenes (or sesquiterpenes), chemotherapy The present invention also includes mixtures and / or co-formulations of at least one therapeutic agent containing the agent.

[0075] While not limited to chemotherapeutic agents, DNA alkylating agents and topoisomerase inhibitors are also included. Harmful agents, endoplasmic reticulum stress inducers, platinum compounds, antimetabolites, vinca alkaloids, taxanes Epothiron, enzyme inhibitors, receptor antagonists, therapeutic antibodies, tyrosine kinase inhibitors, phosphating This includes combination therapy with a primary radiosensitizer (i.e., Velcade) and chemotherapy.

[0076] DNA alkylating agents are well known in this field and are used to treat various tumors. Non-exclusive examples of DNA alkylating agents include mechloretamine and cyclophosphamide (IHO). Sphamide, trophosfamide, chlorambucil (melphalan, prednimustine) Nitrogen Masters such as Bendamustine, Uramustine and Estramustine Carmustine (BCNU), Lomustine (Semustine), Fotemustine, Nimustine Nitrosoureas such as ranimustine and streptozocin; busulfan (manno Alkyl sulfonates such as sulfan, treosulfan; carbocone, ThioTE Aziridines such as PA, triadicone, and triethylenemelamine; hydrazine (procarba Triazenes such as dacarbazine and temozolomide; altoretamine and mito It's bronitrate.

[0077] Non-limiting examples of topoisomerase I inhibitors include Pommier Y. (2006) N at.Rev.Cancer 6(10):789-802 and U.S. Patent Publication No. 200 CPT-11 (irinotecan), SN-38, A, as listed in registration number 510250854. PC, NPC, campothecin, topotecan, mesylate extract Satecan, 9-nitrocamptothecin, 9-aminocamptothecin, raltothecan, ruby Tecan, Shiratecan, Jaimatecan, Diflomotecan Extatecan, BN-80927, DX-8951f and M Camptothecin derivatives containing AG-CPT; Li et al. (2000) Bioch Emistry 39(24):7107-7116 and Gatto et al. 1996) Cancer Research.As described in 15(12):2795-2800 Protoberberine alcohol containing berberrubine and coralin Kaloids and their derivatives; Makhey et al. (2003) Geoorg.M ed.Chem Benzo[i]fena, as described in .11(8):1809-1820 Phenanthroline derivatives including antidine, nitidine, and fagaronine; Xu(199) 8) DNA Chemistry The text described in 37(10):3558-3566 Lubenzimidazole and its derivatives; and Foglesong et al. 1992) Cancer Chemist. Pharma Col. 30(2):12 3-]25, Crow et al. (1994) J.Med.Chem. 37(19) :31913194 and Crespi et al. (1986) Biochem.B iophys.Res.Commun. Doki as described in 136(2):521-8 Anthracycline derivatives including sorbicin, daunorubicin, and mitoxantrone It can be listed. Topoisomerase II inhibitors include, but are not limited to, etoposide. This includes teniposide. It is not limited to dual topoisomerase I and II inhibitors. However, Denny and Baguley (2003) Curr.Top.M ed.Chem. Sinus pins and other nasal pins are described in 3(3):339-353. Naphthecenedione, DACA, and other acridines -4-Carboxamide, Intoprisin and other benzopyridindoles, TAS-I 03 and other 7H-indeno[2,1-c]quinoline-7-one, pyrazoloacridine XR 11576 and other benzophenazines, XR 5944 and other dimer compounds The substance, 7-oxo-7H-dibenzo[f,ij]isoquinoline and 7-oxo-7H-be Contains nz[e]perimidine and anthracenyl amino acid complex. However, anthracyclines (acralubicin, daunorubicin, doxorubicin, Epirubicin, Idarubicin, Amrubicin, Pirarubicin, Barurubicin, Zorubicin ) and some drugs such as anthracendiones (mitoxantrone and pixantrone) The agent inhibits topoisomerase II and has DNA intercalation activity.

[0078] Examples of endoplasmic reticulum stress inducers include, but are not limited to, dimethylcelecoxib (D MC), nelfinavir, celecoxib and boron radiosensitizer (i.e., Belkey (Vortezomib) is one example.

[0079] Platinum compounds, a subclass of DNA alkylating agents. Non-exclusive examples of such drugs. This includes carboplatin, cisplatin, nedaplatin, oxaliplatin, and tripe tetranitrate. Examples include latin, satraplatin, alloplatin, lovaplatin, and JM-216. (McKeage et al. (1997)) J.Clin.Oncol. 201:12 32-1237 and generally, CHEMOTHERAPY FOR GYNECOLOG ICAL NEOPLASM, CURRENT THERAPY AND NOVEL APPROACHES,in the Series Basic and Clini (See Cal Oncology, Angioli et al. Eds., 2004) .

[0080] Non-exclusive examples of antimetabolites include folate-based drugs, i.e., dihydrofolate reductase inhibitors. For example, aminopterin, methotrexate and pemetrexed; thymidylate synth Adeno-glycemic inhibitors, e.g., larcitrexed, pemetrexed; purines, i.e., adenoids Synthetic amino acid inhibitors, such as pentostatin, thiopurine, and thioguanine. and mercaptopurines, halogenated / ribonucleotide reductase inhibitors, for example, Cladribine, clofarabine, fludarabine, or guanine / guanosine: thiop Phosphorus, e.g., thioguanine; or pyrimidines, i.e., cytosine / cytidine: low Methylating agents, for example, azacitidine and decitabine, DNA polymerase inhibitors, for example For example, cytarabine, a ribonucleotide reductase inhibitor, such as gemcitabine, or This refers to thymine / thymidine:thymidylate synthase inhibitors, such as fluorouracil (5-F U) is one example. Equivalents of 5-FU include, for example, Papamicheal (1999). ) 5'-deoxy as described in The Oncologist 4:478-487 -5-Fluorouridine (doxifluroidine), 1 -Tetrahydrofuranil-5-fluorouracil (Futraful), capecitabine (Zero Da), SI (MBMS-247616, Tegafool ​​and two modulators, 5-Cro (consisting of 2,4-dihydroxypyridine and potassium oxonate), larcitrex Ced (Tomudex), Nolatrexide (Thymitaq, AG33) 7) its prodrugs, analogues and derivatives such as LY231514 and ZD9331 The body is included.

[0081] Examples of vinca alkaloids include, but are not limited to, vinblastine, vincristine, vinflunine, vindesine and vinorelbine.

[0082] Examples of taxanes include, but are not limited to, docetaxel, larotaxel, ortataxel, paclitaxel and tesetaxel. An example of epothilone is iabepilone. [[ID=ll]]

[0083] Examples of enzyme inhibitors include, but are not limited to, farnesyl transferase inhibitor (tipifarnib); CDK inhibitor (albosidib, seliciclib); proteasome inhibitor (bortezomib); phosphodiesterase inhibitor (anagrelide; loliplam); IMP dehydrogenase inhibitor (thiazofurin); and lipoxygenase inhibitor (masoprocol). Examples of receptor antagonists include, but are not limited to, ERA (atrasentan); retinoid X receptor (bexarotene); and sex steroid (testolactone).

[0084] Examples of therapeutic antibodies include, but are not limited to, anti-HER1 / EGFR (cetuximab, [[ID= )panitumumab); anti-HER2 / neu (erbB2) receptor (trastuzumab); anti-EpCAM (catumaxomab, edrecolomab); anti-VEGF-A (bevacizumab); anti-CD20 (rituximab, tositumomab, ibritumomab); anti-CD52 (alemtuzumab); and anti-CD33 (gemtuzumab). U.S. Patent No. 5,776,427 and U.S. Patent No. 7,601,355. < ,

[0085] Examples of tyrosine kinase inhibitors include, but are not limited to, inhibitors of ErbB:HER1 / E GFR (erlotinib, gefitinib, lapatinib, vandetanib, suni tinib, neratinib); inhibitors of HER2 / neu (lapatinib, neratinib); RTK class III: inhibitors of C-kit (axitinib, sunitinib, sorafen ib), inhibitors of FLT3 (lestaurtinib), inhibitors of PDGFR (a xitinib, sunitinib, sorafenib); and inhibitors of VEGFR (vandeta nib, semaxanib, cediranib, axitinib, sorafenib); inhibitors of bcr-abl (imatinib, nilotinib, dasatinib); inhibitors of Src (bosutin ib) and inhibitors of Janus kinase 2 (lestaurtinib).

[0086] Cetuximab is an example of an anti-EGFR antibody. Cetuximab is a chimeric human / mouse monoclonal antibody that targets the epidermal growth factor receptor ( EGFR). Biologically equivalent antibodies are herein identified as antibodies that bind to the same epitope of the modified antibody and the EGFR antigen, inhibit ligand binding of EGFR, prevent activation of the EGFR receptor, block downstream signaling of the EGFR pathway, and produce substantially equivalent biological responses such as interfering with cell proliferation.

[0087] “Lapatinib” (Tykerb®) is a dual EGFR and erbB-2 inhib itor. Lapatinib has been used in numerous clinical trials as a single anti-cancer therapy and in combination with trastuz umab, capecitabine, letrozole, paclitaxel and FOLFIR1 (irinote ​​​​It is currently being studied in combination with can, 5-fluorouracil, and leucovorin. , metastatic breast cancer, head and neck cancer, lung cancer, gastric cancer Oral treatment for cancer, renal cancer, and bladder cancer. Phase III trials are underway. The chemical equivalent of lapatinib is a tyrosine kinase inhibitor. (TKI) or small molecules or compounds that are HER-1 inhibitors or HER-2 inhibitors Several TKIs have been found to have effective antitumor activity and have been approved. It is either being tested or is in clinical trials. Examples of such cases include, but are not limited to, Xacti. Ma (ZD6474), Iressa (gefitinib) and Tarceva (erlotinib), Mesi Imatinib ruate (STI571; Gleevec), Erlotinib (OSI-1774; Ta Luceva, canertinib (CI1033), semaxinib (SU5416), batalanib (PTK787 / ZK222584), sorafenib (BAY43-9006), suute (SUI1248) and lefltmomide (SUI01) ) are examples. The bioequivalents of lapatinib are HER-1 inhibitors and / or HE These are peptides, antibodies, or antibody derivatives that are R-2 inhibitors. Examples of such inhibitors include limited While not definitively established, examples include the humanized antibodies trastuzumab and Herceptin.

[0088] PTK / ZK is a receptor for all VEGF receptors (VEGFRs) and platelet-derived growth factor (PD). A small GF receptor, c-KIT, and c-Fms targeting broad specificity. It is a molecular tyrosine kinase inhibitor. Drevs (2003) Idrugs 6(8) : 787 - 794. PTK / ZK inhibits angiogenesis and lymphangiogenesis by inhibiting the activity of any known receptor that binds to VEGF, including VEGFR-1 (Flt-1), VEGFR-2( KDR / Flk-1), and VEGFR-3 (Flt-4). The chemical name of PTK / ZK is 1-[4-chloroanilino]-4- [4-pyridylmethyl]phthalazine succinate or 1-phthalazineamine, N-(4- chlorophenyl)-4-(4-pyridinylmethyl)-butanedioate (1:1). Synonyms and analogs of PTK / TK are batatinib, CGP79787D, PTK78 7 / ZK 222584, CGP-79787, DE-00268, PTK-787, P TK787A, VEGFR-TK inhibitor, ZK 222584, and ZK, known as such. 7 / ZK 222584, CGP-79787, DE-00268, PTK-787, P TK787A, VEGFR-TK inhibitor, ZK 222584, and ZK, known as such.

[0089] In addition, chemotherapeutic agents that can be used in combination with monoterpenes or sesquiterpenes include amsacrine, trabectedin, retinoids (alitretinoin, tretinoin), arsenic trioxide, asparagine-depleting substances asparaginase / pegaspargase), celecoxib, dexamethasone, elesclomol, elsamitrucin, etoglucide, lonidamine, lucanthone, mitoguazone, mitotane, oblimersen, temsirolimus, and vorinostat may be included. may be included.

[0090] Other therapeutic agents that can be used with the compositions and methods of the present invention include, for example, CAR-T cells, CAR-macrophages, or CAR-NK cells.

[0091] The present compositions and methods are paracellularly permeable, for example, paracellularly permeable to endothelial or epithelial cells. It can be used to increase permeability. This composition and method increase blood-brain barrier permeability. It can be used to achieve this. The effect of administration on blood-brain barrier permeability lasts from 5 minutes to 10 hours. It may continue. Other ranges include at least about 15 minutes, at least about 30 minutes, and less At least about 1 hour, at least about 2 hours, at least about 3 hours, at least about 5 hours, less than At least about 10 hours, at least about 24 hours, at least about 48 hours, or at least about 7 This includes 2 hours.

[0092] This composition and method may be used to reduce or inhibit angiogenesis. The substances and methods may include, but are not limited to, vascular endothelial growth factor (VEGF) and interferan - May reduce or inhibit the production of pro-angiogenic cytokines, including leukin-8 (IL-8). ru.

[0093] Monoterpenes or sesquiterpenes can be used in combination with angiogenesis inhibitors. Examples of angiogenesis inhibitors, though not limited to them, include angiostatins and angiozymes. Antithrombin III, AG3340, VEGF inhibitors (e.g., anti-VEGF antibodies) Batimast, bevacizumab (Avastin), BMS-275291, CAI, 2C 3. HuMV833 canstatin, captopril, carcinamide triazole, cartilage Derived inhibitor (CDI), CC-5013, 6-O-(chloroacetylcarbonyl) Fumagi Roll, COL-3, Combretastatin, Combretastatin A4 phosphate, Dal Teparin, EMD121974 (silendide), endostatin, erlotinib, ge Fitinib (Iressa), Genistein, Halofudinone hydrobromide, Id1, Id3, I M862, imatinib mesylate, IMC-IC11-inducing protein 10, interferon Nα, Interleukin-12, Lavender Dustin A, LY317615 or AE-941 Marimast, mspin, medroxyprogesterone acetate, Meth -1, Meth-2, 2-methoxyestradiol (2-ME), Neovastat, O Theopontin cleavage products, PEX, pigment epidermal growth factor (PEGF) ), platelet factor 4, prolactin fragment, proliferin-related protein (PRP), PT K787 / ZK 222584, ZD6474, Recombinant human platelet factor 4 (rPF4), Restin, Squalamine, SU5416, SU6668, SU11248 Squalamine, Taki Sole, Tecogalan, Thalidomide, Thrombospondin, TNP-470, Troponin -1, vasostatin, VEG1, VEGF-Trap, and ZD6474 are examples.

[0094] Non-exclusive examples of angiogenesis inhibitors include tyrosine kinase inhibitors, for example, tyrosine kinase inhibitors. Inhibition of the enzyme receptors Flt-1 (VEGFR1) and Flk-1 / KDR (VEGFR2) Harmful agents, inhibitors of epithelial, fibroblast-derived, or platelet-derived growth factors, MMPs (Matrix Inhibitors of kusmetalloproteinases, integrin blockers, pentosan polysulfate, Angiotensin II antagonists, cyclooxygenase inhibitors (aspirin and ibuprofen) Nonsteroidal anti-inflammatory drugs (NSAIDs) such as fen, as well as celecoxib and rof (including selective cyclooxygenase-2 inhibitors such as ecoxib) and steroids Anti-inflammatory drugs (corticosteroids, mineralocorticoids, dexamethasone, prednisone) Other examples include prednisolone, methylpred, and betamethasone. It is possible.

[0095] They regulate or inhibit angiogenesis, and can also be used in combination with monoterpenes or sesquiterpenes. Other therapeutic agents that may be used include drugs that modulate or inhibit the coagulation and fibrinolytic systems. Examples of such drugs that modulate or inhibit the coagulation and fibrinolytic pathways include, but are not limited to, However, heparin, low molecular weight heparin and carboxypeptidase U inhibitors (active tron) (Also known as an inhibitor of tin-activated fibrinolysis inhibitors [TAFIa]). Publication No. 20090328239. U.S. Patent No. 7,638,549.

[0096] Immunomodulators, though not limited to them, include cytokines, such as interleukins. This includes lymphokines, monokines, interferons, and chemokines.

[0097] Other penetration enhancers that may be used with monoterpenes (or sesquiterpenes) include: While not definitively established, glycerol fatty acid esters, such as capric acid and caprylic acid, are likely candidates. , dodecyl, oleic acid; isosorbide, sucrose, polyethylene glycol fat Acid ester; Caproyl lactylic acid; Laureth-2; Laureth-2 acetate; Laureth -2 benzoate; laureth-3 carboxylic acid; laureth-4; laureth-5 carboxylic acid; Oleth-2; Glyceryl pyroglutamate oleate; Glyceryl oleate; N-lau Royl sarcosine; N-myristoyl sarcosine; Noctyl-2-pyrrolidone; Raulua Minopropionic acid; polypropylene glycol-4-laureth-2; polypropylene glycol Co-4-Laureth-5 Dimethyl Lauramide; Lauramide Diethanolamine (D EA), lauryl pyroglutamate (LP), glyceryl monolaurate (GML), Glyceryl monocaprylate, glyceryl monocaprylate, glyceryl monooleate (G It contains polyols (MO) and sorbitan monolaurate. Polyols or ethanol are immersed in It can function as a penetration enhancer or co-solvent. For additional penetration enhancers, see U.S. 5, U.S. Patent No. 785,991, U.S. Patent No. 5,843,468, U.S. Patent No. 5,882,676 See also U.S. Patent No. 6,004,578.

[0098] Cosolvents are well known in the art, and are not limited to glycerols. Ru, Polyethylene glycol (PEG), glycol, ethanol, methanol, propano It contains ethanol, isopropanol, butanol, etc.

[0099] This composition may be administered intra-arterial, intranasal, orally, or orally. Intraperitoneal administration, inhalation, intravenous administration, intracardiac injection (IC), intraventricular injection (ICV), cisterna magna injection Alternatively, administration by injection, subcutaneous injection, implant, vaginal injection, sublingual injection, or urethral injection (e.g., urethral stool). Drugs, subcutaneous administration, intramuscular administration, intravenous administration, transdermal administration, rectal administration, sublingual administration, mucosal administration, Eye drops, spinal administration, intrathecal administration, intra-arterial administration, intra-arterial administration, subarachnoid administration, bronchial administration, and It may be administered by any method known in the art, including bilymphatic drug administration. The preparation may be in the form of a gel, ointment, cream, aerosol, etc. Intranasal preparations are It can be delivered as a spray or in droplets. Transdermal formulations can be delivered as transdermal patches or in It can be administered via iontorphoresis. Inhaled formulation. It can be delivered using a nebulizer or similar device. The composition is also available in tablets. Drugs, pills, capsules, semi-solids, powders, sustained-release formulations, solutions, suspensions, elixirs, aero It can take the form of a sol or any other suitable composition.

[0100] To prepare such a pharmaceutical composition, monoterpenes (or sesquiterpenes) One or more and / or at least one of these therapeutic agents are formulated according to conventional pharmaceutical formulation techniques. This composition may be mixed with pharmaceutically acceptable carriers, adjuvants, and / or excipients. The pharmaceutically acceptable carriers that can be used are any of the standard pharmaceutical carriers, for example For example, a phosphate buffered salt solution, water, and emulsion, such as an oil / water emulsion or The composition includes water / oil emulsions and various types of wetting agents. Formulating agents, for example, starch, cellulose, talc, glucose, lactose, sucrose, Gelatin, malt, rice, wheat flour, chalk, silica gel, magnesium stearate, s Sodium thearate, glycerol monostearate, sodium chloride, skim milk powder, etc. It may further contain: Liquid and semi-solid excipients include glycerol, propylene Glycol, water, ethanol, and substances of petroleum, animal, plant or synthetic origin, for example A variety of oils can be selected, including peanut oil, soybean oil, mineral oil, and sesame oil. In particular, it is injectable. The liquid carrier for the solution contains water, physiological saline, aqueous dextrose, and glycol. Examples of carriers, stabilizers, and adjuvants are available. Remington's P Harmaceutical Sciences Edited by EWMar tin(Mack Publishing Company,18th ed.,199 See 0). The composition may also contain stabilizers and preservatives.

[0101] As used herein, the term “therapeutic dose” means the amount of a dose used to treat a particular disorder or disease. A sufficient amount for that purpose, or to obtain a pharmacological response to treat a disorder or disease. The method for determining the most effective means of administration and dosage is determined by the composition used in the treatment and the target of the treatment. Safety and efficacy may vary depending on the target, the target cells being treated, and the entity being treated. To optimize the treatment, the therapeutic dose may generally be gradually increased. The dose to be chosen by the treating physician. Depending on the level and pattern, single or multiple doses can be administered. The drug formulation and the method of administering the drug can be easily determined by those skilled in the art. For example, the composition , about 0.01mg / kg~about 200mg / kg, about 0.1mg / kg~about 100mg / k It is administered in doses of g or approximately 0.5 mg / kg to approximately 50 mg / kg. When a compound is administered concurrently with another drug or treatment, the effective dose is calculated based on whether the drug is used alone. It may be less than in the case where it is.

[0102] This disclosure also provides the above-mentioned compositions for intranasal administration. Thus, the compositions are It may further contain a penetration enhancer. Southall et al. Develop This composition is: In liquid form such as solutions, emulsions, suspensions, or droplets, or in powder, gel, or ointment form. It can be administered intranasally in any solid form. Devices for delivering intranasal drugs are available in the art. It is well known that nasal drug delivery includes, but is not limited to, intranasal inhalers and intranasal spray devices. Atomizers, nasal spray bottles, unit dose containers, pumps, droppers, squeeze bottles Toll, nebulizer, metered-dose inhaler (MDI), pressurized dose inhaler, injector and dual This can be done using a device that includes a directional device. Nasal delivery devices can accurately deliver the effective dose. It can be measured for administration into the nasal cavity. The nasal delivery device can deliver a single unit or multiple units. It may be used for multi-unit delivery. A specific example is Kurve Technology (Bet ViaNase Electronic Ato (made in Washington, Hell) Mizer can be used in this invention (http: / / www.kurvetec (h.com). The compounds of the present invention are also used in tubes, catheters, syringes, and packtails. (Delivered via packtail, cotton ball, nasal tampon, or submucosal injection) It is possible. U.S. Patent Publication No. 20090326275, U.S. Patent Publication No. 200902918 Patent No. 94, U.S. Patent Publication No. 20090281522, and U.S. Patent Publication No. 2009031 No. 7377.

[0103] This composition can be formulated as an aerosol using standard procedures. Terpenes (or sesquiterpenes) and / or at least one therapeutic agent using a solvent The formulation may be formulated with or without a carrier, and may be formulated with or without a carrier. It may be a solution, or an aqueous emulsion containing one or more surfactants. , dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethylene Suitable propellants such as hydrocarbons, compressed air, nitrogen, carbon dioxide, or other suitable gases. An aerosol spray can be generated from a pressurized container. The dosage unit is the measured amount. This can be determined by providing a valve for delivery. Pump spray dispensers are Dispensing measured doses, or doses having a specific particle or droplet size. Yes, it is possible. As used herein, the term "aerosol" means fine solid particles in a gas or This refers to a suspension of solution droplets. Specifically, aerosols are used in MDI, nebulizers, or micro-discharge systems. Monoterpenes (or sesquiterpenes) that can be produced in any suitable device such as a sprayer. The aerosol contains a suspension of droplets of (n) in a gas. The aerosol is also in air or other carrier gas. The present invention comprises a suspended, dried powder composition of the present invention. Gonda (1990) Criti cal Reviews in Therapeutic Drug Carrier Systems 6:273-313.Raeburn et al.,(1992) P harmacol.Toxicol.Methods 27:143-159. This composition is delivered as a powder in the form of microspheres or other particles via a nasal injector. It may be delivered into a cavity. The composition may be absorbed into a solid surface, such as a carrier. Alternatively, microspheres may be administered in a dry, air-distributable form. Crossfairs may be stored in an injector container. Alternatively, they may be stored as a powder or microfairs. A is a capsule such as a gelatin capsule, or other single-dose units suitable for intranasal administration. It may be filled.

[0104] Pharmaceutical compositions include, for example, gels, ointments, nasal emulsions, lotions, creams, and nasal formulations. The composition is placed directly into the nasal cavity in the form of a tampon, dropper, or bioadhesive strip. This allows it to be delivered to the nasal cavity. In certain embodiments, for example, absorption is enhanced. Therefore, it is sometimes desirable to extend the residence time of the pharmaceutical composition in the nasal cavity. Therefore, the pharmaceutical composition contains a bioadhesive polymer, gum (e.g., xanthan gum), chitosa (For example, highly purified cationic polysaccharides), pectin (or administered to the nasal mucosa) (and any carbohydrates that thicken like a gel or emulsify), microspheres (for example, (Pumps, albumin, dextran, cyclodextrin), gelatin, liposomes, Carbamer, polyvinyl alcohol, alginate, acacia, chito Sunflower and / or cellulose (e.g., methyl or propyl; hydroxyl or carboxymethyl cellulose) May be formulated using ruboxy (carboxymethyl or hydroxypropyl). .

[0105] The composition can be administered by oral inhalation into the airways, i.e., the lungs.

[0106] Typical delivery systems for inhalable medications include nebulizers and dry powder inhalers. This includes DPIs and MDIs (Deep-Pass Inhalers).

[0107] A nebulizer device generates a high-speed airflow that atomizes a liquid form of therapeutic agent. The therapeutic agent is formulated in liquid form, such as a solution or suspension of particles of a suitable size. In the embodiment, the particles are pulverized. The term "pulverized" refers to particles having a diameter of less than approximately 10 μm. It is defined as having approximately 90% or more particles. A suitable nebulizer device is, for example, PAR. It is commercially available from I GmbH (Starnberg, Germany). The riser device includes a Respimat (Boehringer Ingelheim), Furthermore, for example, U.S. Patent No. 7,568,480 and U.S. Patent No. 6,123,068 This includes those disclosed in publications and international publication 97 / 12687. Monoterpenes (or sesquiterpenes) are used in nebulizers as aqueous solutions or liquid suspensions. It can be formulated for this purpose.

[0108] DPI devices are typically in the form of a free-flowing powder that can be dispersed in the patient's airflow during inhalation. A therapeutic agent is administered. In this invention, a DPI device using an external energy source is used. Alternatively, to obtain a free-flowing powder, a suitable excipient (e.g., lactose) can be used. Therapeutic agents can be formulated. For example, dried ions having a particle size of approximately 1 μm to approximately 100 μm. Combining ctose with finely ground monoterpene (or sesquiterpene) particles, dry process By mixing, a dry powder formulation can be prepared. Alternatively, a monoterpene can be used. It can be formulated without the use of excipients. The formulation can be dispensed using a dry powder dispenser, and It is filled into an inhalation cartridge or capsule for use with a dry powder delivery device. Examples of commercially available DPI devices include Diskhaler (GlaxoSmithK). Line, Research Triangle Park, NC) (For example, USA) See Patent No. 5,035,237); Diskus (GlaxoSmithKline) (For example, see U.S. Patent No. 6,378,519; Turbuhaler (Astr aZeneca, Wilmington, Del.) (For example, U.S. 4,524, See issue 769); and Rotahaler (GlaxoSmithKline) (Example) For example, see U.S. Patent No. 4,353,365. Addition of suitable DPI device Examples include U.S. Patent No. 5,415,162, U.S. Patent No. 5,239,993 and U.S. This is described in Japanese Patent No. 5,715,810 and its references.

[0109] MDI devices typically use compressed injection gas to release a measured amount of therapeutic agent. MDI formulations contain a solution or suspension of the active ingredient in a liquefied propellant. Examples of propellants include hydrofluoroalklane. (HFA), for example, 1,1,1,2-tetrafluoroethane (HFA 134a) 1,1,1,2,3,3,3-heptafluoro-n-propane (HFA 227), Furthermore, chlorofluorocarbons, such as CCl3F, are used for MDI administration. Additional components of HFA formulations include cosolvents, such as ethanol, pentane, water; and the sulfate. Surfactants, such as sorbitan triolate, oleic acid, lecithin, and glycerin It is included. (For example, U.S. Patent No. 5,225,183, European Patent No. 0717987) See also International Publication No. 92 / 22286). The formulation is an air that forms part of the MDI device. Filled into a rosol canister. Specially developed for use with HFA propellant. Examples of MDI devices include U.S. Patent No. 6,006,745 and U.S. Patent No. 6,143,2 This is described in issue 27. A process for preparing suitable formulations and devices for inhalation administration. For example, see U.S. Patent No. 6,268,533, U.S. Patent No. 5,983,956, U.S. Japanese Patent No. 5,874,063 and U.S. Patent No. 6,221,398 and International Publication Publication No. 99 / 53901, International Publication No. 00 / 61108, International Publication No. 99 / 55319 See also International Publication No. 00 / 30614.

[0110] Monoterpenes (or sesquiterpenes) and / or at least one therapeutic agent are absorbed For delivery by means of [unclear], it may be encapsulated in liposomes or microcapsules. A vesicle is a small vesicle composed of a lipid bilayer and an aqueous interior. Lipid membranes include, for example, Sphatidylcholine, e.g., lecithin and lysolecithin; acidic phospholipids, e.g., ho Sphatidylserine and phosphatidylglycerol; as well as sphingophospholipids, Phospholipids such as phosphatidylethanolamine and sphingomyelin are examples of phospholipids. It may be made from a substance. Alternatively, cholesterol may be added. Microcaps A cell is a particle coated with a coating material. For example, coating The materials include film-forming polymers, hydrophobic plasticizers, surface activators and / or lubricants. It may consist of a mixture of polymers containing elements. U.S. Patent No. 6,313,176 and U.S. Patent No. 7,563,768.

[0111] Monoterpenes are also used via topical administration due to their ability to easily penetrate the dermis. Monoterpenes can be used alone or in combination with at least one therapeutic agent. Furthermore, as a transdermal delivery agent, it is used in combination with narcotics or analgesics for the transdermal delivery of pain medications. It can be used in this way.

[0112] The present invention also provides the above-mentioned compositions for ocular administration. Thus, the compositions penetrate The composition may further contain an accelerator. The compositions described herein are for ophthalmic administration. It can be formulated as a liquid, emulsion, suspension, etc. The compound is administered to the eye. Various vehicles suitable for this are known in the art. A specific, non-limiting example is the United States Special License No. 6,261,547, U.S. Patent No. 6,197,934, U.S. Patent No. 6,056, U.S. Patent No. 950, U.S. Patent No. 5,800,807, U.S. Patent No. 5,776,445, U.S. Patent No. License No. 5,698,219, U.S. Patent No. 5,521,222, U.S. Patent No. 5,403, U.S. Patent No. 841, U.S. Patent No. 5,077,033, U.S. Patent No. 4,882,150 and U.S. It is described in Japanese National Patent No. 4,738,851.

[0113] This composition can be administered over a short or long period of time. This composition is suitable for infant feeding. It can be administered to animals, preferably humans. It is not limited to mammals, however... , mice, rats, rabbits, monkeys, cows, sheep, pigs, dogs, cats, livestock, sports animals This includes objects, pets, horses, and primates.

[0114] Devices for intranasal administration include intranasal spray devices, atomizers, nebulizers, and metered-dose devices. MDI (medium-dose inhaler), pressurized dose inhaler, injector, intranasal inhaler, nasal spray bottle This could be a bottle, a unit dose container, a pump, a dropper, a squeeze bottle, or a bidirectional device.

[0115] The drugs may be administered simultaneously or sequentially.

[0116] The present invention also provides a method for inhibiting cell proliferation in vitro, ex vivo, or in vivo. Provided, and here, cells such as cancer cells are provided in an effective amount of purified monote as described herein. Contact with lupen (or sesquiterpene). This composition and method are used for chemotherapeutic agents. It can be used to inhibit the proliferation of cells that are resistant to it. For example, this composition and method It can be used to inhibit the proliferation of temozolomide-resistant cells.

[0117] Pathological cells or tissues such as overgrowth cells or overgrowth tissues are cells or The treatment can be performed by bringing the tissue into contact with an effective amount of this composition. This includes treating cells such as cancer cells. Is it possible that it is a primary cancer cell, or is it related to the American Type Culture Collection (AT)? These may be cultured cells available from tissue banks such as CC. Pathological cells may be systemic cancer cells. , glioma, meningioma, pituitary adenoma cells, or systemic cancer, lung cancer, prostate cancer (prost (Atelier cancer), breast cancer, hematopoietic cancer, or ovarian cancer These cells may be CNS metastases from ovarian cancer. It may be derived from an animal, preferably a mammal, and more preferably from a human. U.S. Patent Publication No. 200 No. 4 / 0087651. Balassiano et al.(2002) Intern J.Mol.Med. 10:785-788. Thorne, et al. (2004) ) Neuroscience 127:481-496. Fernandes, et a l. (2005) Oncology Reports 13:943-947.Da F onseca, et al. (2008) Surgical Neurology 70 :259267.Da Fonseca,et al.(2008) Arch.Immu nol.Ther.Exp. 56:267-276. Hashizume, et al. (2008) Neuroncology 10:112-120. Cancer stem cells (CSCs) or tumor progenitor cells possess stem cell characteristics, such as the ability to self-replicate. These are mature cells. However, self-renewal is impaired in CSCs. (Reya et al., S) tem cells, cancer, and cancer stem cells. N ature 2001, 414(6859):105-11. Furthermore, glioma CSCs are It is resistant to chemotherapy and radiotherapy. Bao et al., Glioma st em cells promote radioresistance by pref erential activation of the DNA damage re sponse. Nature 2006, 444(7120):756-60. Rich et al.,Chemotherapy and cancer stem cell ls. Cell Stem Cell. 2007;1(4):353-5. This composition and The method is not limited to inhibiting the proliferation of cancer stem cells, including glioblastoma cancer stem cells. It can be used for that purpose.

[0118] The following examples are provided for illustrative purposes only and are not intended to limit the invention. stomach.

[0119] [Example 1] NEO100-mediated human CAR T cell delivery to the brain and tumors Preparation of human CAR T cells Human CAR T cells (CD19 and Lym-1) were identified by Dr. Epstein (USC). ) was provided by. Chimeric antigen receptors (CARs) consist of three different modules, that is, The recognition site is based on an extracellular antibody, the transmembrane module is fixed to the cell membrane, and the active It is a synthetic molecule containing a chimeric intracellular signaling domain that transmits sexualization signals. nsen et al.,Designing chimeric antigen r eceptors to effectively and safely target t tumors.Curr.Opin.Immunol.2015,33,9-15. CAR T cells targeting CD19 are used in relapsed or refractory (R / R) acute lymphoblastic disease. Remarkable results have been achieved in the treatment of leukemia (ALL) patients. Ruella et al. al.,Dual CD19 and CD123 targeting preven ts antigen-loss relapses after CD19-dire cted immunotherapies.J.Clin.Invest.2016, 126,(10),3814-3826.Maude et al.,CD19-tar got chimeric antigen receptor T-cell t therapy for acute lymphoblastic leukemia. Blood 2015,125,(26),4017-23.Grupp et al. ,Durable Remissions in Children with Rel apsed / Refractory ALL Treated with T Cell s Engineered with a CD19-Targeted Chimer ic Antigen Receptor(CTL019).Blood 2015,1 26,(23),681-681. Using nuclei isolated from Raji lymphoma cells, By immunizing with the mouse, Lym-1, a mouse IgG2a monoclonal antibody, is produced. accomplished. Epstein et al.,Two new monoclonal an tibodies,Lym-1 and Lym-2,reactive with h uman B-lymphocytes and derived tumors,wi th immunodiagnostic and immunotherapeuti c potential.Cancer Res.1987,47,(3),830-4 0.Lym-1 is a discontinuous structural epitope on several HLA-DR subtypes. It binds to malignant B cells and shows higher binding affinity to malignant B cells than to normal B cells. Rose et al. al.,Critical Lym-1 binding residues on polymorphic HLA-DR molecules.Mol Immunol 1999, 36, (11-12), 789-97. As shown in Figure 1, Lym-1 C Schematic diagrams of the AR structure and the CD19 (FMC 63) CAR structure.

[0120] 0.9% physiological for use in IV injection in the presence and absence of intracardiac NEO100 Two million CD19 human CAR T cells and Lym-1 cells suspended in a saline solution. T-CAR T cells.

[0121] NEO100 cardiac puncture Working solution for intracardiac injection of NEO100 suspended in 0.9% physiological saline: 3% NEO100 Preparation of the liquid.

[0122] Standard procedure for ultrasound-guided cardiac puncture In summary, animals were anesthetized using 2% isoflurane gas and then palpated for cardiac puncture. It was fixed to the home. Under ultrasound imaging guidance, the left ventricle was examined through the skin and muscle layer. This involves quickly inserting the injection needle into the intercostal space.

[0123] A sign of successful needle insertion into the left ventricle is the presence of fresh arterial blood in the syringe (unlike dark red venous blood). This is a contrasting pink backflow. 40 μl of 3% NEO100 physiological saline solution is slowly... The injection was completed by adding the solution. Direct cell injection into the heart is possible because the cells aggregate during injection. In such cases, localized microinfarcts may develop, leading to pericardial hematoma, and potentially resulting in death. Yes. Therefore, in order to minimize these potential adverse effects, (1) Visualization of the course is necessary. (2) This makes it possible to ensure that the needle enters only the left ventricle, and subsequently, only the ECG after injection Instead, it monitors the heart through visualization of cardiac wall function using an ultrasonic device with a small 30G needle. Wave-guided injection is important. A thin gauge needle allows cells to be injected via cardiac puncture. At that time, prevent the cells from clumping together.

[0124] Confirmation of intracardiac injection A sign of successful needle insertion into the left ventricle is the presence of fresh arterial blood in the syringe (unlike dark red venous blood). It is a contrasting pink (backflow).

[0125] Immediately after the completion of the NEO100 injection, the tail vein catheter, which had been pre-primed with saline solution, Two million human CAR T cells in 40 μl of PBS were injected via tel.

[0126] To avoid the above potential adverse effects of direct cell injection via intracardiac administration, this study A two-step procedure was set up for the experiment.

[0127] Step 1: Slowly inject 40 μl of 3% NEO100 saline solution into the heart. This procedure was completed. This allows NEO100 to perform its BBB-breaking function. ru.

[0128] Step 2: Two million CAR T cells were intravenously injected through a tail vein catheter.

[0129] Evaluation of CAR T cell diffusion by IHC and confocal imaging Cerebral perfusion - 10 ml of fluid is administered through the left ventricle to remove residual material remaining in the blood vessels after euthanasia. The test animals were perfused with a 0.9% normal saline solution to wash away the blood. Then, the brains were removed. The samples were extracted, embedded in an OCT scanner, and stored at -80°C for subsequent analysis.

[0130] Confocal imaging-cryostasis system for 8 μM fresh frozen samples. A sample was prepared and attached to a microslide. Before confocal examination, DAPI mounting was performed. A coverslip was attached to the brain section using a solution.

[0131] IHC staining - Standardized IHC staining procedure is employed to stain the brain and formed tumors (GL We detected the permeability of human CAR T cells within mouse gliomas (261). The primary antibody was anti-H. CD3 antibody (CD3ε(D7A6E(trademark))XP(registered trademark) Rabbit mAb Using (#85061)(Cell Signaling, Boston, MA), Human-derived CD3-positive cells were identified (as shown in Figure 2).

[0132] Tests of a syngeneic mouse glioma animal model using C57 BL / 6 mice. Immunoimmunized C57 BL / 6 mice were injected with 100,000 GL261 mouse glioma cells. The cells were injected intracranially. Three weeks after the injection of tumor cells, brain tumor-bearing mice were administered intravenously (I V), and IV combined with intracardiac (IC), 2 million human CAR T cells (anti-C) D19 and Lym-1 were injected. The treated mice were euthanized 6 hours after the intervention. For intracardiac administration: After intracardiac injection of 3% NEO100 PBS solution, IV injection is administered. Two million anti-CD19 CAR T cells or Lym-1 CAR T cells are administered. For intravenous administration: 2 million anti-C cells in 40 µl of PBS injected through the tail vein. D19 CAR T cells or Lym-1 CAR T cells were suspended.

[0133] The brain was perfused with a 0.9% saline solution, extracted, and then subjected to -80 for subsequent analysis. o Keep at C It existed.

[0134] The antibody administered in the test includes a control antibody for negative staining: Rabbit(DA1E)m Ab IgG isotype, as well as CD3-positive cells, can be detected in vitro and in vivo. Antibody used: CD3ε(D7A6E(trademark))XP(registered trademark)Rabb it mAb(#85061) is included.

[0135] conclusion No detectable CD3-positive cells were found in the brains of normal C57 BL / 6 mice. .

[0136] Compared to conventional intravenous injection (IV), human CAR mediated by NEO100 Intracardiac injection of T cells (anti-CD19 and Lym-1) can penetrate tumors formed in the brain. It can be increased significantly.

[0137] 3% NEO100-mediated intracardiac injection does not cause any serious adverse effects or death in animals. stomach.

[0138] In normal brain tissue treated with intracardiac injection of NEO100, the results were better than in samples treated with IV injection alone. Many CD3-positive cells were observed.

[0139] [Example 2] C57 BL / 6 carrying intracranial syngeneic mouse glioma (GL261) Anti-mouse PD-1 antibody-mediated therapeutic effect in mice Immunoimmunized C57 BL / 6 mice were injected with 100,000 GL261 mouse glioma cells. The cells were injected intracranially. Seven days after the injection, the mice were randomly divided into four experimental groups and treated on the same day. It has started.

[0140] • Group 1, control: IV and intracardiac injection of 40 μl of saline solution (5).

[0141] • Group 2, antibody-treated mice: 40 μl of anti-mouse PD1 antibody at a dose of 2.5 mg / kg IV(5).

[0142] • Group 3, NEO100-treated mice: 40 μl of 5% NEO100 administered intracardiacly (5).

[0143] • Group 4, mice treated with NEO100 and antibody: 40 μl of 5% NEO100 administered to the heart Intravenous administration followed by IV administration of 40 μl of anti-PD1 antibody at a dose of 2.5 mg / kg (6).

[0144] The results are shown in Figure 3. Intracardiac injection of NEO100 (equivalent to intra-arterial injection in mice) was effective in reducing the antibody This demonstrated that the BBB could be opened. Then, a mouse G was implanted intracranially. A syngeneic model was conducted using L26 glioma cells. Physiological saline and NEO100 alone were used. Intravenous administration of anti-PD1 alone, or intracardiac administration of NEO100 followed by intravenous administration of anti-PD1. Mice were treated with intravenous administration of anti-PD1 in combination with NEO100. All mice survived, except for one mouse that received intravenous administration of anti-PD1. They all died.

[0145] Periryl alcohol is used in interventional neuroradiation to treat the femoral artery (cerebral blood). It can be administered via methods such as ductography.

[0146] statistical analysis The Kaplan-Meier method was used to plot animal survival data. Overall differences One-way ANOVA was used for the statistical test. Tukey's method was used to adjust for multiple comparisons. A comparison was performed using a log-rank (Mantel-Cox) test. The log-rank (Mantel-Cox) test was applied to compare survival curves. The statistical evaluation result was considered significant when p<0.05.

[0147] • Control vs. IC NEO100+IV anti-mouse PD-1: ***P<0.0003 • Control vs. IV anti-mouse PD-1: ns, p=0.31 • IV anti-mouse PD-1 vs. IC NEO100+ IV anti-mouse: **P<0.005 • Control pair IC NEO100: ns, p=0.397 [Example 3] NEO100 was administered across in vitro BBB models, and NEO100 was used to target The identified antibody may temporarily be able to pass through the in vitro BBB model. This was demonstrated (Figures 4A to 4D).

[0148] Periryl alcohol (e.g., NEO100) is used for intra-arterial delivery to temporarily reduce BBB. It breaks down the barrier, allowing small or large molecules that were previously impermeable to penetrate the brain. An experiment was conducted to investigate whether this was possible.

[0149] For administering periryl alcohol (e.g., NEO100), intracardiac injection (in mice) This may include intra-arterial injection and intravenous infusion.

[0150] The formulation is 10% NEO100 (glycerol 27.5ml + ethanol 27.5ml + Contains NEO100 (3.0ml).

[0151] Cerebral perfusion - Before euthanasia, the test animals were perfused through the left ventricle with a 0.9% normal saline solution. They flushed it out. The brain was removed, implanted in an OCT scanner, and stored at -80°C for further analysis.

[0152] Ultrasound-guided cardiac puncture - In summary, anesthetize animals using 2% isoflurane gas. The patient was fixed onto a platform for cardiac puncture. Under the guidance of ultrasound imaging, the skin To rapidly penetrate the left ventricle through the muscle layer and into the intercostal space with the injection needle. A sign of successful insertion is the presence of fresh arterial blood in the syringe (pink in color, in contrast to the dark red venous blood). This is a reverse flow.

[0153] Evans Blue is an azo dye that has a very high affinity for serum albumin. We were able to visualize the overflow of stained albumin from the circulation.

[0154] NEO100 was delivered via intracardiac injection (left ventricle) to Evans Blue, which is BBB-impermeable. We determined whether the uptake of sex molecules (dopamine) or antibodies into the brain was increased. Figure 5A shows intracardiac injection (IC) of a mixture of NEO100 and 2% Evans Blue (EB). This indicates a cardiac puncture followed immediately by intravenous administration of 2% Evans Blue (40 μl). By administering these solutions, different concentrations of NE0100 (40 μl in 0.9% physiological saline) can be tested. The brain was removed after perfusion. The result was N1:1000 dilution (6.5 mM 40 μl). This shows that EO100 is still effective in disrupting BBBs.

[0155] Figure 5B shows the brain after NEO100 has been administered via IC (intracardiac injection) or IV injection. This shows EB transmission.

[0156] The experimental group included: • IC 2%EB (standalone) • IC 20% ethanol + 2% EB • IC 20% Ethanol + 2% EB + 5% NEO100 • IC 20% ethanol + 5% NEO100, followed by 2% EB tail vein injection IV 20% Ethanol + 2% EB + 5% NEO100 IV 20% Ethanol + 2% EB

[0157] Figure 6 shows that in brains treated with 5% NEO100 intracardiac injection, compared to normal brains, This demonstrated that tight junctions are being dramatically destroyed.

[0158] The pharmacological treatment of Parkinson's disease (PD) is primarily based on dopamine (DA) replacement therapy. This is a symptomatic treatment, as it addresses the exogenous DA and other catecholamines that permeate the blood-brain barrier (BBB). This is because it cannot be administered due to poor quality. Dopamine is a water-soluble, hydrophilic drug. Furthermore, it does not meet the characteristics of a substance that can enter the brain through blood-brain barrier (BBB) ​​penetration.

[0159] Figure 7 shows that NEO100 mediated dopamine delivery across a disrupted blood-brain barrier. This indicates that.

[0160] Figure 8 shows the measurement of BBB opening and closing times in immunocompetent C57 BL / 6 mice. Inject 5% NEO100 (v / v) by intracardiac injection (IC), followed by 0.5 minutes after IC injection , Inject 2% Evans Blue intravenously at different time points such as 15 minutes, 30 minutes, 1 hour, 2 hours, 3 hours and 4 hours.

[0161] The experimental procedures included the following: 1. Intracardiac injection (IC): 5% NEO100.

[0162] 2. Subsequently, intravenous injection (IV) of 2% EB at different times.

[0163] 3. The test animals were euthanized 1 hour after IV injection.

[0164] Figure 9 shows the delivery of anti-mouse IgG antibody (rabbit anti-mouse IgG H&L (Texas Red)-Ab6726) in the absence or presence of perillyl alcohol.

[0165] Figure 10 shows the delivery of anti-PD-1 antibody (Armenian hamster anti-mouse CD279 (PD-1) monoclonal antibody (J43)) in the absence or presence of perillyl alcohol. PD-L1 binds to PD-1 and inhibits T cells from killing tumor cells . Blocking PD-L1 or PD-1 enables T cells to kill tumor cells.

[0166] NEO100 is safe for arterial administration. <00,01611>

[0167] [Example 4] NEO100-mediated delivery of human CAR T cells (Lym-1 CAR) in the treatment of intracranial Raji lymphoma xenografts in NSG mice (a) Intracranial lymphoma xenograft: 50,000 (5x10 4 ) human B cell lymphoma cells, Raji’s-Luc / G FP was injected intracranially into NSG mice.

[0168] (b) Confirmation of tumor uptake: Optical imaging was performed five days after tumor cell injection to confirm tumor uptake. (100% tumor uptake).

[0169] (c) Initiation of CAR T infusion via tail vein catheter and intracardiac (IC) NEO100 : Three experimental groups were set up: (1) control, (2) IV CAR T(5x10e6), ( 3)IV CAR T(5x10e6)+IC NEO100(0.3%v / v=492 μM) (d) Monitoring of NSG mice carrying IC lymphoma: The health status of mice during treatment was monitored by weight. Optical imaging was used. Tumor growth was monitored.

[0170] (e) Animal survival rate (Kaplan-Meier curve) As is clear from the survival curve (Figure 11), the control mouse, i.e., human B-cell lymphoma, Mice injected with the cells died within 15-20 days after injection, but Lym-1 CAR T Mice injected with cells + NEO100 survived (P=0.0029).

[0171] [Example 5] Intranasal inhalers (e.g., Kurve Technology (Bethell, Was) (Hington) ViaNase Electronic Atomizer) Insert OH. The intranasal delivery system from Kurve Technology is predetermined. The device can accurately deliver the prescribed drug amount (e.g., 0.2-6 mL). It is filled and cleaned in the same way as a blister. The device is designed for use with animals and humans. In a smear test, drugs can be delivered to the olfactory region.

[0172] Male athymoid nu / nu mice (6-8 weeks old) will be used in this study. Subcutaneous / intracranial rodent population. The glioma model can be established as follows: Ketamine (80 mg / kg) Intraperitoneal injection of bixylazine (10 mg / kg) was used to treat athymia in 6-8 week old nu / nu mice. Anesthetize the squirrel. In the case of an intracranial glioma model, use a stereotactic head frame (Harvard A A mouse is placed on a pparatus (a type of oysterol), and a local anesthetic (0.25% lidocaine 0.2cc) is administered. Inject the solution into the right frontal scalp. Make a small incision using a knife blade and use a drill bit Then, a small opening is made in the right frontal skull at the location of the coronal suture. Calibrated Hamiltonian In the syringe, glioma cells (1 × 10 5 (10 μl), for example, U-87 human glioma cells Fill the cell. Precisely position the tip of the needle in the rat's right frontal lobe and insert the contents from the Hamilton syringe. Use a Trollpush to slowly inject the cells. Once the injection is complete, remove the syringe. Remove the needle and close the wound.

[0173] Two weeks after surgical transplantation, the mice were divided into four groups (6 mice / group) and each group was given saline droplets. Only (control), crude POH from Sigma (0.03%, 50 μl / drop, 1 per nostril) (drops), POH (purified to over 98.5% purity; 0.03%, 50 μl / drop, 1 per nostril) Treatment involves drops and TMZ (5 mg / kg, forced oral administration). TMZ is used as a positive control. It functions as such.

[0174] The brain is collected and the tumor size is determined. The mice are then tracked until neurological defects occur. A survival curve is constructed based on this. In our experience, the survival period in untreated mice is after transplantation. The incubation period is approximately 4 weeks, and up to 8 weeks in TMZ-treated mice.

[0175] Additionally, RG2 rat glioma cells (1 × 10⁶) were found in the right frontal lobe of Fisher344 rats. 5 We also use immunocompetent syngeneic rat models in which (10µl / 10µl) are transplanted. The cells are separated. Also, RG2 cells move freely and therefore infiltrate the rat parenchyma. Therefore, we will use the rat RG2 model to investigate the anti-invasive properties of POH.

[0176] [Example 6] A recent clinical study in Brazil showed that periryl alcohol was used in patients with relapsed malignant glioma. Intranasal delivery of the drug resulted in disease regression or stabilization in 140 treated patients. Fifty percent of the cases achieved a six-month progression-free period, and several patients enjoyed disease remission for as long as three years. Furthermore, there were virtually no side effects from the treatment. Da Fonseca et al. orrelation of tumor topography and perit umoral edema of recurrent malignant glio mas with therapeutic response to intrana sal administration of perylyl alcohol. I nvest New Drugs January 13, 2009. For patients suffering from malignant glioma, purified POH (with a purity of over 98.5%) is administered. ) will be delivered intranasally. We will investigate whether POH can be directly delivered to brain tumor cells. In order to, 11 14C-labeled POH was delivered to the patient, followed by positron emission tomography (PET) imaging. The distribution of purified POH is examined by performing a aging test. Then, the patient is given the following treatment. A limited therapeutic trial will be conducted using gradually increasing doses of inhaled POH. Three groups will be used to evaluate the patients. The dose was gradually increased, with each group receiving 0.05% (w / v), 1% (w / v), and 1.5% (w / v). ), 2% (w / v), 2.5% (w / v) purified POH (purity over 98.5%) nasally It is administered orally. 2% (w / v) is the one currently used in Brazil. Delivery is via Vi Administered via aNase nasal inhaler, three times daily. PET imaging test. Siemen Using a Biograph TruePoint HD PET / CT scanner , 11 After intranasal inhalation of 5-10 mCi of C-POH preparations, malignant gliomas were pathologically confirmed. Ten confirmed patients will be scanned. Static imaging will be performed in a single-bed position covering the skull. Use a 10-minute inhalation period, starting 30 minutes after inhalation. Continue with 30 consecutive inhalations. The procedure is performed every minute for two hours to assess the progressive accumulation of brain and tumor tissue. Patient compliance Depending on the level of activity and residual and accumulated activity, attempt imaging for more than 2 hours. For all patients, we compared co-registered PET / CT images with contrast-enhanced MRI scans to determine activity accumulation and Evaluate the correlation with the contrast enhancement pattern.

[0177] The scope of the present invention is not limited to what is specifically shown and described above. If so, there are suitable alternatives to the illustrated examples of materials, composition, structure, and dimensions. This will be recognized. The description of this invention refers to numerous references, including patents and various publications. Such references are cited and discussed. Such citations and discussions are merely the theory of the present invention. These references are provided for clarity and do not apply to the present invention as described herein. This does not acknowledge that the above is prior art. All references are incorporated herein by reference in their entirety. Any modification, alteration, or other implementation of the present invention shall not deviate from the spirit and scope of the present invention. It is not obvious to those skilled in the art. Although specific embodiments of the present invention have been shown and described, The invention may be modified and altered without departing from its spirit and scope. It will be obvious to those skilled in the art. The matters described above and in the attached drawings are illustrative examples. It is only available through [specific means] and is not offered as a limited-time offer.

Claims

1. A method for administering a therapeutic agent to the central nervous system of a mammal, wherein the therapeutic agent is administered before or after the administration of the therapeutic agent. A method that includes administering a monoterpene simultaneously with a therapeutic agent.

2. The method according to claim 1, wherein the central nervous system is the brain.

3. The method according to claim 1, wherein the monoterpene is periryl alcohol.

4. The method according to claim 3, wherein periryl alcohol is administered intra-arterially.

5. Periryl alcohol is present in a range of approximately 0.050 mg / kg body weight to approximately 500 mg / kg body weight. The method according to claim 3, administered in the specified dose.

6. The method according to claim 1, wherein the mammal is a human.

7. The monoterpene is administered approximately 0.2 minutes to approximately 60 minutes before the therapeutic agent is administered. The method according to claim 1.

8. The monoterpene is administered approximately 1 to 15 minutes before the therapeutic agent is administered, The method described in item 7.

9. The method according to claim 1, wherein the monoterpene and the therapeutic agent are administered separately.

10. The method according to claim 1, wherein the monoterpene and the therapeutic agent are administered simultaneously.

11. Claim 10, wherein the monoterpene and the therapeutic agent are administered together in the pharmaceutical composition. Method of description.

12. The method according to claim 1, wherein the therapeutic agent is a chemotherapeutic agent.

13. The aforementioned chemotherapeutic agents include DNA alkylating agents, topoisomerase inhibitors, and endoplasmic reticulum stress inducers. Conductors, platinum compounds, antimetabolites, enzyme inhibitors, receptor antagonists, therapeutic antibodies and related products. The method according to claim 12, selected from a group consisting of combinations.

14. The aforementioned chemotherapeutic agents are dimethylcelecoxib (DMC) and irinotecan (CPT-11). The method according to claim 12, wherein the material is temozolomide or rolipram.

15. The method according to claim 1, wherein the therapeutic agent is an antibody or an antibody fragment.

16. The method according to claim 1, wherein the therapeutic agent is an immune cell expressing a chimeric antigen receptor.

17. The method according to claim 16, wherein the immune cell is a T cell.

18. The method according to claim 16, wherein the therapeutic agent is CAR-T cells.

19. The monoterpene is administered by inhalation, intranasal administration, or orally. The person described in claim 1, who is administered intravenously, subcutaneously, or intramuscularly. Law.

20. The method according to claim 1, wherein the mammal has cancer.

21. The method according to claim 20, wherein the cancer is a tumor of the nervous system.

22. The method according to claim 21, wherein the tumor is a glioblastoma.

23. The method according to claim 1, further comprising treating the mammal with radiation.

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