• 专利附录
  • 专利说明
  • 权利要求
  • 类似技术
  • 同族专利
  • 引用文献
  • 法律状态
  • 优先权
    • 专利摘要:
    Use of melatonin for the treatment of tumors. The present invention describes the use of melatonin for the preparation of a pharmaceutical composition suitable for intratumoral administration for the treatment of tumors. This composition comprises high concentrations of melatonin, melatonin derivatives or metabolites, so that melatonin exerts an oxidizing effect, increasing the production of free radicals and producing an activation of cell death. (Machine-translation by Google Translate, not legally binding)
    公开号:ES2684408A1
    申请号:ES201730598
    申请日:2017-03-31
    公开日:2018-10-02
    发明作者:Germanine ESCAMES ROSA；Darío Acuña Castroviejo；Ana GUERRA-LIBRERO RITE；Beatriz Irene FERNÁNDEZ GIL；Javier FLORIDO RUIZ
    申请人:Universidad de Granada；
    IPC主号:
    专利说明:

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    Melatonin, describes a dose of 19 pg / ml of melatonin to exert its antioxidant effects. At these concentrations, melatonin produces an effect that does not increase mitochondrial function, so there are no free radicals that can activate cell death.
    Therefore, although it is known that melatonin inhibits cell proliferation and increases cell death as long as it enters the tumor cell in adequate amounts, so far, a use of melatonin has not been described that allows reducing recurrences in the treatment of cancer, as well as resistance to cost-effective treatments.
    BRIEF DESCRIPTION OF THE INVENTION
    The present invention relates to a pharmaceutical composition for intratumoral administration comprising high concentrations of melatonin, melatonin derivatives or metabolites, so that melatonin exerts an oxidizing effect, as opposed to its usual use and, in particular, as recommended. , for example, in [US 9289428 B2]. It increases mitochondrial function and, consequently, the production of free radicals causing an activation of cell death.
    In a second aspect, the present invention relates to the use of melatonin, in particular the use of the aforementioned intratumoral composition, for the treatment of tumors, preferably for the removal of tumors.
    The invention also describes a method of treatment comprising intratumoral administration of a therapeutically effective amount of melatonin.
    BRIEF DESCRIPTION OF THE FIGURES
    Figure 1.-Analysis of the penetration of melatonin in tumor cells. It is observed that melatonin easily enters the tumor cells in a dose-dependent manner in in-vitro experiments. It reaches maximum levels of 450 ng / mg proteins after incubating the cells with melatonin at a dose of 1500 M for 24 hours.
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    DETAILED DESCRIPTION OF THE INVENTION
    Definitions
    5 The term "intratumoral administration" used herein includes any technique that allows a compound of general formula X, in particular melatonin, to be introduced into a tumor. These techniques include injection, electroporation or electropermeabilization, ultrasound-mediated administration, creams, lotions or other forms of administration.
    10
    The term "treatment" or "treat" in the context of this document refers to the administration of a compound or a composition according to the invention to improve or eliminate a disease, pathological condition or one or more symptoms associated with said disease or condition in a mammal, preferably in canines or humans,
    15 more preferably in dogs. "Treatment" also covers the improvement or elimination of the physiological sequelae of the disease. Specifically, the concept "treat" can be interpreted as:
    i. Inhibit the disease or pathological condition, that is, stop its development;
    20 ii. Relieve the disease or the pathological condition, that is, it causes the regression of the disease or the pathological condition;
    iii. Stabilize the disease or pathological condition.
    In particular, the term treatment includes the selective destruction of tumor cells, and, in particular, the total removal of a tumor.
    Throughout the description and claims the term "comprises", which may also be construed as "consists of", and its variants are not intended to exclude other technical characteristics, additives, components or steps. For experts in the field,
    Other objects, advantages and features of the invention will be derived partly from the description and partly from the practice of the invention.
    Pharmaceutical compositions
    35
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    The term "solvate" according to this invention is to be understood as that derivative of melatonin having another molecule, for example a polar solvent, joined by means of a non-covalent bond. Examples of such solvates include hydrates and alcoholates, for example methanolates.
    The preparation of salts, solvates and prodrugs can be carried out by methods known in the state of the art. Non-pharmaceutically acceptable salts, solvates or prodrugs are also within the scope of the invention since they can be useful in the preparation of pharmaceutically acceptable salts, solvates or prodrugs. The composition of the invention invention may also refer to a composition comprising a functional biological equivalent of melatonin in a concentration that is equivalent to that described in the compositions of the invention.
    The term "functional biological equivalent" or "bioequivalent variable" as used in the present description refers to a molecule with the same function as the described molecule, which may have slight variations with respect to the described molecule without said Variations provide no technical effect added to said molecule. In the present invention, it therefore refers to melatonin variants that have the same function and that show slight variations without such variations providing any technical effect added to melatonin.
    By "concentration that is equivalent" is meant that concentration necessary for the functional biological equivalent of melatonin that produces the same effect as described in the present invention by the composition of the invention.
    Melatonin is also produced in vegetables. For example, the presence of melatonin in algae, edible plants, cereals, fruits, seeds, roots, stems, leaves and medicinal herbs has been described. For example, the presence of melatonin in cocoa, grapes, tomatoes, tea, green tea, seaweed, cereals and olives has been described. Therefore, the origin of the melatonin of the composition of the invention can be vegetable. Obtaining melatonin of plant origin (also called phytomelatonin) can be carried out by any method known to the person skilled in the art for this purpose.
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    The term "adjuvant" refers to any substance that potentiates the response of an active substance. In the present invention it refers to any substance that potentiates the effects of the composition of the invention, may refer to any adjuvant known to the person skilled in the art.
    5 The term "pharmaceutically acceptable" refers to the compound referred to being allowed and evaluated so as not to cause damage to the organisms to which it is administered.
    Another preferred embodiment relates to the use where the composition further comprises a gelling agent. Preferably the gelling agent is selected from the list comprising copolymer of polyethylene and polypropylene, cellulose and guar gum. It preferably refers to polyethylene and polypropylene copolymer. As described herein, another embodiment referred to refers to the use where the composition is a gel (or
    15 also called "hydrogel").
    In the case of intratumoral administration, in particular injectable administration, of a gel, an example of a pharmaceutically acceptable carrier is a 5% isotonic solution of pluronic.
    The term "gelling agent" refers to a substance that forms a gel, that is, a three-dimensional network formed by the gelling agent and generally containing a liquid phase.
    Thus, the gelling agents that can be used to make the gel that is administered intratumorally may be those known to those skilled in the art for the preparation of a pharmaceutical composition. For example, among the copolymers of polyethylene and polypropylene copolymers of poloxamer (or poloxamer) could be used, for example the agents called Pluronic®, including Pluronic® F127 (number
    30 CAS 9003-11-6) or Pluronic® F127NF.
    In another preferred embodiment, the composition further comprises at least one preservative.
    35 “Preservative” means a substance that maintains the properties of the drug by inhibiting germ contamination, can be an ionic preservative


    or non-ionic. The preservative used will not be toxic, will be chemically stable, and compatible with melatonin. As preservatives, those known in the state of the art can be used, for example, the preservative may refer to benzoic acid, sodium benzoate, ascorbic acid, potassium sorbate, methylparaben, ethylparaben
    5 or butylparaben. "Germs" means any cell that can grow and multiply in the composition of the invention, for example bacteria, fungi and yeasts.
    The amounts of active substances to be administered may vary depending on the particularities of the therapy.
    The compositions of the invention are prepared using standard methods such as those described or referred to in the Spanish and US Pharmacopoeias and similar reference texts.
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    Combined Preparations
    The term "combined preparation" or also called "juxtaposition", in this
    20 memory means that the components of the combined preparation need not be present as a joint, for example in a true composition, in order to be available for combined, separate or sequential application. In this way, the expression "juxtaposed" implies that it is not necessarily a true combination, in view of the physical separation of the components.
    Thus, in another aspect, the invention relates to a pharmaceutical composition, preparation or form suitable for intratumoral administration, hereinafter "combined preparation of the invention", comprising:
    a) a therapeutically effective amount of the compound of general formula X, preferably melatonin, and b) another active principle against tumors.
    Invention kit
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    权利要求:
    Claims (1)
    [1]
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    同族专利:
    公开号 | 公开日
    ES2684408B1|2019-07-09|
    WO2018178497A2|2018-10-04|
    BR112019020519A2|2020-05-05|
    EP3603635A4|2021-01-20|
    US11234964B2|2022-02-01|
    US20210106562A1|2021-04-15|
    WO2018178497A3|2018-11-15|
    EP3603635A2|2020-02-05|
    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    US20140329785A1|2011-06-10|2014-11-06|Ramscor, Inc.|Conveniently Injectable or Implantable Sustained-Release Antioxidant Formulations for Therapies of Ocular Maladies or Cancer|
    EP1656939A1|2004-11-10|2006-05-17|Pooger Properties Limited|Use of melatonin in the manufacture of a medicament for treating cancer|
    US8075902B2|2007-01-03|2011-12-13|Michael Powell|Diagnosis and treatment of cancer related to human dormancy|
    CA2666036C|2008-05-16|2017-09-12|Chien-Hung Chen|Novel compositions and methods for treating hyperproliferative diseases|
    ES2384798B1|2011-10-19|2013-06-04|Universidad De Granada|USE OF MELATONIN FOR THE TREATMENT AND / OR PREVENTION OF MUCOSITIS.|
    ES2394245B2|2012-11-28|2013-12-16|Universidad De Granada|COMPOSITION OF MELATONIN OR ITS DERIVATIVES WITH COENZYME Q10 AND ITS USE AGAINST SKIN AGING|
    EP3124023A4|2014-03-27|2017-09-06|Servicio Andaluz De Salud|Durable preparation of an injectable of melatonin exhibiting long-term stability|
    法律状态:
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    优先权:
    申请号 | 申请日 | 专利标题
    ES201730598A|ES2684408B1|2017-03-31|2017-03-31|USE OF MELATONIN FOR TUMOR TREATMENT|ES201730598A| ES2684408B1|2017-03-31|2017-03-31|USE OF MELATONIN FOR TUMOR TREATMENT|
    US16/498,825| US11234964B2|2017-03-31|2018-04-02|Use of melatonin for the treatment of tumors|
    EP18776647.2A| EP3603635A4|2017-03-31|2018-04-02|Use of melatonin for the treatment of tumours|
    BR112019020519A| BR112019020519A2|2017-03-31|2018-04-02|use of melatonin for the treatment of tumors|
    PCT/ES2018/070289| WO2018178497A2|2017-03-31|2018-04-02|Use of melatonin for the treatment of tumours|
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