WO2017148129A1 - Composition pharmaceutique destinée au traitement de la cachexie et son utilisation - Google Patents

Composition pharmaceutique destinée au traitement de la cachexie et son utilisation Download PDF

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Publication number
WO2017148129A1
WO2017148129A1 PCT/CN2016/099329 CN2016099329W WO2017148129A1 WO 2017148129 A1 WO2017148129 A1 WO 2017148129A1 CN 2016099329 W CN2016099329 W CN 2016099329W WO 2017148129 A1 WO2017148129 A1 WO 2017148129A1
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WO
WIPO (PCT)
Prior art keywords
cytarabine
ketorolac
pharmaceutical composition
cachexia
analogue
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Ceased
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PCT/CN2016/099329
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English (en)
Chinese (zh)
Inventor
张东旭
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Changchun Nuosai Biotechnology Co Ltd
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Changchun Nuosai Biotechnology Co Ltd
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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
    • A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
    • A61K31/7068—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/407—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with other heterocyclic ring systems, e.g. ketorolac, physostigmine

Definitions

  • the invention relates to the field of pharmaceutical preparations, in particular to a pharmaceutical composition containing cytarabine and ketorolac and application.
  • cachexia comes from the Greek words “kakos” and “hexis”, which literally mean “bad conditions.” (Cachexia as a major underestimated and unmet medical need: facts and numbers J Cachexia Sarcopenia Muscle (2010) 1:1–5). The main symptoms of cachexia include weight loss, muscle atrophy, fatigue, and loss of appetite. The medical definition of cachexia is weight loss and body weakness that cannot be reversed by increased nutrition.
  • Cachexia is common in cancer, AIDS, sepsis, severe trauma, chronic obstructive pulmonary disease, multiple sclerosis, congestive heart failure, tuberculosis, familial amyloid polyneuropathy, chronic kidney disease, cystic fibrosis, type I diabetes and other progressive Chronic chronic disease (Biology of Cachexia, J Natl Cancer Inst (1997) 89 (23): 1763-1773; Cancer cachexia, mechanism and treatment, World J Gastrointest Oncol. 2015 Apr 15; 7(4): 17-2).
  • Cachexia is a risk factor that can lead to death in patients, which means that in the case of cachexia, the likelihood of death will increase significantly. According to reports in the literature, 30% of cancer patients die directly from cachexia, rather than die from tumor occupying.
  • cachexia In addition to being directly to death, once the cachexia occurs, the impact on the patient is very serious.
  • the cachexia not only causes the patient's body to weaken rapidly until the loss of self-care ability, but also seriously reduces the response and tolerance of the above patients to standard treatment. According to statistics, 80% of patients with advanced cancer have cachexia symptoms, which brings great pain and pressure to the extremely family members. Once a cancer patient has a serious cachexia, it means the patient enters the end stage. Cancer The patient's treatment strategy will be changed to palliative care, and the patient's survival time can be calculated in weeks. In addition to cancer, cachexia is also a high incidence in patients with chronic obstructive pulmonary disease.
  • the drugs currently used are mainly pregnancy hormones (including megestrol acetate and medroxyprogesterone acetate), as well as corticosteroids (including dexamethasone, methylprednisolone and prednisolone).
  • pregnancy hormones including megestrol acetate and medroxyprogesterone acetate
  • corticosteroids including dexamethasone, methylprednisolone and prednisolone.
  • megestrol acetate and medroxyprogesterone acetate can increase appetite, calorie intake and nutritional status, but the increased body weight is mainly fat. The patient's quality of life and survival were not significantly extended.
  • a first object of the present invention is to provide a use of cytarabine or an analogue thereof for the preparation of a medicament for treating cachexia.
  • Cytarabine is a pyrimidine nucleoside analog that interferes with cell proliferation by inhibiting the synthesis of cellular DNA. The first was founded by Berkeley's Richard Walwick in 1959. synthesis. Cytarabine is mainly used in acute leukemia, including acute myeloid leukemia and acute lymphocytic leukemia, and also in lymphoma. Among them, acute myeloid leukemia has the best effect, but cytarabine or its analogues have not been reported for the treatment of cachexia.
  • the cachexia according to the present invention may be tumor, AIDS, sepsis, severe trauma, chronic obstructive pulmonary disease, multiple sclerosis, congestive heart failure, tuberculosis, familial amyloid polyneuropathy, chronic kidney disease, cystic fibrosis, type I Induction of diabetes and other progressive chronic diseases.
  • the cachexia of the present invention is induced by a tumor, such as pancreatic cancer, lung cancer, gastric cancer, and colorectal cancer.
  • the cytarabine analogs of the present invention include pharmaceutically acceptable salts, solvates, hydrates, stereoisomers, clathrates or prodrugs of cytarabine.
  • the ketorolac analog is a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate or prodrug of ketorolac.
  • the pharmaceutically acceptable salt of cytarabine includes pharmaceutically acceptable cytarabine salt including cytarabine hydrochloride; solvate means a solvate containing the above medicinal ingredient; hydrate means an aqueous compound of the above active ingredient
  • the clathrate refers to a clathrate containing the above-mentioned active ingredient; the prodrug thereof includes a compound which can react in the body to form the above-mentioned active ingredient.
  • Cytarabine prodrugs include, but are not limited to, prolyl cytarabine, cytarabine fatty acid derivative CP-4055, cytarabine phosphoramidate, Astarabine (cytarabine and aspartyl A conjugate of cytosine, etc., an ideal cytarabine analog such as cytarabine hydrochloride.
  • the present invention unexpectedly finds that cytarabine or its analog can be used alone for the treatment of cachexia, which can improve the health status of cachexia mice and prolong the survival of cachexia mice without affecting tumor growth.
  • the above results indicate that it is suitable for cachexia.
  • the treatment has significant activity.
  • a second object of the present invention is to provide a use of ketorolac or an analogue thereof, or a combination of ketorolac or an analogue thereof with cytarabine or an analogue thereof for the preparation of a medicament for the treatment of cachexia.
  • Ketorolac is a derivative of pyrrolic acid, a non-steroidal anti-inflammatory drug that inhibits PG synthesis, has analgesic, anti-inflammatory, antipyretic effects and inhibits platelet aggregation.
  • ketorolac is mainly used for short-term treatment of various pains including various post-operative pains (such as abdomen, chest, Acute skeletal muscle pain caused by various causes such as urology, gynecology, stomatology, orthopedics, such as sprains, dislocations, fractures and soft tissue injuries, and pain caused by other diseases such as postpartum pain, acute renal colic, Toothache, sciatica, advanced cancer pain, traumatic pain, biliary colic, etc., can be used as a substitute for morphine and pethidine.
  • ketorolac or its analogues for cachexia has not been reported.
  • ketorolac analogs of the present invention are pharmaceutically acceptable salts, solvates, hydrates, stereoisomers, clathrates or prodrugs of ketorolac.
  • ketorolac is a pharmaceutically acceptable salt of ketorolac including ketorolac tromethamine; a solvate means a solvate containing the above medicinal ingredient; and a hydrate is an aqueous compound of the above active ingredient.
  • the clathrate refers to a clathrate containing the above-mentioned active ingredient; the prodrug thereof includes a compound which can react in the body to form the above-mentioned active ingredient.
  • Prodrugs of ketorolac include, but are not limited to, galactosyl ketorolac, alkyl ketoroate, piperazine alkyl ketoroate, ketorolac amide, and the like. Among them, ketorolac tromethamine is preferred.
  • ketorolac or an analog thereof can be used alone for the treatment of cachexia, which can increase body weight and improve quality of life, that is, ketorolac or an analog thereof can effectively alleviate symptoms caused by cachexia.
  • the present inventors have unexpectedly discovered that when the above two active ingredients (cytarabine or the like thereof are combined with ketorolac or the like), the two achieve a remarkable synergistic effect and can be more ideally applied. Treatment of cachexia.
  • a third object of the present invention is to provide a novel pharmaceutical composition for filling the gap in the current clinical lack of effective cachexia treatments.
  • the present invention adopts the following technical solutions:
  • a pharmaceutical composition comprising an active ingredient consisting of cytarabine or an analogue thereof and one or more of ketorolac or an analogue thereof, preferably one of cytarabine or an analogue thereof and a ketone
  • a composition of oleic acid or an analog thereof comprising an active ingredient consisting of cytarabine or an analogue thereof and one or more of ketorolac or an analogue thereof, preferably one of cytarabine or an analogue thereof and a ketone
  • the above pharmaceutical composition may be cytarabine or the like alone
  • One or more of the active ingredients may also be exemplified by one or more of ketorolac or the like as an active ingredient, or cytarabine or an analogue thereof and ketorolac or the like thereof, respectively. One or several of them are used together as an active ingredient.
  • the inventors found that when the two are used in combination, the molar ratio change of the two has an influence on the degree of synergistic effect. Based on the in-depth study, the cytarabine or its analog and ketone are shown.
  • the molar ratio of oleic acid or an analog thereof is from 154.8 to 0.8:1. Within the above dosage range, the synergistic effect of the two can be maximized.
  • the molar ratio of the two is preferably from 30 to 1.5:1.
  • the active ingredient in the pharmaceutical composition is composed of cytarabine and ketorolac tromethamine, and the molar ratio of the two is preferably from 30 to 1.5:1, preferably from 6 to 1.5:1.
  • the total content of the above active ingredient in the pharmaceutical composition is from 0.5 to 50%, preferably from 1 to 20%.
  • compositions of the present invention further comprise a pharmaceutically acceptable adjuvant to prepare a particular dosage form.
  • pharmaceutically acceptable excipients herein are understood by those skilled in the art, and different dosage forms prepared according to the requirements may be selected to select suitable excipient types, which are specifically controlled by those skilled in the art, and the present invention is not particularly limited thereto.
  • the pharmaceutical composition of the present invention is preferably an oral preparation, a scalp absorbent or an injection preparation, etc.
  • the oral preparation is preferably a tablet, a granule, or a syrup
  • the injection preparation is preferably a lyophilized powder injection or an injection.
  • the invention also provides the use of the above pharmaceutical composition for the preparation of a medicament for treating cachexia.
  • the cachexia according to the present invention may be tumor, AIDS, sepsis, severe trauma, chronic obstructive pulmonary disease, multiple sclerosis, congestive heart failure, tuberculosis, familial amyloid polyneuropathy, chronic kidney disease, cystic fibrosis, type I Induction of diabetes and other progressive chronic diseases.
  • the above pharmaceutical composition is more effective in the preparation of a therapeutic effect on tumor-induced cachexia, which is preferably pancreatic cancer, lung cancer, gastric cancer and colorectal cancer. Also it is said that the pharmaceutical composition of the present invention is most effective for the treatment of cachexia caused by the above-mentioned several types of tumors.
  • cytarabine or its analogs and ketorolac or its analogs as an active ingredient of a composition for the treatment of cachexia, especially for the treatment of cachexia induced by tumors, has produced an unexpected effect.
  • the pharmaceutical composition of the invention completely reverses the progress of cachexia without affecting the growth of the tumor, and the healthy state of the mouse completely returns to the normal state, reaches the state of cure of cachexia, and the survival period is greatly prolonged. Due to the extremely prolonged survival period, the tumor burden at the end of the treatment group was twice as high as that of the control group. It can be seen that the present invention provides a new means for treating cachexia without inhibiting tumor growth.
  • the active ingredients of the pharmaceutical composition of the present invention are all known compounds and can be purchased from raw material pharmaceutical companies, such as cytarabine, which can be purchased from Wuhan Yuancheng Co-creation Technology Co., Ltd., etc., ketorolac tromethamine can be purchased. Since Hubei Jusheng Technology Co., Ltd. and so on.
  • the present invention for the first time, uses cytarabine or an analog thereof and ketorolac or an analog thereof as a composition for the treatment of cachexia, exhibiting surprising therapeutic effects in the study.
  • the efficacy of this composition exceeds the currently used clinically used drugs as well as the reported on-the-spot drugs for cachexia. Based on the severity of cachexia, the present invention has broad clinical application prospects.
  • the present embodiment provides a pharmaceutical composition in which the active ingredients are: cytarabine and ketorolac, and the mass ratio of the two is 1.5:1.
  • the present embodiment provides a pharmaceutical composition, wherein the active ingredients in the pharmaceutical composition are: cytarabine and ketorolac tromethamine, and the mass ratio of the two is 3:1.
  • This embodiment provides a pharmaceutical composition in which the active ingredient is Divided into: cytarabine hydrochloride and ketorolac, the mass ratio of the two is 3:1.
  • the present embodiment provides a pharmaceutical composition, wherein the active ingredients in the pharmaceutical composition are: cytarabine hydrochloride and ketorolac tromethamine, the mass ratio of which is 4.5:1.
  • the present embodiment provides a pharmaceutical composition, wherein the pharmaceutical composition is an injection solution, and the specific prescription of the injection solution is: 20 parts by weight of cytarabine, 10 parts by weight of ketorolac tromethamine, and increased 2 parts by weight of the solvent poloxamer, 15 parts by weight of the isotonicity adjusting agent sodium chloride, an appropriate amount of the pH adjuster (pH adjusted to 7.0-7.4), and 50 parts by weight of water for injection.
  • the specific prescription of the injection solution is: 20 parts by weight of cytarabine, 10 parts by weight of ketorolac tromethamine, and increased 2 parts by weight of the solvent poloxamer, 15 parts by weight of the isotonicity adjusting agent sodium chloride, an appropriate amount of the pH adjuster (pH adjusted to 7.0-7.4), and 50 parts by weight of water for injection.
  • the present embodiment provides a pharmaceutical composition
  • the pharmaceutical composition is a lyophilized powder injection
  • the specific prescription of the lyophilized powder injection is: 30 parts by weight of cytarabine, ketorolac tromethamine 10 Parts by weight, excipient mannitol 20 parts by weight, antioxidant vitamin C3 parts, and pH adjusting agent (pH adjusted to 7.0-7.4).
  • This embodiment also provides a preparation method of the above lyophilized powder injection: weigh the above-mentioned prescription amount of the active ingredient and the excipient, dissolve it in a prescribed amount of water for injection, stir to a complete solvent, and then add a prescription amount of anti-drug The oxidant is adjusted to pH 7.0-7.4 with a prescribed amount of pH adjuster. The drug solution was filtered and sterilized, and filled in a glass bottle. After lyophilization, the seal is obtained.
  • the efficacy verification involved in this experimental example was performed on a C26 colon cancer cachexia animal model.
  • the C26 colon cancer cachexia model is a universal animal model of cancer cachexia. It is widely used in screening tests for anti-cachexia drugs. This model can cause rapid and sustained weight loss and body weakness until death in patients with advanced cancer.
  • Model establishment was performed using female BALB/C mice weighing approximately 20 grams, using subcutaneously inoculated 500,000 C26 tumor cells. Mice weigh more than 5% as a standard for cachexia.
  • Control group normal saline
  • a cytarabine group a physiological saline solution having a cytarabine concentration of 3 mg/ml;
  • composition group cytarabine and ketorolac tromethamine solution, wherein the concentration of cytarabine is 3 mg / ml, the concentration of ketorolac tromethamine is 1 mg / ml;
  • the cytarabine group was administered subcutaneously with 0.1 ml of a cytarabine solution
  • the composition group was administered subcutaneously with 0.1 ml of a mixture solution of cytarabine and ketorolac tromethamine.
  • mice The health status and body weight changes of the mice were closely followed during the experiment.
  • Control group normal saline
  • Ketorolata tromethamine group a physiological saline solution having a ketorolac tromethamine concentration of 1 mg/ml;
  • composition group cytarabine and ketorolac tromethamine solution, wherein the concentration of cytarabine is 3 mg / ml, the concentration of ketorolac tromethamine is 1 mg / ml;
  • the diseased mice were divided into three groups, namely a saline control group, a ketorolac group and a composition group.
  • the ketorolac group was administered subcutaneously with 0.1 ml of a ketorolac tromethamine solution
  • the composition group was administered with 0.1 ml of a physiological saline solution of ketorolac tromethamine and cytarabine subcutaneously.
  • the survival time of each group of mice was recorded after administration, and the control group and each treatment group were compared by t test.
  • mice in the composition treatment group was prolonged, and the difference was significant (p ⁇ 0.05).
  • the survival time of the ketorolac tromethamine group was not significantly different from that of the control group (p>0.05).
  • the present invention relates to the use of cytarabine or an analogue thereof and ketorolac or an analogue thereof for the treatment of cachexia, and in particular to a pharmaceutical composition useful for the treatment of cachexia.
  • the present invention is the first to creatively use one or more of cytarabine or its analogs and ketorolac or an analogue thereof as an active ingredient of a composition for the treatment of cachexia, exhibiting surprising treatment in animal experiments. Efficacy. Based on the severity of cachexia, the present invention has broad clinical application prospects and desirable industrial applicability.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Molecular Biology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne l'utilisation de cytarabine ou d'analogues de celle-ci, et de kétorolac ou d'analogues de celui-ci, dans le traitement de la cachexie, et une composition pharmaceutique pour le traitement de la cachexie.
PCT/CN2016/099329 2016-03-01 2016-09-19 Composition pharmaceutique destinée au traitement de la cachexie et son utilisation Ceased WO2017148129A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN201610115938.7A CN107137417B (zh) 2016-03-01 2016-03-01 一种用于治疗恶病质的药物组合物及其应用
CN2016101159387 2016-03-01

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB2571849A (en) * 2018-01-15 2019-09-11 Yinuoke Medicine Science And Tech Company Ltd Treatments for cachexia
US11104698B2 (en) 2015-12-03 2021-08-31 Biosight Ltd. Salts of conjugates for cancer therapy
US12071450B2 (en) 2015-12-03 2024-08-27 Biosight Ltd. Salts of conjugates for cancer therapy

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR20220137028A (ko) * 2020-02-04 2022-10-11 바이오사이트 리미티드 아스파시타라빈 약제학적 조성물 및 이의 용도
WO2021173707A1 (fr) * 2020-02-24 2021-09-02 Yinuoke Medicine Science Technology Company Ltd. Compositions et méthodes pour le traitement d'un choc cytokinique et d'un syndrome de libération de cytokines

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CN104337828A (zh) * 2014-09-18 2015-02-11 张领兵 吉西他滨及其盐在制备治疗恶病质药物中的应用

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WO2008144880A1 (fr) * 2007-05-31 2008-12-04 F.P.L. Pharma Inc. Compositions servant à prévenir ou à traiter le syndrome d'anorexie-cachexie et leurs procédés d'utilisation
CN104337828A (zh) * 2014-09-18 2015-02-11 张领兵 吉西他滨及其盐在制备治疗恶病质药物中的应用

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11104698B2 (en) 2015-12-03 2021-08-31 Biosight Ltd. Salts of conjugates for cancer therapy
US12071450B2 (en) 2015-12-03 2024-08-27 Biosight Ltd. Salts of conjugates for cancer therapy
GB2571849A (en) * 2018-01-15 2019-09-11 Yinuoke Medicine Science And Tech Company Ltd Treatments for cachexia
GB2571849B (en) * 2018-01-15 2020-05-20 Yinuoke Medicine Science And Tech Company Ltd Treatments for cachexia
CN111655341A (zh) * 2018-01-15 2020-09-11 长春亿诺科医药科技有限责任公司 用于恶病质的治疗
US12059427B2 (en) 2018-01-15 2024-08-13 Yinuoke Medicine Science And Technology Company Ltd. Treatments for cachexia

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