+

WO2018006689A1 - Utilisation de fulvestrant dans la préparation d'un médicament destiné au traitement de l'adénome pituitaire non fonctionnel - Google Patents

Utilisation de fulvestrant dans la préparation d'un médicament destiné au traitement de l'adénome pituitaire non fonctionnel Download PDF

Info

Publication number
WO2018006689A1
WO2018006689A1 PCT/CN2017/088121 CN2017088121W WO2018006689A1 WO 2018006689 A1 WO2018006689 A1 WO 2018006689A1 CN 2017088121 W CN2017088121 W CN 2017088121W WO 2018006689 A1 WO2018006689 A1 WO 2018006689A1
Authority
WO
WIPO (PCT)
Prior art keywords
fulvestrant
medicament
adenoma
use according
treatment
Prior art date
Application number
PCT/CN2017/088121
Other languages
English (en)
Chinese (zh)
Inventor
高华
李储忠
张亚卓
刘潜
Original Assignee
北京市神经外科研究所
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 北京市神经外科研究所 filed Critical 北京市神经外科研究所
Publication of WO2018006689A1 publication Critical patent/WO2018006689A1/fr

Links

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
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/565—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the present invention relates to the field of biochemistry and medicine, and in particular to the use of fulvestrant for the preparation of a medicament for the treatment of non-functioning pituitary adenomas.
  • Non-functional pituitary adenoma is the most common brain tumor in pituitary tumors. Although it is a benign tumor, it is very harmful and easily relapses. It can damage the patient's vision and cause sudden blindness and affect endocrine function. Infertility, serious can also lead to life-threatening.
  • the treatment methods of pituitary adenoma mainly include drug treatment, surgical treatment and radiotherapy.
  • the current treatment is mainly surgery.
  • a considerable number of patients have poor surgical results. Residual and recurrence often occur after surgery, which is a difficult problem for neurosurgery. . Medication is an effective way to solve this problem.
  • the treatment is improper and over-treatment is coexisting, which makes the treatment efficiency low, the disability rate is high, and the overall recurrence rate exceeds 30%.
  • Dopamine receptor antagonists are a commonly used treatment for pituitary adenomas, but the overall efficiency in the treatment of nonfunctioning pituitary adenomas is only 5-10%. It can be seen that there is still no targeted and effective drug treatment. It is necessary to develop methods and drugs that can affect the differentiation, proliferation, apoptosis and invasion of pituitary adenomas, thereby providing an effective way to improve the therapeutic and prognostic effects of non-functional pituitary adenomas.
  • Fulvestrant group (molecular formula: C 41 H 65 O 4 F 5 S 2 , Chinese alias: (7a, 17b)-7-[9-(4,4,5,5,5-pentafluoropentylsulfinyl) ⁇ alkyl]-estrazine-1,3,5-(10)-triene-3,17-diol) is the first simple antiestrogens to complete phase III clinical trials without estrogen-like Acts and reduces estrogen receptor protein expression at the cellular level. Similar to the mechanism of action of tamoxifen, it competitively binds to estrogen receptors, but its binding rate is as high as 89%. Fulvestrant completely inhibits the transcription of estrogen-sensitive genes, and there is no induction of endometrial cancer. Tumor.
  • fulvestrant can effectively inhibit tumor growth in tamoxifen-resistant breast cancer patients.
  • In vitro tests have shown that fulvestrant can inhibit breast cancer cell growth more strongly than aromatase inhibitors.
  • fulvestrant is not cross-resistant to other endocrine drugs. There are no reports on the treatment of adenoma in fulvestrant.
  • a first object of the present invention is to provide the use of fulvestrant for the preparation of a medicament for the treatment of non-functioning pituitary adenomas.
  • a second object of the present invention is to provide the use of functional fragments, derivatives and their salts or solvates of fulvestrant for the preparation of a medicament for the treatment of non-functioning pituitary adenomas.
  • the derivative of fulvestrant is a halogenated, sulfonated, nitrated, hydroxylated, alkoxylated or esterified product of fulvestrant.
  • the fulvestrant derivative may be a salt or a solvate, wherein the salt includes a sodium salt, a potassium salt, etc., and the solvate means a hydrate, an ethanolate or the like.
  • the derivative can be used to at least partially inhibit the differentiation and proliferation of non-functional pituitary adenomas.
  • the derivatives and functionalized fragments of fulvestrant have the same core structure as fulvestrant. Therefore, its functional fragments, derivatives, and salts or solvates thereof also have desirable effects in the preparation of a medicament for treating or preventing non-functioning pituitary adenomas.
  • the non-functional pituitary adenomas of the present invention encompass a variety of known pituitary adenomas, including apocytic adenomas, large eosinophils, gonadotropin adenomas, resting corticosteroid adenomas, and glycoprotein secretory glands. At least one of the tumors.
  • the medicament of the present invention also includes at least one excipient that is pharmaceutically acceptable.
  • excipients are understood by those skilled in the art, including but not limited to disintegration
  • the agent, the lubricant, the dispersing agent and the like can be selected according to the actual needs of the preparation by the person skilled in the art, and the present invention is not particularly limited thereto.
  • the medicament of the present invention can be prepared into various common pharmaceutical dosage forms, such as tablets, capsules, pills, powders, granules, suspensions, oral solutions, powder injections or injections, etc., by a conventional method.
  • the mode of administration can be administered orally, sublingually, intravenously, subcutaneously, transdermally or topically, etc., and administered to the animal or human in unit dosage form.
  • Suitable unit administration forms of the medicament of the present invention include oral dosage forms (for example, tablets, capsules, pills, powders, granules, oral solutions or suspensions), sublingual or buccal administration forms, intravenous, subcutaneous, and permeable.
  • oral dosage forms for example, tablets, capsules, pills, powders, granules, oral solutions or suspensions
  • sublingual or buccal administration forms intravenous, subcutaneous, and permeable.
  • a dermal or intramuscular dosage form eg, injection, powder, etc.
  • the drug may be a general preparation, a sustained release preparation, an immediate release preparation, and a controlled release preparation.
  • the medicament of the present invention is an oral dosage form, an intravenous administration form or an intramuscular administration form.
  • the invention also provides a desirable embodiment for the pharmaceutical preparation comprising fulvestrant, a functional fragment of fulvestrant, a fulvestrant derivative and a salt or solvate thereof, in particular when preparing a tablet or capsule form
  • excipients which may be added to the active ingredient, including diluents such as lactose, dextrin, starch, pregelatinized starch, sucrose, mannitol, microcrystalline cellulose, etc.; adhesives, such as Polyvinylpyrrolidone, methylcellulose, hypromellose, etc.; disintegrants, such as sodium carboxymethyl starch, crosslinked carboxymethylcellulose, low-substituted hydroxypropylcellulose, sodium carboxymethylcellulose, Bipolyvinyl pyrrolidone, etc.; lubricants such as silica, magnesium stearate, stearate, corn starch, talc, etc., flavoring agents such as mannitol, aspartame, sodium
  • excipients which may be added to the active ingredient include diluents and absorbents such as lactose, glucose, dextrin, starch, sucrose, cocoa butter, etc.; adhesives such as gum arabic , tragacanth, gelatin, honey, etc.; disintegrating agents, such as methyl cellulose, ethyl cellulose, dried starch, agar powder, alginate Wait.
  • Oral solutions or suspensions may be added to excipients, including sweeteners such as sodium saccharin, sucrose, cyclamate, aspartame and stevioside; suspending agents such as polyvinylpyrrolidone, microcrystalline cellulose, sucrose , hydroxypropyl methylcellulose, etc.; preservatives, such as parabens, sodium benzoate, methyl paraben, propyl paraben, and the like.
  • Excipients to which granules can be added include fillers, binders, colorants, flavors, and the like.
  • various diluents commonly used in the art such as water, ethanol, polyethylene glycol, propylene glycol, isostearyl alcohol, etc., cosolvents, buffers, can be used. Or a pH adjuster, etc.
  • sodium chloride, glucose or glycerin or the like may be added.
  • the tablet of the present invention may be a pure tablet, and the tablet may be further formed into a coated tablet such as a film coat, a sugar coat or the like.
  • Tablets can be formulated into immediate release, sustained release or controlled release dosage forms by preparing a polymeric matrix or by using a particular polymer in a film coating.
  • the capsules may be soft or hard capsules without a film or film to provide immediate release, sustained release or controlled release properties.
  • fulvestrant is typically formulated in dosage units. Each dose unit contains 50 to 250 mg of fulvestrant, administered once or more per month. Higher or lower doses may also be employed in certain circumstances, and the appropriate dosage for each patient is ultimately determined by the physician based on the mode of administration, the age, weight and response of the patient.
  • the drug can be used in combination with treatments already available (eg, chemotherapy, surgery, or radiation).
  • treatments already available eg, chemotherapy, surgery, or radiation.
  • the medicament of the invention may be used as an additive to other therapies. It will be appreciated that the treatment of the invention may be combined with any other known treatment method.
  • fulvestrant can significantly inhibit the growth of non-functional pituitary adenoma cells and transplanted tumors.
  • Different doses of fulvestrant in primary growth non-functional pituitary adenoma tumor cells can significantly inhibit the proliferation of primary pituitary adenoma cells.
  • an optimal proliferation inhibiting effect can be obtained.
  • fulvestrant is a commercial product of Sigma, and the article number is i4409.
  • Specimens were taken from tumor tissue surgically removed from patients with pituitary adenomas. Preoperative diagnosis based on clinical manifestations, serum hormone levels and imaging examination, and confirmed by intraoperative findings and postoperative pathology and immunohistochemical staining, as non-functional pituitary adenoma: empty cell adenoma, large hobby Acid granuloma, gonadotropin adenoma, 30 cases of each type of non-functional pituitary adenoma.
  • Trypsin, DMEM medium, fetal bovine serum, dimethyl sulfoxide, and polylysine are all commercially available products.
  • the surgically removed pituitary adenoma tissue was placed in serum-free DMEM culture medium under aseptic operation, and rinsed 2-3 times with sterile PBS in a clean bench to remove connective tissue, necrotic tissue and blood clots, and the specimen was cut with ophthalmic scissors.
  • DMEM culture solution containing 10% fetal bovine serum
  • filter through 100 mesh cell filter centrifuge at 1000r/min for 10min, discard The supernatant was added to the DMEM medium to resuspend the cells, counted by microscopy, and the cell density was adjusted to 1 ⁇ 10 6 /mL.
  • FCM analyzes cellular DNA, and the fluorescence of PI-DNA complex
  • apoptosis is expressed as a percentage of cells with less than 2-fold body peak. The results are shown in Table 2.
  • DMEM medium Six different doses of the treatment group were set, and the fulvestrant at the final concentrations of 0.5, 1, 5, 10, 20, and 100 ng/mL was added to the DMEM medium, and the control group was added with an equal volume of DMSO.
  • Functional pituitary adenoma cells were cultured in 96-well cells in a logarithmic growth phase, and DMEM medium (plus 10% calf serum) was added to each well for 24 hours in a saturated water vapor carbon dioxide incubator at 37 ° C in 5% CO 2 . Add 20 ⁇ l of MTS/PMS mixture to each well and continue to culture for 3-4 hours.
  • the plate was shaken for 10 seconds before the test, and the color was mixed, and the light absorption value (OD) of each well was measured at a wavelength of 570 nm on an enzyme-linked detector. A curve was plotted against the OD value (OD570) using sample dilution.
  • the statistical cell proliferation was as shown in Table 3.
  • mice Thirty tumor-bearing mice were randomly divided into 3 groups, 10 in each group. Each group was administered with different doses of fulvestrant via tail vein, and administered once a day, each dose was 1 mg/kg. ,
  • TVI% (tumor volume on the day of the blank group - tumor volume on the day of the administration group) / (tumor volume on the day of the blank group) ⁇ 100%.

Landscapes

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

Abstract

L'utilisation de fulvestrant dans la préparation d'un médicament, destiné au traitement de l'adénome pituitaire non fonctionnel, peut efficacement améliorer le pronostic d'un adénome pituitaire non fonctionnel au moyen de la technique décrite.
PCT/CN2017/088121 2016-07-04 2017-06-13 Utilisation de fulvestrant dans la préparation d'un médicament destiné au traitement de l'adénome pituitaire non fonctionnel WO2018006689A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN201610520524.2A CN107569493B (zh) 2016-07-04 2016-07-04 氟维司群在制备治疗无功能垂体腺瘤的药物中的用途
CN201610520524.2 2016-07-04

Publications (1)

Publication Number Publication Date
WO2018006689A1 true WO2018006689A1 (fr) 2018-01-11

Family

ID=60901395

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2017/088121 WO2018006689A1 (fr) 2016-07-04 2017-06-13 Utilisation de fulvestrant dans la préparation d'un médicament destiné au traitement de l'adénome pituitaire non fonctionnel

Country Status (2)

Country Link
CN (1) CN107569493B (fr)
WO (1) WO2018006689A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN114099518A (zh) * 2020-05-25 2022-03-01 江苏先声药业有限公司 一种口服氟维司群药物组合物及其制备方法

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102123712A (zh) * 2006-12-13 2011-07-13 先灵公司 使用igf1r抑制剂治疗癌症的方法

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CA2702637A1 (fr) * 2007-10-22 2009-04-30 Schering Corporation Anticorps anti-vegf entierement humains et leurs procedes d'utilisation

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102123712A (zh) * 2006-12-13 2011-07-13 先灵公司 使用igf1r抑制剂治疗癌症的方法

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
LI, DAN ET AL.: "Effects of Fulvestrant on Proliferation and Secretion of Prolactinoma GH3 Cells", CHINESE JOURNAL OF MINIMALLY INVASIVE NEUROSURGERY, vol. 18, no. 10, 20 October 2013 (2013-10-20), pages 464 - 467 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN114099518A (zh) * 2020-05-25 2022-03-01 江苏先声药业有限公司 一种口服氟维司群药物组合物及其制备方法

Also Published As

Publication number Publication date
CN107569493A (zh) 2018-01-12
CN107569493B (zh) 2020-03-06

Similar Documents

Publication Publication Date Title
TWI607754B (zh) 醫藥組合
US20130022609A1 (en) Method of treating androgen independent prostate cancer
JP6833816B2 (ja) 骨髄腫を治療するためのセルデュラチニブ（ｃｅｒｄｕｌａｔｉｎｉｂ）
KR20190110128A (ko) Hsp90 억제제를 사용하여 암을 치료하는 방법
WO2008034346A1 (fr) Composition et méthode de traitement de tumeurs
JP7001599B2 (ja) 急性骨髄性白血病の処置のためのダクチノマイシン組成物および方法
CN111328280A (zh) 制备和使用内昔芬的方法
EP4119557A1 (fr) Combinaison pharmaceutique comprenant un composé pyridino[1,2-a]pyrimidinone
US20220184066A1 (en) Clinical regimen for treating myelodysplastic syndrome with phosphatase inhibitor
CN101429201A (zh) 柠檬酸小檗胺盐及制备方法和应用
WO2019097426A1 (fr) Association pharmaceutique comprenant le lsz102 et le ribociclib
WO2018006689A1 (fr) Utilisation de fulvestrant dans la préparation d'un médicament destiné au traitement de l'adénome pituitaire non fonctionnel
EP3191094B1 (fr) Traitement des symptômes associés à une thérapie par déprivation androgénique
CA3166379A1 (fr) Inhibiteurs de glutathion s-transferases (gst) et de nad(p)h:quinone oxydoreductase 1 (nqo1), compositions pharmaceutiques et utilisations dans la gestion du cancer
CN114828842A (zh) 用于治疗急性髓系白血病的包含dhodh抑制剂的组合物
CN104039330A (zh) 化疗耐药性的癌症的联合治疗
WO2024022080A1 (fr) Utilisation d'un médicament ciblant la plk4 dans le traitement de tumeurs résistantes aux médicaments contenant du platine
TW200901989A (en) Anti-tumor activity of CCI-779 in papillary renal cell cancer
AU2019286572B2 (en) Injectable composition
WO2017194031A1 (fr) Utilisation de l'inhibiteur du fonctionnement des protéines dapt dans la préparation d'un médicament pour le traitement de l'adénome
WO2023035200A1 (fr) Application de pentafluorine dans la préparation d'un médicament pour le traitement du cancer de l'endomètre
WO2017194030A1 (fr) Utilisation de l'inhibiteur du fonctionnement des protéines dapt dans la préparation d'un médicament pour le traitement de maladies endocriniennes
WO2018006688A1 (fr) Utilisation de fulvestrant dans la préparation de médicaments pour le traitement de l'adénome à hormone de croissance
WO2019129182A1 (fr) 2β,3α,5α-TRIHYDROXYLANDROSTANE-6-CÉTONE POUR LE TRAITEMENT DE RÉACTIONS INFLAMMATOIRES
TW202329968A (zh) 包含mdm2抑制劑、bcl2抑制劑和低甲基化劑的藥物組合及其用於治療血液惡性腫瘤之用途

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 17823501

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 17823501

Country of ref document: EP

Kind code of ref document: A1

点击 这是indexloc提供的php浏览器服务，不要输入任何密码和下载