CN116570593B - 一种防止卵巢早衰的药物及其用途 - Google Patents
一种防止卵巢早衰的药物及其用途 Download PDFInfo
- Publication number
- CN116570593B CN116570593B CN202310754794.XA CN202310754794A CN116570593B CN 116570593 B CN116570593 B CN 116570593B CN 202310754794 A CN202310754794 A CN 202310754794A CN 116570593 B CN116570593 B CN 116570593B
- Authority
- CN
- China
- Prior art keywords
- vinblastine
- ovarian failure
- medicine
- premature ovarian
- luli
- Prior art date
- Legal status (The legal status 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 status listed.)
- Active
Links
- 239000003814 drug Substances 0.000 title claims abstract description 38
- 206010036601 premature menopause Diseases 0.000 title claims abstract description 33
- 208000002500 Primary Ovarian Insufficiency Diseases 0.000 title claims abstract description 29
- 208000017942 premature ovarian failure 1 Diseases 0.000 title claims abstract description 28
- 229940079593 drug Drugs 0.000 title abstract description 14
- JXLYSJRDGCGARV-WWYNWVTFSA-N Vinblastine Natural products O=C(O[C@H]1[C@](O)(C(=O)OC)[C@@H]2N(C)c3c(cc(c(OC)c3)[C@]3(C(=O)OC)c4[nH]c5c(c4CCN4C[C@](O)(CC)C[C@H](C3)C4)cccc5)[C@@]32[C@H]2[C@@]1(CC)C=CCN2CC3)C JXLYSJRDGCGARV-WWYNWVTFSA-N 0.000 claims abstract description 34
- 229960003048 vinblastine Drugs 0.000 claims abstract description 34
- JXLYSJRDGCGARV-XQKSVPLYSA-N vincaleukoblastine Chemical compound C([C@@H](C[C@]1(C(=O)OC)C=2C(=CC3=C([C@]45[C@H]([C@@]([C@H](OC(C)=O)[C@]6(CC)C=CCN([C@H]56)CC4)(O)C(=O)OC)N3C)C=2)OC)C[C@@](C2)(O)CC)N2CCC2=C1NC1=CC=CC=C21 JXLYSJRDGCGARV-XQKSVPLYSA-N 0.000 claims abstract description 34
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 24
- 229920002472 Starch Polymers 0.000 claims abstract description 23
- 239000008107 starch Substances 0.000 claims abstract description 23
- 235000019698 starch Nutrition 0.000 claims abstract description 18
- 239000008101 lactose Substances 0.000 claims abstract description 16
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 claims abstract description 13
- 229920000168 Microcrystalline cellulose Polymers 0.000 claims abstract description 11
- 239000008108 microcrystalline cellulose Substances 0.000 claims abstract description 11
- 235000019813 microcrystalline cellulose Nutrition 0.000 claims abstract description 11
- 229940016286 microcrystalline cellulose Drugs 0.000 claims abstract description 11
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 claims abstract description 10
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 claims abstract description 8
- 238000002360 preparation method Methods 0.000 claims abstract description 8
- 239000004480 active ingredient Substances 0.000 claims abstract description 6
- 239000003937 drug carrier Substances 0.000 claims abstract description 5
- 235000019359 magnesium stearate Nutrition 0.000 claims abstract description 5
- 239000011734 sodium Substances 0.000 claims abstract description 5
- 229910052708 sodium Inorganic materials 0.000 claims abstract description 5
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 claims abstract description 3
- 229930195725 Mannitol Natural products 0.000 claims abstract description 3
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 claims abstract description 3
- 229960000913 crospovidone Drugs 0.000 claims abstract description 3
- 235000010947 crosslinked sodium carboxy methyl cellulose Nutrition 0.000 claims abstract description 3
- 239000000594 mannitol Substances 0.000 claims abstract description 3
- 235000010355 mannitol Nutrition 0.000 claims abstract description 3
- 235000013809 polyvinylpolypyrrolidone Nutrition 0.000 claims abstract description 3
- 229920000523 polyvinylpolypyrrolidone Polymers 0.000 claims abstract description 3
- 229940057948 magnesium stearate Drugs 0.000 claims abstract 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 4
- 239000003795 chemical substances by application Substances 0.000 claims description 3
- 229940075614 colloidal silicon dioxide Drugs 0.000 claims description 2
- 238000009472 formulation Methods 0.000 claims description 2
- 229940031703 low substituted hydroxypropyl cellulose Drugs 0.000 claims description 2
- 239000000203 mixture Substances 0.000 claims description 2
- 229940093429 polyethylene glycol 6000 Drugs 0.000 claims description 2
- 230000002265 prevention Effects 0.000 claims 1
- 239000000454 talc Substances 0.000 claims 1
- 229910052623 talc Inorganic materials 0.000 claims 1
- 229940033134 talc Drugs 0.000 claims 1
- 235000012222 talc Nutrition 0.000 claims 1
- RJKFOVLPORLFTN-LEKSSAKUSA-N Progesterone Chemical compound C1CC2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H](C(=O)C)[C@@]1(C)CC2 RJKFOVLPORLFTN-LEKSSAKUSA-N 0.000 abstract description 26
- VOXZDWNPVJITMN-ZBRFXRBCSA-N 17β-estradiol Chemical compound OC1=CC=C2[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3CCC2=C1 VOXZDWNPVJITMN-ZBRFXRBCSA-N 0.000 abstract description 13
- 229960005309 estradiol Drugs 0.000 abstract description 13
- 229930182833 estradiol Natural products 0.000 abstract description 13
- 239000000186 progesterone Substances 0.000 abstract description 13
- 229960003387 progesterone Drugs 0.000 abstract description 13
- 230000002611 ovarian Effects 0.000 abstract description 11
- FPAFDBFIGPHWGO-UHFFFAOYSA-N dioxosilane;oxomagnesium;hydrate Chemical compound O.[Mg]=O.[Mg]=O.[Mg]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O FPAFDBFIGPHWGO-UHFFFAOYSA-N 0.000 abstract description 10
- 210000002966 serum Anatomy 0.000 abstract description 10
- 230000000694 effects Effects 0.000 abstract description 7
- 238000002474 experimental method Methods 0.000 abstract description 5
- 229940032147 starch Drugs 0.000 abstract description 3
- 230000002195 synergetic effect Effects 0.000 abstract description 3
- 229920002785 Croscarmellose sodium Polymers 0.000 abstract description 2
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 abstract description 2
- 229960001681 croscarmellose sodium Drugs 0.000 abstract description 2
- 230000003285 pharmacodynamic effect Effects 0.000 abstract description 2
- 241000699670 Mus sp. Species 0.000 description 31
- 230000000295 complement effect Effects 0.000 description 10
- 210000001672 ovary Anatomy 0.000 description 10
- 201000010065 polycystic ovary syndrome Diseases 0.000 description 9
- 239000007916 tablet composition Substances 0.000 description 9
- 239000008187 granular material Substances 0.000 description 7
- 238000002156 mixing Methods 0.000 description 6
- 238000011160 research Methods 0.000 description 6
- 238000007873 sieving Methods 0.000 description 6
- 239000000243 solution Substances 0.000 description 6
- 240000006122 Chenopodium album Species 0.000 description 5
- 235000009344 Chenopodium album Nutrition 0.000 description 5
- 108010010803 Gelatin Proteins 0.000 description 5
- 230000000052 comparative effect Effects 0.000 description 5
- 229920000159 gelatin Polymers 0.000 description 5
- 239000008273 gelatin Substances 0.000 description 5
- 235000019322 gelatine Nutrition 0.000 description 5
- 235000011852 gelatine desserts Nutrition 0.000 description 5
- 210000004291 uterus Anatomy 0.000 description 5
- 238000005303 weighing Methods 0.000 description 5
- 238000000034 method Methods 0.000 description 4
- 210000000056 organ Anatomy 0.000 description 4
- 210000004369 blood Anatomy 0.000 description 3
- 239000008280 blood Substances 0.000 description 3
- 210000005252 bulbus oculi Anatomy 0.000 description 3
- 230000006378 damage Effects 0.000 description 3
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 3
- 238000001035 drying Methods 0.000 description 3
- 210000004696 endometrium Anatomy 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- 230000007246 mechanism Effects 0.000 description 3
- 231100000915 pathological change Toxicity 0.000 description 3
- 230000036285 pathological change Effects 0.000 description 3
- 238000003825 pressing Methods 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 238000012360 testing method Methods 0.000 description 3
- 201000000736 Amenorrhea Diseases 0.000 description 2
- 206010001928 Amenorrhoea Diseases 0.000 description 2
- 208000023275 Autoimmune disease Diseases 0.000 description 2
- CMSMOCZEIVJLDB-UHFFFAOYSA-N Cyclophosphamide Chemical compound ClCCN(CCCl)P1(=O)NCCCO1 CMSMOCZEIVJLDB-UHFFFAOYSA-N 0.000 description 2
- 206010062717 Increased upper airway secretion Diseases 0.000 description 2
- 241000700159 Rattus Species 0.000 description 2
- 230000002159 abnormal effect Effects 0.000 description 2
- 238000001467 acupuncture Methods 0.000 description 2
- 230000004075 alteration Effects 0.000 description 2
- 231100000540 amenorrhea Toxicity 0.000 description 2
- YBHILYKTIRIUTE-UHFFFAOYSA-N berberine Chemical compound C1=C2CC[N+]3=CC4=C(OC)C(OC)=CC=C4C=C3C2=CC2=C1OCO2 YBHILYKTIRIUTE-UHFFFAOYSA-N 0.000 description 2
- 229940093265 berberine Drugs 0.000 description 2
- QISXPYZVZJBNDM-UHFFFAOYSA-N berberine Natural products COc1ccc2C=C3N(Cc2c1OC)C=Cc4cc5OCOc5cc34 QISXPYZVZJBNDM-UHFFFAOYSA-N 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 210000000349 chromosome Anatomy 0.000 description 2
- 229960004397 cyclophosphamide Drugs 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- 239000000945 filler Substances 0.000 description 2
- 230000002068 genetic effect Effects 0.000 description 2
- 230000000642 iatrogenic effect Effects 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 239000000314 lubricant Substances 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000010172 mouse model Methods 0.000 description 2
- 230000008506 pathogenesis Effects 0.000 description 2
- 239000008194 pharmaceutical composition Substances 0.000 description 2
- 208000026435 phlegm Diseases 0.000 description 2
- 238000003127 radioimmunoassay Methods 0.000 description 2
- 238000012552 review Methods 0.000 description 2
- 208000011580 syndromic disease Diseases 0.000 description 2
- 238000002560 therapeutic procedure Methods 0.000 description 2
- 210000001519 tissue Anatomy 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- HVCOBJNICQPDBP-UHFFFAOYSA-N 3-[3-[3,5-dihydroxy-6-methyl-4-(3,4,5-trihydroxy-6-methyloxan-2-yl)oxyoxan-2-yl]oxydecanoyloxy]decanoic acid;hydrate Chemical compound O.OC1C(OC(CC(=O)OC(CCCCCCC)CC(O)=O)CCCCCCC)OC(C)C(O)C1OC1C(O)C(O)C(O)C(C)O1 HVCOBJNICQPDBP-UHFFFAOYSA-N 0.000 description 1
- 208000021959 Abnormal metabolism Diseases 0.000 description 1
- 206010001367 Adrenal insufficiency Diseases 0.000 description 1
- 208000007984 Female Infertility Diseases 0.000 description 1
- 208000001914 Fragile X syndrome Diseases 0.000 description 1
- 229930186217 Glycolipid Natural products 0.000 description 1
- 206010021928 Infertility female Diseases 0.000 description 1
- 206010022489 Insulin Resistance Diseases 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 208000005647 Mumps Diseases 0.000 description 1
- 206010033165 Ovarian failure Diseases 0.000 description 1
- 208000029082 Pelvic Inflammatory Disease Diseases 0.000 description 1
- 208000026928 Turner syndrome Diseases 0.000 description 1
- 208000027418 Wounds and injury Diseases 0.000 description 1
- 210000000683 abdominal cavity Anatomy 0.000 description 1
- 230000003044 adaptive effect Effects 0.000 description 1
- 230000032683 aging Effects 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 208000006424 autoimmune oophoritis Diseases 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000036770 blood supply Effects 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 230000002354 daily effect Effects 0.000 description 1
- 238000012217 deletion Methods 0.000 description 1
- 230000037430 deletion Effects 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 239000007884 disintegrant Substances 0.000 description 1
- 208000035475 disorder Diseases 0.000 description 1
- 230000035622 drinking Effects 0.000 description 1
- 229940000406 drug candidate Drugs 0.000 description 1
- 230000002996 emotional effect Effects 0.000 description 1
- 230000002357 endometrial effect Effects 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 229940011871 estrogen Drugs 0.000 description 1
- 239000000262 estrogen Substances 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 230000003203 everyday effect Effects 0.000 description 1
- 239000003777 experimental drug Substances 0.000 description 1
- 238000000556 factor analysis Methods 0.000 description 1
- 238000002657 hormone replacement therapy Methods 0.000 description 1
- 229940088592 immunologic factor Drugs 0.000 description 1
- 239000000367 immunologic factor Substances 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 208000014674 injury Diseases 0.000 description 1
- 230000002262 irrigation Effects 0.000 description 1
- 238000003973 irrigation Methods 0.000 description 1
- 238000002350 laparotomy Methods 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 230000006371 metabolic abnormality Effects 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 238000000465 moulding Methods 0.000 description 1
- 208000010805 mumps infectious disease Diseases 0.000 description 1
- 201000004535 ovarian dysfunction Diseases 0.000 description 1
- 231100000539 ovarian failure Toxicity 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 239000008213 purified water Substances 0.000 description 1
- 238000011127 radiochemotherapy Methods 0.000 description 1
- 230000000384 rearing effect Effects 0.000 description 1
- 230000001850 reproductive effect Effects 0.000 description 1
- 206010039073 rheumatoid arthritis Diseases 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 235000012239 silicon dioxide Nutrition 0.000 description 1
- 230000000391 smoking effect Effects 0.000 description 1
- 230000002269 spontaneous effect Effects 0.000 description 1
- 238000007619 statistical method Methods 0.000 description 1
- 239000003270 steroid hormone Substances 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 238000012353 t test Methods 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 230000005945 translocation Effects 0.000 description 1
- 201000008827 tuberculosis Diseases 0.000 description 1
- 208000001072 type 2 diabetes mellitus Diseases 0.000 description 1
- 230000009385 viral infection Effects 0.000 description 1
- 210000001835 viscera Anatomy 0.000 description 1
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
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/475—Quinolines; Isoquinolines having an indole ring, e.g. yohimbine, reserpine, strychnine, vinblastine
-
- 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
- A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
- A61K31/05—Phenols
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
- A61P15/08—Drugs for genital or sexual disorders; Contraceptives for gonadal disorders or for enhancing fertility, e.g. inducers of ovulation or of spermatogenesis
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Reproductive Health (AREA)
- Epidemiology (AREA)
- Gynecology & Obstetrics (AREA)
- Pregnancy & Childbirth (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Endocrinology (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
本发明属于医药技术领域,具体涉及一种防止卵巢早衰的药物及其用途。该防止卵巢早衰的药物包含活性成分长春碱和白芦藜醇,长春碱和白芦藜醇的重量比为1:(0.2‑3)。上述药物可以与药学上可接受的载体包括乳糖、甘露醇、淀粉、微晶纤维素、纤维素‑乳糖、纤维素‑淀粉、羧甲基淀粉钠、交联聚维酮、交联羧甲基纤维素钠、硬脂酸镁、滑石粉等制成口服制剂。通过小鼠子宫指数、卵巢指数、小鼠血清中孕酮、雌二醇含量等药效学实验,证明了两者具有协同增效的作用,可以大幅提升防止卵巢早衰的效果。
Description
技术领域
本发明属于医药领域,具体涉及一种包含活性成分长春碱和白芦藜醇的防止卵巢早衰的药物及其用途。
背景技术
卵巢早衰(Premature ovarian failure,POF)是指正常发育的妇女在40岁以前因某种原因引起卵巢功能衰竭,具有高促性腺激素及低雌激素特征,卵巢组织学呈围绝经期或老年妇女绝经后改变。原发性闭经患者中发生率为10~28%,继发性闭经患者中发生率为4%~18%。卵巢早衰的发病率有逐年上升的趋势。
目前国内外研究多认为卵巢衰老与遗传、免疫、代谢、病毒感染以及医源性等因素有关。遗传因素:现代研究认为XX染色体上存在着决定卵巢生长所需要的区域,是维持卵巢功能的基础,XX染色体数量异常或部分缺失和易位等是造成POF的常见原因,如Turner综合征、脆性X综合征等。免疫因素:自1968年Ir-wine提出POF与自身免疫疾病相关以来,研究表明5%~30%的POF患者同时患有其他自身免疫性疾病,如常伴有肾上腺皮质功能不全,类风湿关节炎等,自身免疫性卵巢炎是某些自发性卵巢早衰的发病机制,并发现此POF患者血液中存在抗卵巢抗体或抗透明带抗体等。医源性因素:放化疗,或者卵巢周围组织手术可能损伤卵巢血液供应以及组织。环境因素:5%的幼女腮腺炎,严重的盆腔结核,淋菌性和化脓性盆腔炎等疾病也可引起卵巢损害而发生。此外,强烈的情绪刺激、吸烟、饮酒、咖啡等推测可能与潜在卵巢功能较差有关。
本发明的申请人针对与卵巢相关的疾病进行了持续的研究,部分研究成果以论文和专利申请的形式进行了发表和公开。例如,黄连素对痰湿型多囊卵巢综合征大鼠的治疗作用及疗效机制研究,中华中医药学刊,2019年8月,第37卷第8期,揭示了黄连素能够改善痰湿型多囊卵巢综合征模型大鼠糖脂代谢异常,调控血清甾体激素水平,起到治疗PCOS生殖障碍与代谢异常的作用。多囊卵巢综合征子宫内膜病变的研究进展,中华中医药学刊,2019年10月,第37卷第10期,系统总结了多囊卵巢综合征子宫内膜病变的发病机制,即胰岛素抵抗和高雄激素血症是影响多囊卵巢综合征子宫内膜病变的主要因素。针灸疗法治疗多囊卵巢综合征研究进展,河北中医,2020年9月,第42卷第9期,系统总结了针灸疗法治疗多囊卵巢综合征的方法。中医妇科临床试验标准化研究进展和思考,中华中医药杂志,2020年10月,第35卷,第10期,总结了卵巢综合征的临床试验标准。The Treatment ofComplementary and Alternative Medicine on Premature Ovarian Failure,Evidence-Based Complementary and Alternative Medicine,2021Apr 15;The Complementary andAlternative Medicine for Polycystic Ovary Syndrome:A Review of ClinicalApplication and Mechanism,Evidence-Based Complementary and AlternativeMedicine,2021Feb 26;The Treatment of Complementary and Alternative Medicineon Female Infertility Caused by Endometrial Factors,Evidence-BasedComplementary and Alternative Medicine,2022Sep7;The Efficacy of Complementaryand Alternative Medicine in the Treatment of Female Infertility.Evidence-Based Complementary andAlternative Medicine,2021Apr 23;ComplementaryandAlternative Medicine for Premature Ovarian Insufficiency:A Review ofUtilization and Mechanisms.Evidence-Based Complementary andAlternativeMedicine,2022Apr 1,系列论文均是关于卵巢综合征的总结和研究。
激素替代疗法是目前临床常采用的治疗方法,这种方法具有较大的副作用,对患者的身体会造成不同程度的伤害。因此,需要开发更为安全有效的方法。
发明内容
本发明的目的是提供一种防止卵巢早衰的药物及其用途。
具体地,通过以下几个方面的技术方案实现了本发明。
在第一个方面中,本发明提供了一种防止卵巢早衰的药物,所述药物包含活性成分长春碱和白芦藜醇,所述长春碱和白芦藜醇的重量比为1:(0.2-3)。
优选的,上述药物中所述长春碱和白芦藜醇的重量比为1:(0.5-2)。
更优选的,上述药物中所述长春碱和白芦藜醇的重量比为1:(0.5-1.5),还优选为1:0.5、1:1、1:1.5。
本发明的防止卵巢早衰的药物包含活性成分长春碱和白芦藜醇以及药学上可接受的载体。“药学上可接受的载体”是指可以是任何可与长春碱和白芦藜醇一起制备成药物制剂,并用于临床治疗的辅料。包括但不限于:填充剂、崩解剂、润滑剂、助流剂等。其中填充剂选自乳糖、甘露醇、淀粉、微晶纤维素、纤维素-乳糖、纤维素-淀粉、甘露醇-淀粉中的一种或多种;所述崩解剂选自低取代羟丙基纤维素、羧甲基淀粉钠、交联聚维酮、交联羧甲基纤维素钠中的一种或多种;所述润滑剂选自硬脂酸镁、滑石粉、聚乙二醇6000中的一种或多种;所述助流剂选自二氧化硅、胶态二氧化硅中的一种或两种。
优选的,本发明的药物为口服制剂。
在第二个方面中,本发明提供了上述第一个方面所述的药物在制备防止卵巢早衰的药物中的用途。
本发明相对于现有技术,具有以下有益效果:
本发明以特定的比例使用长春碱和白芦藜醇作为药物组合物制成口服制剂,通过小鼠子宫指数、卵巢指数、小鼠血清中孕酮、雌二醇含量等药效学实验,证明了两者具有协同增效的作用,可以大幅提升防止卵巢早衰的效果。
具体实施方式
下面详细描述本发明的实施例,所举实施例是为了更好地对本发明的内容进行说明,仅用于解释本发明,而不能理解为对本发明的限制。
实施例中未注明具体技术或条件者,按照本领域内的文献所描述的技术或条件,或者按照产品说明书进行。所用试剂或仪器未注明生产厂商者,均为可通过正规渠道购买得到的常规产品。
下面实施例中的实验方法,如无特殊说明,均为常规方法。下述实施例中所用的试验材料,如无特殊说明,均为市售产品。
实施例1:片剂组合物
长春碱 2g
白芦藜醇 1g
羧甲基淀粉钠 10g
淀粉 10g
乳糖 5g
硬脂酸镁 5g
制备方法:将上述成分按照配方量称重,先将长春碱、白芦藜醇、羧甲基淀粉钠、淀粉混匀并用10mg/mL的明胶溶液造粒,然后将湿颗粒过筛并干燥,然后与乳糖、硬脂酸镁混合,过筛,并压制成片剂,每片含有长春碱0.02g、白芦藜醇0.01g。
实施例2:片剂组合物
长春碱 2g
白芦藜醇 2g
微晶纤维素 5g
淀粉 8g
乳糖 8g
滑石粉 5g
制备方法:将上述成分按照配方量称重,先将长春碱、白芦藜醇、微晶纤维素、淀粉混匀并用10mg/mL的明胶溶液造粒,然后将湿颗粒过筛并干燥,然后与乳糖、滑石粉混合,过筛,并压制成片剂,每片含有长春碱0.02g、白芦藜醇0.02g。
实施例3:片剂组合物
长春碱 2g
白芦藜醇 3g
微晶纤维素 10g
淀粉 5g
乳糖 5g
滑石粉 5g
制备方法:将上述成分按照配方量称重,先将长春碱、白芦藜醇、微晶纤维素、淀粉混匀并用10mg/mL的明胶溶液造粒,然后将湿颗粒过筛并干燥,然后与乳糖、滑石粉混合,过筛,并压制成片剂,每片含有长春碱0.02g、白芦藜醇0.03g。
对比实施例1:
长春碱 4g
微晶纤维素 5g
淀粉 8g
乳糖 8g
滑石粉 5g
制备方法:将上述成分按照配方量称重,先将长春碱、微晶纤维素、淀粉混匀并用10mg/mL的明胶溶液造粒,然后将湿颗粒过筛并干燥,然后与乳糖、滑石粉混合,过筛,并压制成片剂,每片含有长春碱0.04g。
对比实施例2:
白芦藜醇 4g
微晶纤维素 5g
淀粉 8g
乳糖 8g
滑石粉 5g
制备方法:将上述成分按照配方量称重,先将长春碱、微晶纤维素、淀粉混匀并用10mg/mL的明胶溶液造粒,然后将湿颗粒过筛并干燥,然后与乳糖、滑石粉混合,过筛,并压制成片剂,每片含有白芦藜醇0.04g。
实施例4:防治卵巢早衰小鼠的试验研究
1.材料
1.1实验动物
清洁级雌性小鼠,140只,体重在20-30g范围内,由黑龙江中医药大学实验动物中心提供。
1.2主要实验药品和试剂
本发明实施例1-3和对比实施例1-2制备得到的片剂组合物,注射用环磷酰胺,孕酮放射免疫试剂盒,雌二醇放射免疫分析药盒。
2.实验方法
2.1小鼠卵巢早衰模型的建立和给药
清洁级雌性小鼠140只,适应性饲养一周后分为如下七组:正常对照组、模型对照组、治疗1组、治疗2组、治疗3组、对照1组和对照2组,每组20只。除正常对照组每天腹腔注射生理盐水外,其余各组每天腹腔注射环磷酰胺30mg/kg,连续注射5天,制备卵巢早衰模型。造模结束后,治疗组、对照组小鼠通过灌胃的方式给药,其中,治疗1组小鼠给予实施例1所制备的片剂组合物,给药量80mg/kg,治疗2组小鼠给予实施例2所制备的片剂组合物,给药量80mg/kg,治疗3组小鼠给予实施例3所制备的片剂组合物,给药量80mg/kg,对照1组小鼠给予对比实施例1所制备的片剂组合物,给药量80mg/kg,对照2组小鼠给予对比实施例2所制备的片剂组合物,给药量80mg/kg,正常对照组和模型对照组小鼠给予等体积的纯化水,所有给药小鼠每日给药1次,连续给药4周。
2.2评价指标
2.2.1卵巢早衰模型小鼠孕酮、雌二醇含量的检测:实验结束后,小鼠眼球取血,立即置于37℃水浴中孵育2h,3000r/min离心8min,取上清液,测定血清中孕酮、雌二醇的含量。
2.2.2卵巢早衰模型小鼠子宫、卵巢脏器指数的测定:脱颈椎处死小鼠后,剖腹取出卵巢,子宫,迅速置分析天平上精密称重,分别计算脏器指数。
脏器指数=脏器湿重(mg)/小鼠体重(g)×100%。
2.3统计学方法
结果采用SPSS 23.0统计软件进行分析,数据以平均值±标准差表示。多组间比较采用单因素方差分析,两组间比较采用t检验,P<0.05表示差异有统计学意义,P<0.01表示差异有显著统计学意义。
3.实验结果
表1各组小鼠脏器指数比较
组别 | 子宫指数 | 卵巢指数 |
正常对照组 | 141.75±15.15 | 38.74±6.49 |
模型对照组 | 76.11±9.23* | 21.63±3.14* |
治疗1组 | 128.56±13.28##,** | 35.19±3.61##,** |
治疗2组 | 130.69±12.85##,** | 36.29±5.18##,** |
治疗3组 | 122.47±16.98##,** | 34.60±4.55##,** |
对照1组 | 92.87±9.46# | 28.44±3.17# |
对照2组 | 90.55±13.51# | 27.84±2.11# |
注:与正常对照组比较,*p<0.01;与模型对照组比较,##p<0.01,#p<0.05;与对照1组比较,**p<0.01;与对照2组比较,**p<0.01
如表1所示,与正常对照组比较,模型对照组小鼠的子宫及卵巢指数显著降低(P<0.01),说明造模成功。与模型对照组比较,对照1组和对照2组能提高小鼠的子宫及卵巢指数(P<0.05),而治疗1组、治疗2组及治疗3组均能显著提高小鼠的子宫及卵巢指数(P<0.01)。与对照1组、对照2组比较,治疗1组、治疗2组及治疗3组均能显著提高小鼠的子宫及卵巢指数(P<0.01)。从这些结果可以看出,长春碱与白芦藜醇联合用药组的作用效果显著优于单独使用长春碱或白芦藜醇的对照1组或对照2组的作用效果,这表明将长春碱与白芦藜醇联用后,在提高小鼠的子宫及卵巢指数方面具有显著的协同增效作用。
表2各组小鼠血清中孕酮、雌二醇含量比较
组别 | 孕酮(ng/ml) | 雌二醇(pg/ml) |
正常对照组 | 17.02±2.17 | 5.78±1.21 |
模型对照组 | 8.98±1.54* | 2.04±0.54* |
治疗1组 | 15.91±3.22##,** | 5.18±0.77##,** |
治疗2组 | 16.08±2.79##,** | 5.35±0.69##,** |
治疗3组 | 15.32±2.88##,** | 5.08±0.94##,** |
对照1组 | 10.84±1.25# | 3.07±0.31# |
对照2组 | 11.69±1.19# | 3.12±0.64# |
注:与正常对照组比较,*p<0.01;与模型对照组比较,##p<0.01,#p<0.05;与对照1组比较,**p<0.01;与对照2组比较,**p<0.01
如表2所示,与正常对照组比较,模型对照组小鼠血清中的孕酮、雌二醇含量显著降低(P<0.01),说明造模成功。与模型对照组比较,对照1组和对照2组能提高小鼠血清中的孕酮、雌二醇含量(P<0.05),而治疗1组、治疗2组及治疗3组均能显著提高小鼠血清中的孕酮、雌二醇含量(P<0.01)。与对照1组、对照2组比较,治疗1组、治疗2组及治疗3组均能显著提高小鼠血清中的孕酮、雌二醇含量(P<0.01)。从这些结果可以看出,长春碱与白芦藜醇联合用药组的作用效果显著优于单独使用长春碱或白芦藜醇的对照1组或对照2组的作用效果,这表明将长春碱与白芦藜醇联用后,在提高小鼠血清中的孕酮、雌二醇含量方面具有显著的协同增效作用。
综上所述,本发明的药物组合物中长春碱与白芦藜醇的联用可以大幅提升防止卵巢早衰的效果。
显然,上述实施例仅是为清楚地说明本发明所作的举例,而并非是对本发明的实施方式的限定。本领域的技术人员可以对本发明进行各种改动和变型而不脱离本发明的精神和范围。这样,倘若本发明的这些修改和变型属于本发明权利要求及其等同技术的范围之内,则本发明也意图包含这些改动和变型在内。
Claims (6)
1.一种防止卵巢早衰的药物,其特征在于,所述药物包含活性成分长春碱和白芦藜醇,所述长春碱和白芦藜醇的重量比为1:(0.5-2)。
2.根据权利要求1所述的防止卵巢早衰的药物,其特征在于,所述药物中长春碱和白芦藜醇的重量比为1:(0.5-1.5)。
3.根据权利要求1所述的防止卵巢早衰的药物,其特征在于,所述药物包含活性成分长春碱和白芦藜醇以及药学上可接受的载体。
4.根据权利要求3所述的防止卵巢早衰的药物,其特征在于,所述药学上可接受的载体选自乳糖、甘露醇、淀粉、微晶纤维素、纤维素-乳糖、纤维素-淀粉、甘露醇-淀粉、低取代羟丙基纤维素、羧甲基淀粉钠、交联聚维酮、交联羧甲基纤维素钠、硬脂酸镁、滑石粉、聚乙二醇6000、二氧化硅、胶态二氧化硅中的一种或多种。
5.根据权利要求1-4中任意一项所述的防止卵巢早衰的药物,其特征在于,所述药物为口服制剂。
6.权利要求1-5中任意一项所述的药物在制备防止卵巢早衰的药物中的用途。
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202310754794.XA CN116570593B (zh) | 2023-06-26 | 2023-06-26 | 一种防止卵巢早衰的药物及其用途 |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202310754794.XA CN116570593B (zh) | 2023-06-26 | 2023-06-26 | 一种防止卵巢早衰的药物及其用途 |
Publications (2)
Publication Number | Publication Date |
---|---|
CN116570593A CN116570593A (zh) | 2023-08-11 |
CN116570593B true CN116570593B (zh) | 2024-01-23 |
Family
ID=87541557
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN202310754794.XA Active CN116570593B (zh) | 2023-06-26 | 2023-06-26 | 一种防止卵巢早衰的药物及其用途 |
Country Status (1)
Country | Link |
---|---|
CN (1) | CN116570593B (zh) |
Family Cites Families (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2020191297A1 (en) * | 2019-03-20 | 2020-09-24 | The Regents Of The University Of California | Methods of treatment of spontaneous preterm birth |
-
2023
- 2023-06-26 CN CN202310754794.XA patent/CN116570593B/zh active Active
Non-Patent Citations (2)
Title |
---|
Ameliorative Effect of Citrus Lemon Peel Extract and Resveratrol on Premature Ovarian Failure Rat Model: Role of iNOS/Caspase-3 Pathway;Maysa A Mobasher等;Molecules .;第28卷(第1期);1-18 * |
白黎芦醇对小鼠卵巢早衰的干预作用及可能机制;修银玲等;中国比较医学杂志;第32卷(第7期);81-93 * |
Also Published As
Publication number | Publication date |
---|---|
CN116570593A (zh) | 2023-08-11 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US6569845B1 (en) | Neovascularization inhibitor containing dienogest as the active ingredient | |
WO2019149156A1 (zh) | 一种白头翁提取物在制备治疗病毒性和/或细菌性疾病的药物中的用途 | |
KR20200027481A (ko) | 자궁내막증의 치료를 위한 고나도트로핀 방출호르몬 길항제 투약요법 | |
US20210000641A1 (en) | Eva segmented intravaginal rings containing progesterone | |
US5371107A (en) | Use of ascorbic acid in the genital area and corresponding medicinal preparations | |
KR20000048981A (ko) | 에스트로겐 화합물 및 프로게스테론 화합물로 이루어진 호르몬 조성물 | |
KR20180035739A (ko) | 조직 재생 및 저하된 조직 기능의 회복을 자극하기 위한 제제로서의 디카르복시산의 비스아미드 유도체 | |
CN116570593B (zh) | 一种防止卵巢早衰的药物及其用途 | |
IE58368B1 (en) | Improved antiinflammatory composition | |
CN111281867B (zh) | 一种治疗多囊卵巢综合征的药物及其制备方法 | |
CN110101707B (zh) | 一种用于改善卵巢储备功能减退和预防卵巢早衰的组合物及其应用 | |
JPWO2017010515A1 (ja) | エストロゲン受容体α阻害作用を有するエストロゲン受容体βパーシャルアゴニスト及びこれを用いた婦人科疾患治療剤 | |
RU2803967C1 (ru) | Медицинское применение анемозида b4 при лечении язв в полости рта | |
CA2368370C (en) | The use of dienogest in high dosages | |
DK2253228T3 (en) | Composition for controlling and enhancing female and male gametogenesis | |
US20240245707A1 (en) | Compositions for treating insomnia and uses thereof | |
CN110559285B (zh) | 一种预防或治疗脑缺血再灌注损伤药物组合物及其制备方法 | |
KR20100047872A (ko) | 자궁내막증의 요법에서 요법 부작용을 동시 감소시키며 임신의 경우에 선천성 기형의 위험을 감소시키기 위한 (6s)-5-메틸테트라히드로폴레이트와 조합된 게스타겐의 용도 | |
JPH10120557A (ja) | 創傷治療物質 | |
EP2399583B1 (en) | Use of vaginally-administered insulin sensitizing agents | |
CN115887439A (zh) | 一种化合物在制备多囊卵巢综合征卵巢保护药物中的应用 | |
CN114848650A (zh) | 一种稳定的艾司唑仑制剂组合物及其制备方法 | |
CN117462542A (zh) | Aila在治疗贫血中的应用 | |
CN114886889A (zh) | 土木香内酯或其衍生物在制备用于预防或治疗肥胖的药物、保健品或食品中的用途 | |
US20210085711A1 (en) | Use of ferric citrate in prevention and/or treatment of iron-deficiency anemia in hypermenorrhea patient and/or patient suffering from hypermenorrhea-associated gynecologic disease |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
PB01 | Publication | ||
PB01 | Publication | ||
SE01 | Entry into force of request for substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
GR01 | Patent grant | ||
GR01 | Patent grant |