Drug for suppressing chromosome aneuploidy

Abstract

The present invention addresses the problem of specifically clarifying the effects on a fertilized egg when 5-ALA is administered to a human female suffering from infertility, and constructing a more effective means for treating infertility through the suppression of chromosomal abnormalities. It has been confirmed that, when 5-ALA is ingested in combination with a drug therapy that is generally performed in the treatment of female infertility, the rate of chromosome aneuploidy in a fertilized egg or the like is significantly reduced, and the qualitative improvement of an embryo through improvement of the stability of the chromosomes is expected.

Description

Chromosome aneuploidy inhibitors

[0001] The present invention relates to chromosome aneuploidy inhibitors, and more particularly to chromosome aneuploidy inhibitors comprising 5-aminolevulinic acid (5-ALA) as an active ingredient.

[0002] 5-ALA is an amino acid-like compound produced in mitochondria and converted into porphyrins such as heme and chlorophyll. These substances are deeply involved in the production and conversion of energy in life and are therefore also called "pigments of life." The establishment of industrial production of 5-ALA by fermentation has made it possible to apply 5-ALA to various fields (see, for example, Non-Patent Document 1). While conventional chemical synthesis had the problem of low yields, fermentation has enabled the creation of bacterial strains that produce and accumulate high concentrations of 5-ALA using the photosynthetic bacterium Rhodobacter ferroides (see, for example, Non-Patent Document 2). Furthermore, breeding of mutant strains that produce and accumulate high concentrations of 5-ALA independently of light has progressed, and industrial-scale production has been realized by adjusting oxygen concentration and optimizing the sequential addition of glucose (see, for example, Non-Patent Document 3). Fermentation production using genetically modified bacteria has also been reported (see, for example, Non-Patent Document 4). In the agricultural sector, 5-ALA was initially considered as a potential herbicide, and its use has since expanded to include fertilizers and feed additives. Intake of 5-ALA as a food supplement has been shown to improve several health indicators. Furthermore, in the medical field, 5-ALA (and its derivatives) is approved as a diagnostic reagent for gliomas and bladder cancer.

[0003] 5-ALA is a compound that plays an important role in humans. It is converted to protoporphyrin IX in the body, and then combines with iron to form heme. Heme is involved in oxygen transport as a component of hemoglobin in red blood cells, and is also deeply involved in cellular energy metabolism through various heme proteins (e.g., cytochrome C group). One of the main characteristics and effects of 5-ALA is its effect on improving energy metabolism. 5-ALA plays an essential role in energy production in mitochondria, and is believed to enhance energy metabolism by assisting in the production of ATP (adenosine triphosphate). This effect is considered useful for diabetes, obesity, and chronic fatigue syndrome. Furthermore, it has been reported that 5-ALA has the effect of improving insulin resistance in diabetes. Supplementation with 5-ALA may improve mitochondrial function, streamline cellular energy metabolism, enhance insulin action, and potentially improve blood glucose control and diabetes management. Additionally, it has been shown that 5-ALA supplementation may promote insulin secretion and contribute to improved blood glucose control (see, for example, Non-Patent Document 5). Furthermore, it has been reported that 5-ALA improves glucose metabolism and lowers fasting blood glucose levels in prediabetic patients (see, for example, Non-Patent Document 6). It has also been suggested that it may improve conditions in "hidden diabetes," where fasting blood glucose levels are normal but OGTT shows mild abnormalities (see, for example, Non-Patent Document 7).

[0004] Supplementation with 5-ALA is expected to improve mitochondrial function and promote fatty acid β-oxidation, leading to increased energy expenditure and a reduction in body fat. Furthermore, 5-ALA is known to have anti-inflammatory effects that lower levels of inflammatory markers, potentially reducing chronic inflammation associated with obesity. It has been reported that 5-ALA improves lipid metabolism and reduces visceral fat accumulation in rats fed a high-fat diet (see, for example, Non-Patent Document 8).

[0005] 5-ALA is also believed to have a protective effect on nerve cells and may contribute to improving the function of the nervous system. This is expected to improve nervous system abnormalities associated with chronic fatigue syndrome. 5-ALA functions as a precursor to heme (a prosthetic group of heme proteins involved in oxygen transport and electron transport) in the body. Since heme plays a crucial role in energy metabolism and oxygen supply, supplementation with 5-ALA may improve oxygen utilization efficiency and lead to improved fatigue. The effects of 5-ALA are said to include improved basal metabolism, improved glucose and lipid metabolism, improved athletic performance and reduced fatigue, improved anemia, hair growth, and improved atopic dermatitis.

[0006] Commercially available photodynamic diagnostic agents containing 5-ALA, such as Alagrio® (manufactured by SBI Pharma), are used to visualize cancer cells during surgery. In particular, they are covered by insurance and used for photodynamic diagnosis (PDD) to more clearly identify tumor boundaries and lesion sites during the diagnosis and surgery of bladder cancer and brain tumors. When administered orally, Alagrio is taken up by cancer cells several hours later and converted into a photosensitive substance called protoporphyrin IX (PpIX) within the cell. PpIX has the property of emitting fluorescence when irradiated with light of a specific wavelength (usually blue light). When Alagrio is administered orally before surgery for bladder cancer or brain tumors, cancer cells emit fluorescence, which can be visualized as red fluorescence distinct from normal tissue. This is expected to contribute to the clearer identification of tumor boundaries and micro-lesions, thereby contributing to complete tumor resection and prevention of recurrence.

[0007] It has been shown that supplementing the diet with a combination of 5-ALA and ferrous sodium citrate (SFC) reduces age-related decline in motor function in fruit flies (Drosophila melanogaster) and extends the lifespan of individuals (see, for example, Non-Patent Document 9). These findings suggest that 5-ALA / SFC may slow age-related decline in muscle function (sarcopenia-like changes), contribute to the prevention of age-related clinical conditions such as frailty, and potentially contribute to healthy lifespan and life extension.

[0008] The effects of 5-ALA on reproductive function have been reported for sperm, eggs, and fertilized eggs. Regarding sperm, in vitro addition of 5-ALA significantly increased the motility, progressive (forward) motility, linearity, mean path velocity, curvilinear velocity, and linear velocity of chicken sperm (see, for example, Non-Patent Document 10). Administration of 5-ALA (10g) to Japanese Black bulls improved motility and concentration after sperm collection and reduced the malformation rate (see, for example, Non-Patent Document 11, Patent Document 1, etc.). It has also been reported that 5-ALA improves semen function both in vitro and in vivo.

[0009] Regarding the in vitro effects on fertilized eggs, it has been shown that adding 5-ALA to the culture medium of mouse fertilized eggs improves the normal development rate of the fertilized eggs, and that the combined use of 5-ALA and SFC improves in vitro embryonic development of bovine fertilized eggs (see, for example, Non-Patent Document 12, Patent Document 2, etc.). In addition, it has been reported that adding 5-ALA to chicken feed increases the production of chicken eggs (see, for example, Non-Patent Document 13).

[0010] Furthermore, it has been reported that orally administering 500 mg of 5-ALA daily to 294 older broodmares aged 15 years or older tended to increase the rate of conception in natural mating (see, for example, Non-Patent Document 14).

[0011] International Publication No. 2020 / 116361 Brochure International Publication No. 2016 / 006260 Brochure

[0012] ALA-Porphyrin Science, 1;3-17, 2013Microbiol Biotechnol Biosynthesis, 58;23-29, 2002 Journal of Diabetes Research Volume 78 No. 2 48-55. 200031 pages, Aminolevulinicacid: science, technology and application SBI ALApromo Co Ltd, Tokyo, Japan,2011Journal of Diabetes Research Volume 2016,Issue 1. Epub 2016 Sep 22.Clin Transl Sci. 2012Aug;5(4):314-20. Epub 2012 Jun 1Nutrition, 29;1030. 2013109 pages, Aminolevulinicacid : science, technology and application SBI ALApromo Co Ltd, Tokyo, Japan,2011FEBS Open Bio 12 (2022) 295-305 Anim Biosci Vol.34, No.12:1912-1920 December 2022 The 125th Annual Meeting of the Japanese Society of Animal Science, Poster Session [P29-24] March 29, 2019 Azabu University Journal of Reproduction and Development, Vol. 68, No 4, 2022 Asian-Aust. J. Anim. Sci. Vol.23, No.8:1028-1033 Shogo Takeda, Kazu Suenaga, Kazuki Sakai, Sadao Taharaguchi, The 2024 Annual Meeting of the Japanese Society of Industrial Animal Science (Hokkaido), San-54, Hokujukai Jashi 68, 2024

[0013] Infertility involves a complex interplay of factors related to sperm and egg quality, fertilization, embryonic development, and implantation; the contributing factors are not singular. As mentioned above, there have been reports of improvements in semen parameters and increased egg production rates in mice, cattle, and chickens, as well as an increased tendency for conception rates in older breeding mares, following 5-ALA administration. Furthermore, it has been shown that 5-ALA administration improves the normal development rate of fertilized eggs. However, the mechanism by which 5-ALA administration affects target cells is not yet fully understood. The objective of this invention is to specifically clarify the effects of 5-ALA administration on eggs, sperm, fertilized eggs, and various related cells in human men and / or women suffering from infertility, and to construct more effective infertility treatment methods based on these findings.

[0014] The inventors performed preimplantation genetic testing for aneuploidy (PGT-A) on fertilized eggs derived from eggs collected from women who continuously took 5-ALA orally. The results showed a significant decrease in the rate of aneuploidy compared to fertilized eggs derived from eggs collected before the women began taking 5-ALA orally. Therefore, by selecting embryos with a normal chromosome number (euploid) from those obtained through in vitro fertilization, etc., and implanting them in the uterus, a significant improvement in pregnancy rates can be expected. This is the world's first report demonstrating a link between oral administration of 5-ALA and a reduction in embryonic aneuploidy using clinical samples. Furthermore, the inventors confirmed that in women who started taking 5-ALA orally, even when the administration of conventional infertility treatment drugs such as ovulation inducers was reduced, embryonic aneuploidy significantly decreased, and the proportion of euploid embryos in in vitro fertilization increased. Based on the clinical trials described above, the present invention was completed.

[0015] In other words, the present invention is as follows: [1] Formula (I) (In the formula, R １ R represents a hydrogen atom or an acyl group. ２[1] A chromosome aneuploidy inhibitor for oral administration, comprising a compound represented by () or a salt thereof as an active ingredient. [2] The chromosome aneuploidy inhibitor according to [1] above, characterized in that the cells whose chromosome aneuploidy is suppressed are one or more selected from sperm, eggs, fertilized eggs, senescent cells, and tumor cells. [3] The chromosome aneuploidy inhibitor according to [1] above, characterized in that the chromosome aneuploidy of a fertilized egg is determined by PGT-A. [4] The chromosome aneuploidy inhibitor according to [1] above, further characterized in that it contains an iron compound. [5] The chromosome aneuploidy inhibitor according to [1] above, further characterized in that it is used in combination with NMN and / or resveratrol. [6] The chromosome aneuploidy inhibitor according to [1] above, characterized in that the amount administered orally is 1 mg to 500 mg / day in terms of 5-aminolevulinic acid, and it is administered orally once or twice or more times a day. [7] The chromosome aneuploidy inhibitor described in [1] above, characterized by being administered orally for 14 days or more. [8] An infertility treatment for infertile men and women, comprising the chromosome aneuploidy inhibitor of fertilized eggs described in any of [1] to [7] above. [9] An infertility treatment according to [8] above, characterized by being used in combination with one or more selected from ovulation inducers, follicle-stimulating hormone preparations, luteinizing hormone preparations, and human menopausal gonadotropin preparations (HMG).

[10] An infertility treatment according to [8] above, characterized by enabling a reduction in the dosage of ovulation inducers, follicle-stimulating hormone preparations, luteinizing hormone preparations, or postmenopausal gonadotropin preparations.

[11] A preventive agent for Patau syndrome, Edwards syndrome, Down syndrome, Turner syndrome, Triple X syndrome, or Klinefelter syndrome, comprising the chromosome aneuploidy inhibitor of fertilized eggs described in any of [1] to [7] above.

[12] An agent for improving ovarian reserve caused by chromosomal aneuploidy, comprising an inhibitor of chromosomal aneuploidy of a fertilized egg as described in any of [1] to [7] above.

[13] An agent for improving aging and tumor development and progression caused by chromosomal aneuploidy, comprising an inhibitor of chromosomal aneuploidy of a fertilized egg as described in any of [1] to [7] above.

[14] An agent for improving aging caused by chromosomal aneuploidy, comprising an inhibitor of chromosomal aneuploidy of a fertilized egg as described in any of [1] to [7] above.

[0016] Furthermore, the present invention relates to the use of a compound represented by formula (I) or a salt thereof in the manufacture of a preventive and therapeutic agent for diseases caused by chromosomal aneuploidy, such as infertility, Patau syndrome, Edwards syndrome, Down syndrome, Turner syndrome, Triple X syndrome, and Klinefelter syndrome.

[0017] The aneuploidy inhibitor of the present invention can be used to prevent and treat diseases caused by aneuploidy. Specifically, when the presence or absence of aneuploidy is determined in embryos obtained by in vitro fertilization, the administration of the aneuploidy inhibitor reduces the proportion of aneuploid embryos. As a result, by selecting euploid embryos and transferring them into the uterus, an increase in implantation rates, a decrease in miscarriage rates, and an improvement in pregnancy rates can be expected, contributing to the treatment of infertility. Furthermore, it can be used as a preventive agent for the onset of various diseases caused by aneuploidy in newborns, such as Patau syndrome, Edwards syndrome, Down syndrome, Turner syndrome, Triple X syndrome, and Klinefelter syndrome.

[0018] This graph shows the PGT-A results before and after 5-ALA administration. This graph shows the Gardner classification before and after 5-ALA administration. This graph shows the number of Clomid® tablets administered before and after 5-ALA administration. This graph shows the number of Gonal-f® and / or HMG Ferring injections administered before and after 5-ALA administration. This graph shows the E2 values ​​before and after 5-ALA administration. This graph shows the number of punctures before and after 5-ALA administration. This graph shows the number of eggs retrieved before and after 5-ALA administration. This graph shows the number of blastocysts frozen before and after 5-ALA administration. This graph shows the size of blastocysts before and after 5-ALA administration. This graph shows the freezing time before and after 5-ALA administration. This figure shows the morphological changes of embryos before and after 5-ALA administration. This graph shows the change in the number of Clomid tablets administered before and after 5-ALA (+SFC) 150 mg / day administration. This graph shows the change in the number of Gonal-f (registered trademark) and / or HMG injections before and after administration of 5-ALA (+SFC) 150 mg / day. This graph shows the change in the number of eggs retrieved before and after administration of 5-ALA (+SFC) 150 mg / day. This graph shows the change in the number of blastocysts frozen before and after administration of 5-ALA (+SFC) 150 mg / day. This graph shows the change in the rate of euploid embryos before and after administration of 5-ALA (+SFC) 150 mg / day. This graph shows the change in the rate of euploid embryos in blastocysts after administration of 5-ALA + SFC and various combination components. This graph shows the change in AMH before and after administration of 5-ALA + SFC. This graph shows the change in the percentage of aneuploid sperm in severe sperm abnormalities before and after administration of 5-ALA + SFC. This graph shows the rate of chromosomal aneuploidy in senescent BJ cells after administration of 5-ALA (+SFC) and various concomitant drugs. This graph shows the antitumor effect of 5-ALA and 5-ALA + SFC on A549 cells. This graph shows the change in chromosome number after administration of 5-ALA (+SFC) to A549 cells.

[0019] The chromosomal aneuploidy inhibitor (aneuploidy correcting agent) of the present invention is not particularly limited as long as it contains the compound represented by formula (I) above or a salt thereof (hereinafter, these may be collectively referred to as "ALA compounds" or simply "ALA") as an active ingredient. "Infertility" broadly includes the state of not being able to conceive despite desiring to become pregnant, but according to the World Health Organization's definition, it means "a state of not becoming pregnant for 12 months or more despite having sexual intercourse with sufficient frequency without contraception," and is a concept that includes situations with a history of repeated failures in in vitro fertilization embryo transfer or repeated miscarriages and stillbirths, and can be caused by either the male or female.

[0020] In the compound represented by the above formula (I), R １ R represents a hydrogen atom or an acyl group. ２ represents a hydrogen atom, a linear or branched alkyl group, a cycloalkyl group, an aryl group, or an aralkyl group.

[0021] R １ Examples of acyl groups in this invention include linear or branched C1-C8 alkanoyl groups such as formyl group, acetyl group, propionyl group, butyryl group, isobutyryl group, valeryl group, isovaleryl group, pivaloyl group, hexanoyl group, octanoyl group, and benzylcarbonyl group, as well as C7-C14 alloyl groups such as benzoyl group, 1-naphthoyl group, and 2-naphthoyl group. In this invention, for convenience, the acyl group is assumed to include alkoxycarbonyl groups such as methoxycarbonyl group, ethoxycarbonyl group, n-propoxycarbonyl group, and isopropoxycarbonyl group.

[0022] R ２ Examples of alkyl groups in this context include linear or branched alkyl groups having 1 to 8 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, and octyl groups.

[0023] R ２Examples of the cycloalkyl group in [description] include cycloalkyl groups having 3 to 8 carbon atoms with saturated or partially unsaturated bonds such as cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, cycloheptyl group, cyclooctyl group, cyclododecyl group, 1-cyclohexenyl group, etc.

[0024] R ２ Examples of the aryl group in [description] include aryl groups having 6 to 14 carbon atoms such as phenyl group, naphthyl group, anthryl group, phenanthryl group, etc.

[0025] R ２ Examples of the aralkyl group in [description] include the same examples as the above aryl group for the aryl part and the same examples as the above alkyl group for the alkyl part. Specifically, aralkyl groups having 7 to 20 carbon atoms such as benzyl group, phenethyl group, phenylpropyl group, phenylbutyl group, benzhydryl group, trityl group, naphthylmethyl group, naphthylethyl group, etc. can be mentioned.

[0026] The above R １ and R ２ may have substituents within a chemically acceptable range as necessary. Examples of such substituents include halogen atoms, alkyl groups, haloalkyl groups, alkoxy groups, nitro groups, aryl groups, etc.

[0027] Examples of the above 5-ALA derivatives include compounds in which R １ is formyl, acetyl, propionyl, butyryl group, etc., and compounds in which the above R ２ is methyl, ethyl, propyl, butyl, pentyl group, etc. are preferred. Combinations of the above R １ and R ２ can preferably be exemplified by combinations such as formyl and methyl, acetyl and methyl, propionyl and methyl, butyryl and methyl, formyl and ethyl, acetyl and ethyl, propionyl and ethyl, butyryl and ethyl.

[0028] ALA compounds are not particularly limited as long as they exert the effects of the present invention as an active ingredient in the body in the form of 5-ALA of formula (I) or its derivatives. Depending on the form of administration, they can be administered as various salts, esters to increase solubility, or as prodrugs (precursors) that are broken down by enzymes in the body. For example, examples of salts of 5-ALA and its derivatives include pharmacokinetically acceptable acid addition salts, metal salts, ammonium salts, organic amine addition salts, etc. Examples of acid addition salts include various inorganic acid salts such as hydrochloride, hydrobromide, hydroiodide, phosphate, nitrate, and sulfate, and various organic acid addition salts such as formate, acetate, propionate, toluenesulfonate, succinate, oxalate, lactate, tartrate, glycolate, methanesulfonate, butyrate, valerate, citrate, fumarate, maleate, and malate. Examples of metal salts include alkali metal salts such as lithium salts, sodium salts, and potassium salts; alkaline earth metal salts such as magnesium and calcium salts; and metal salts such as aluminum, zinc, and iron. Examples of ammonium salts include alkylammonium salts such as ammonium salt and tetramethylammonium salt. Examples of organic amine salts include triethylamine salt, piperidine salt, morpholine salt, and toluidine salt. These salts can also be used in solution form.

[0029] Of the above ALA compounds, preferred are 5-ALA (aminolevulinic acid), and various esters such as 5-ALA methyl ester, 5-ALA ethyl ester, 5-ALA propyl ester, 5-ALA butyl ester, and 5-ALA pentyl ester, as well as their hydrochlorides, phosphates, and sulfates. 5-ALA, 5-ALA hydrochloride, and 5-ALA phosphate are particularly preferred examples.

[0030] The above-mentioned ALA compounds can be produced by any known method, such as chemical synthesis, microbial production, or enzymatic production. Furthermore, the ALA compounds may be in the form of hydrates or solvates, and either one or two or more can be used individually or in appropriate combinations.

[0031] The above ALA compounds are preferably administered in combination with iron compounds. The iron compounds may be organic or inorganic salts. Examples of inorganic salts include ferric chloride, ferric oxide, ferric sulfate, and ferrous pyrophosphate. Examples of organic salts include carboxylates, such as hydroxycarboxylates, such as ferrous citrate, sodium ferric citrate, sodium ferrous citrate, ammonium ferric citrate, ferric pyrophosphate, ferric lactate, ferrous gluconate, sodium diethylenetriaminepentaacetate, ammonium diethylenetriaminepentaacetate, and ethylene Examples of organic salts include sodium ferric diaminetetraacetate, ammonium ferric ethylenediaminepentaacetate, sodium ferric dicarboxymethylglutamate, ammonium ferric dicarboxymethylglutamate, ferrous fumarate, iron acetate, iron oxalate, ferrous succinate, and sodium ferric citrate succinate, as well as heme iron, dextran iron, triethylenetetraamine iron, lactoferrin iron, transferrin iron, iron chlorophyllin sodium, ferritin iron, saccharified iron oxide, and glycine iron sulfide, but sodium ferrous citrate is preferred.

[0032] The above iron compounds may be used individually or in mixtures of two or more. The amount of iron compound used (amount added / dosage) can be exemplified as a molar ratio of 0.01 to 100 times the dose of ALA compounds (in terms of aminolevulinic acid), with 0.05 to 10 times being preferable. For example, 1 to 200 mg in terms of ferrous sodium citrate can be exemplified for 50 mg of 5-ALA phosphate, with 2 to 150 mg being preferable, 3 to 100 mg being preferable, 4 to 80 mg being more preferable, and 5 to 70 mg being preferable. Also, 1 to 200 mg in terms of ferrous sodium citrate can be exemplified for 50 mg of 5-ALA phosphate, with 5 to 150 mg being preferable, 10 to 100 mg being more preferable, 20 to 80 mg being even more preferable, and 40 to 65 mg being particularly preferable.

[0033] The dosage form of the chromosome aneuploidy inhibitor of the present invention is not particularly limited, and examples include oral formulations such as tablets, capsules, granules, fine granules, and liquids, and injectable formulations such as liquids and powders that dissolve immediately before use.

[0034] In the aneuploidy inhibitor of the present invention, other optional components such as other medicinal ingredients, nutritional agents, carriers, etc. can be added as necessary. As the optional components, for example, pharmaceutically acceptable ordinary carriers, binders, stabilizers, solvents, dispersion media, extenders, excipients, diluents, pH buffers, disintegrants, solubilizers, solubilizing aids, isotonic agents, etc., such as crystalline cellulose, gelatin, lactose, starch, magnesium stearate, talc, vegetable and animal fats, oils, gums, polyalkylene glycols, etc. can be added.

[0035] As a method of administering the aneuploidy inhibitor of the present invention, oral administration or administration by injection is preferred. As the dosage in the case of oral administration, 1 mg to 500 mg / day in terms of aminolevulinic acid can be exemplified, 1 to 300 mg / day is preferred, 1 to 150 mg / day is preferred, 5 to 100 mg / day is preferred, 10 to 80 mg / day is preferred, 10 to 70 mg / day is more preferred, 15 to 60 mg / day is further preferred, and 15 to 50 mg / day is further preferred. Also, 1 mg to 1000 mg / day in terms of 5-ALA phosphate can be exemplified, 1 mg to 500 mg / day is preferred, 1 to 300 mg / day is preferred, 1 to 150 mg / day is preferred, 5 to 100 mg / day is preferred, 10 to 80 mg / day is preferred, 10 to 70 mg / day is more preferred, 15 to 60 mg / day is preferred, 15 to 50 mg / day is preferred, 2 to 250 mg / day is preferred, 3 to 200 mg / day is preferred, 100 to 500 mg / day is preferred, 100 to 300 mg / day is preferred, and 100 to 200 mg / day is preferred. As the administration form, it can be exemplified that it is orally administered once, twice or more times a day.

[0036] As the period of administering the aneuploidy inhibitor of the present invention (orally), 1 week or more can be mentioned, 14 days or more is preferred, 30 days or more is preferred, 45 days or more is more preferred, 60 days or more is more preferred, 75 days or more is more preferred, 90 days or more is more preferred, 100 days or more is more preferred, and 120 days or more is further preferred.

[0037] The aneuploidy inhibitor of the present invention is characterized in that it can reduce the aneuploidy of chromosomes in cells such as fertilized eggs, sperm, eggs, senescent cells, senescent fibroblasts, and tumor cells. Here, the fertilized egg referred to herein means a zygote that can grow by somatic cell division, formed by the entry of sperm into the egg and the fusion of the sperm nucleus and the egg nucleus. In the treatment of infertility, as methods for obtaining fertilized eggs, known methods such as a method of collecting (retrieving eggs) the in-vivo fertilized eggs outside the body and a method of obtaining fertilized eggs by in-vitro fertilization or microinjection can be mentioned, but in-vitro fertilization is preferable in terms of low invasiveness. The decrease in the aneuploidy of the chromosomes of the fertilized egg is due to the effect of reducing the aneuploidy of the egg, which is similarly due to the effect of reducing the aneuploidy of the sperm, so it is also applicable to male infertility. Therefore, it is also effective for infertile women or men at the right timing and infertility treatment by artificial insemination. Also, in egg freezing that has recently come to be performed, by administering 5-ALA in advance, an effect of improving the pregnancy rate of frozen eggs can also be expected.

[0038] The aneuploidy of the chromosomes of the above-mentioned fertilized egg refers to a state in which there is an excess or deficiency in the number of chromosomes. In the case of humans, there are a total of 23 pairs (46 chromosomes) including 22 pairs of autosomes (44 in total) numbered 1 to 22 and 1 pair of sex chromosomes (2 in total), and usually, each pair consists of 2 chromosomes from a combination of 1 chromosome from the father and 1 chromosome from the mother. A state in which a chromosome other than 2 exists, such as trisomy in which 3 chromosomes are present or monosomy in which the number of chromosomes is 1, is called aneuploidy. Aneuploid embryos have a significant impact on the developmental ability of embryos, and most often result in failed implantation. Even if implantation occurs, the risk of miscarriage or stillbirth increases.

[0039] On the other hand, diseases caused by chromosomal aneuploidy include trisomy 13, where there is an extra copy of chromosome 13, which is known to cause Patau syndrome; trisomy 18, where there is an extra copy of chromosome 18, which is known to cause Edwards syndrome; trisomy 21, where there is an extra copy of chromosome 21, which is known to cause Down syndrome; partial or complete deletion of the X chromosome in females (X-: X monosomy), which is known to cause Turner syndrome; trisomy of the X chromosome in females, which is known to cause triple X syndrome; and addition of an X chromosome (XXY) in males, which is known to cause Klinefelter syndrome. However, by using the chromosomal aneuploidy inhibitor of the present invention, chromosomal aneuploidy can be reduced, thereby reducing the incidence of these diseases and preventing the onset of diseases primarily caused by aneuploidy, such as Down syndrome, Turner syndrome, triple X syndrome, and Klinefelter syndrome. Furthermore, chromosomal translocations can cause miscarriage, and as people age, 10-30% of their chromosomes exhibit aneuploidy, a ratio that increases with age. 5-ALA works to prevent miscarriage and promote anti-aging by suppressing these translocations and aneuploidy, and it also helps prevent translocations and aneuploidy that cause cancer, contributing to the prevention of cancer development and the suppression of cancer development, progression, and metastasis.

[0040] Whether or not the above-mentioned fertilized egg has chromosomal aneuploidy can be determined by PGT-A. PGT-A is a genetic test that comprehensively examines the chromosomes of fertilized eggs obtained through in vitro fertilization before the blastocyst is implanted into the uterus. In Japan, the Japan Society of Obstetrics and Gynecology had long refused to approve it due to concerns that it could lead to the selection of lives. However, in response to increasing patient needs, a "pilot trial for a multicenter collaborative study on the usefulness of PGT-A" was conducted at four in vitro fertilization facilities in Japan. Subsequently, the clinical usefulness of PGT-A was recognized, and currently, 223 facilities in Japan are registered as PGT-A approved facilities.

[0041] The PGT-A method described above is not particularly limited as long as it can determine the presence or absence of aneuploidy in a fertilized egg. For example, one method involves taking a sample of cells from the trophectoderm of a fertilized egg that has undergone in vitro fertilization, or an embryo that has been cryopreserved as needed after in vitro fertilization, once it has grown to the blastocyst stage, and submitting it to a testing laboratory for chromosome number analysis. More specifically, one example is a method in which, after in vitro fertilization is performed and the embryo has grown from an early blastocyst to a blastocyst and then an expanded blastocyst through culture, the zona pellucida is opened, a portion of the trophectoderm cells is excised and sent to a testing laboratory for actual testing.

[0042] Methods for examining the chromosome number of various cells, including sperm, eggs, fertilized eggs, senescent cells, and / or tumor cells, are not particularly limited as long as they can determine whether there is an excess or deficiency of chromosomes. Examples include base sequence information analysis and methods for detecting aneuploidy using sequencing technology. For example, one method involves amplifying a target region using PCR (polymerase chain reaction) with a primer set that can specifically amplify part or all of a gene region, and then determining the base sequence of the resulting amplified product by a known method to detect chromosomal abnormalities or gene mutations. Furthermore, examples include microarrays capable of simultaneously detecting numerous gene regions, next-generation sequencers (NGS), which can simultaneously sequence thousands to millions of DNA molecules, and the Sanger sequencing method, a classical base sequence determination method suitable for high-precision analysis of specific regions. By using these technologies, it becomes possible to detect chromosomal abnormalities (trisomy, monosomy, etc.) and structural mutations (translocation, deletion, duplication, etc.) with high precision.

[0043] Examples of the microarrays mentioned above include known methods such as evaluating the excess or deficiency of chromosome number using cells excised from blastocysts.

[0044] Examples of next-generation sequencers used to examine the number of chromosomes in blastocysts include Illumina's (San Diego, CA) MiSeq9™, HiSeq™, NextSeq™, MiSeq™, and NovaSeq™; Thermo Fisher's (Waltham, MA) Ion Proton™ and Ion PGM™; Roche's (Basel, Switzerland) GSFLX+™ and GS Junior™; Pacific Biosciences (PacBio) Sequel IIe™; Oxford Nanopore Technologies' MinION™, PromethION™, and GridION™; and BGIGenomics' MGISEQ™.

[0045] As an example of the PGT-A method used for determination, the following methods can be used: • A blastocyst that receives an "A" rating (Embryo A) is a chromosomally euploid embryo, meaning that chromosomal euploidy has been confirmed and there are no problems with its transfer. • A blastocyst that receives a "B" rating (Embryo B) is a so-called mosaic embryo, which can be transferred but may be difficult to maintain pregnancy with. • A blastocyst that receives a "C" rating (Embryo C) is an embryo that has been confirmed to have chromosomal aneuploidy and is considered unsuitable for transfer.

[0046] In addition, the aneuploidy of a fertilized egg can be determined by the following known method, for example: (i) a step of preparing nucleic acids contained in the culture supernatant of a mammalian fertilized egg cultured in vitro; (ii) a step of obtaining the base sequence information of the nucleic acids using a base sequence information acquisition means; and (iii) a step of determining the presence or absence of a genetic abnormality by analyzing the obtained base sequence information. This method is characterized by using a culture supernatant obtained from a fertilized egg culture in which no opening is made in the zona pellucida of the fertilized egg after fertilization, and since it does not involve direct manipulation of the embryo, it is possible to minimize the impact on the viability and development of the embryo (see, for example, Japanese Patent Application Publication No. 2018-61453).

[0047] Specifically, for example, PGT-A can also be performed by the following steps 1-4: 1. Embryo biopsy (cell collection) When the embryo reaches the blastocyst stage (5-6 days of development), 5-10 cells are collected from the outer layer of trophectoderm (the part that will become the placenta). 2. DNA extraction DNA is extracted from the collected cells. 3. DNA analysis method: Next-generation sequencing (NGS) This process includes the following steps: DNA fragmentation: The extracted DNA is broken down into short fragments. Library preparation: Short DNA sequences called "adapters" are attached to the DNA fragments to prepare for NGS analysis. Sequencing is performed using this library. Sequencing: The copy number of chromosomes in the embryo is detected by simultaneously reading a large amount of DNA sequences using an NGS instrument. Data alignment: The sequences of the obtained DNA fragments are matched with the human reference genome sequence to identify the region corresponding to each chromosome and calculate the copy number of each chromosome. 4. Microarrays and other microarray technologies use an "array" in which thousands to millions of DNA fragments (probes) are arranged on a small glass tube or silicon chip to examine their binding to the DNA or RNA of a sample, thereby detecting the copy number of a specific gene. The process of a CGH array (comparative genome hybridization array) involves labeling the DNA of the sample (DNA extracted from an embryo) and a reference DNA with different fluorescent dyes, hybridizing both DNAs onto the array, comparing which DNA binds more, analyzing the fluorescence intensity, and determining whether the copy number of a chromosomal region is normal.

[0048] The administration of the chromosome aneuploidy inhibitor of the present invention is preferably used in combination with the above-mentioned in vitro fertilization, which is commonly used in the treatment of infertility in women and men, as well as advanced or general reproductive medicine such as drug therapy, timed intercourse, and artificial insemination. The above-mentioned drug therapy is preferably administered in combination with one or more selected from ovulation inducers, follicle-stimulating hormone preparations, luteinizing hormone preparations, and pituitary gonadotropin preparations. Specific embodiments include: administration of ovulation inducers only; administration of follicle-stimulating hormone preparations only; administration of luteinizing hormone preparations only; administration of pituitary gonadotropin preparations only; administration of ovulation inducers and follicle-stimulating hormone preparations; administration of ovulation inducers and luteinizing hormone preparations; administration of ovulation inducers and postmenopausal pituitary gonadotropin preparations; and administration of follicle-stimulating hormone preparations and postmenopausal pituitary gonadotropin preparations. Examples of combinations of ovulation induction agents and postmenopausal pituitary gonadotropin preparations include: administration with gonadotropin preparations; administration with ovulation induction agents, follicle-stimulating hormone preparations, and luteinizing hormone preparations; administration with ovulation induction agents, follicle-stimulating hormone preparations, and postmenopausal pituitary gonadotropin preparations; and administration of ovulation induction agents, follicle-stimulating hormone preparations, luteinizing hormone preparations, and postmenopausal pituitary gonadotropin preparations (hereinafter sometimes simply referred to as "drugs"). These combinations can also be changed depending on the timing and administration can continue.

[0049] When the chromosome aneuploidy inhibitor of the present invention is used in combination with the above-mentioned drug, each can be administered individually, simultaneously, or before or after the other. When administered individually or before or after the other, it is preferable that the chromosome aneuploidy inhibitor of the present invention and the above-mentioned drug are administered in such a manner that they produce at least an additive, preferably synergistic, effect.

[0050] The ovulation-inducing agents mentioned above are not particularly limited to drugs that stimulate the ovaries to make ovulation easier and promote the secretion of follicle-stimulating hormone (FSH) and / or luteinizing hormone (LH), which are necessary for ovulation. Examples of drugs that promote FSH secretion include Clomid (clomifene citrate) tablets and letrozole.

[0051] The dosage of ovulation-inducing agents such as Clomid can be determined according to the instructions in the manual or by a doctor. For example, one cycle consists of taking one tablet (50 mg of the active ingredient) once a day, orally from the third day after the start of menstruation until the decision to retrieve eggs is made. A key feature of the present invention is that even if the dosage of the ovulation-inducing agent after the start of 5-ALA administration is significantly reduced from the dosage before the start of 5-ALA administration, it is still possible to reduce the aneuploidy of fertilized eggs. For example, the dosage for one cycle can be reduced from an average of 17-21 tablets to 9-15 tablets, preferably from 14-17 tablets to 11-14 tablets, preferably from 14-16 tablets to 10-13 tablets, more preferably from 14-16 tablets to 7-10 tablets, and even more preferably from 14-16 tablets to 5-7 tablets.

[0052] The above-mentioned follicle-stimulating hormone (FSH) is one of the gonadotropins, a 35.5 kDa glycoprotein polypeptide in which two polypeptides, alpha and beta, form a heterodimer. Commercially available recombinant human follicle-stimulating hormone (r-hFSH), such as Gonal-f® injection or subcutaneous pen, Follistim® injection or subcutaneous pen, and Recobel® injection or subcutaneous pen, are widely used to induce superovulation.

[0053] The above-mentioned follicle-stimulating hormone (FSH) can be used alone, or it can be used by injection or other means in the form of a human menopausal gonadotropin (HMG) preparation mixed with LH, for example in a 1:1 ratio. Examples of HMG preparations include HMG Ferring (manufactured by Ferring Pharmaceuticals), HMG "F" (manufactured by Fuji Pharmaceutical Co., Ltd.) mixed in a 3:1 ratio, and HMG "Asuka" (manufactured by Asuka Pharmaceutical Co., Ltd.).

[0054] The luteinizing hormone (LH) mentioned above is a type of gonadotropin secreted from the anterior pituitary gland together with the follicle-stimulating hormone (FSH), and plays a role in stimulating the maturation of follicles and eggs.

[0055] The dosage of the above-mentioned follicle-stimulating hormone (FSH) and / or human postmenopausal pituitary gonadotropin (HMG) can be determined according to the instructions in the manual or by a physician. A key feature of the present invention is that by using the chromosome aneuploidy inhibitor of the present invention in combination, the number of FSH and / or HMG injections after the start of 5-ALA administration can be significantly reduced from the number of FSH and / or HMG injections before the start of 5-ALA administration, while still reducing aneuploidy of fertilized eggs. For example, the number of injections per cycle can be reduced from an average of 7 to 25 to 4 to 17, from 7 to 20 to 4 to 10, from 7 to 12 to 4 to 7, from 8 to 10 to 3 to 6, from 8 to 10 to 1 to 5, and more preferably from 8 to 10 to 1 to 4.

[0056] Administration of the chromosomal aneuploidy inhibitor of the present invention significantly reduces the Gardner classification score described below, decreases the blastocyst freezing time, increases the number of retrieved eggs, increases the number of frozen blastocysts, increases the euploid embryo rate of blastocysts, improves sperm aneuploidy, improves chromosomal aneuploidy in senescent cells, and improves chromosomal aneuploidy in cancer cells.

[0057] Furthermore, administration of the chromosomal aneuploidy inhibitor of the present invention can also yield secondary effects such as improvement in indicators (AMH values) in ovarian reserve testing, increased antitumor effects against cancer cells, and prevention of aging in the elderly. These secondary effects are thought to be due to the stabilization of cell function, inhibition of aging, and normalization of cell proliferation control through the suppression of chromosomal aneuploidy, suggesting its potential as a new auxiliary approach in reproductive medicine, geriatric medicine, and cancer treatment.

[0058] The Gardner morphological blastocyst grading system described above is a classification method for evaluating embryos based on their growth stage and the morphological state of the inner cell mass and trophectoderm. In each embryo, the cell group that will become the fetus is defined as the inner cell mass (ICM), and the cell group that will become the placenta is defined as the trophectoderm (TE). The evaluation of the ICM and TE is performed in the following three stages: A: High cell count, clear structure, and good condition B: Moderate cell count, somewhat unclear structure C: Low cell count, poor structure Furthermore, each evaluation of the ICM and TE is quantified and scored as A=1, B=2, C=3, and by adding the scores of both, the morphological maturity of the entire embryo can be quantitatively evaluated. Using this score, it is possible to compare the evaluation results of embryos before and after administration of the chromosomal aneuploidy improving agent or inhibitor of the present invention. In other words, if the score after administration is significantly lower, it can be determined that the developmental state of the embryo after fertilization has significantly improved due to the administration of the drug.

[0059] The freezing time described above can be evaluated by comparing the freezing process before and after administration of the chromosome aneuploidy inhibitor of the present invention. Administration of the chromosome aneuploidy inhibitor of the present invention significantly reduced the freezing time of fertilized eggs. This result suggests that administration of 5-ALA improves the quality of eggs and the developmental state of embryos, potentially shortening the time required for freezing. This is thought to contribute to improving the efficiency of the cryopreservation process and enhancing embryo viability in reproductive medicine.

[0060] The number of eggs retrieved, as mentioned above, refers to the number of eggs that could be collected from the woman's ovaries and is an important indicator that reflects the responsiveness of the ovaries and the developmental status of the follicular cells. Administration of the chromosome aneuploidy inhibitor of the present invention significantly increased the number of eggs retrieved. This is thought to indicate that the agent promotes follicular development and improves ovarian function, thereby enabling the retrieval of more mature eggs.

[0061] The above-mentioned number of blastocysts to be frozen refers to the number of blastocysts that have developed to a size of 160 μm or more and are deemed suitable for freezing. Before freezing, the zona pellucida can be opened with a laser, and 5 to 10 trophoblastic cells can be collected and submitted for PGT-A testing. Administration of the chromosome aneuploidy inhibitor of the present invention significantly increases the number of freezeable blastocysts obtained from eggs collected from women who received 5-ALA compared to blastocysts obtained from eggs collected from women who did not receive 5-ALA.

[0062] The chromosomal euploidy rate of blastocysts mentioned above refers to the percentage of blastocysts in which chromosomal euploidy has been confirmed and which are considered suitable for transplantation. It has been confirmed that administration of the chromosomal aneuploidy inhibitor of the present invention significantly increases the percentage of chromosomal euploidy embryos compared to before administration. Specifically, an increase of 1.1 to 30 times, preferably 1.5 to 20 times, and more preferably 2 to 15 times compared to before administration may be observed. This result indicates that administration of the agent improves the chromosomal stability of embryos and increases the selection rate of normal embryos suitable for transplantation, which is an important finding that contributes to improving the success rate of pregnancy and reducing the risk of miscarriage in in vitro fertilization (IVF).

[0063] When the chromosomal aneuploidy inhibitor of the present invention is further administered with NMN and / or resveratrol, the percentage of chromatic aneuploid embryos, as measured by PGT-A testing six months after administration, is significantly higher than that of 5-ALA (+SFC) 150 mg / day alone. For example, it can be about 5% to 15% higher. This result suggests that the cellular senescence-inhibiting and mitochondrial function-improving effects of NMN and resveratrol work synergistically with the effects of 5-ALA + SFC to further improve the chromosomal stability and developmental state of embryos, making it a promising combination that can contribute to improving the quality of embryos and increasing pregnancy success rates in reproductive medicine.

[0064] The above-mentioned aneuploidy of sperm chromosomes refers to a condition in males where sperm, which begin as diploid germ cells called spermatogonia and undergo somatic cell division, meiosis, and cell differentiation to form haploid gametes, have an excess or deficiency in the number of chromosomes. In humans, sperm have 22 autosomes and an X chromosome, or 22 autosomes and a Y chromosome. However, if errors occur in chromosome segregation during mitosis and / or meiosis I or II in spermatogenesis, sperm with numerical chromosomal abnormalities (aneuploidy) characterized by an excess or deficiency of chromosomes are formed. Such aneuploid sperm are considered to be factors that increase the risks in reproductive medicine, such as a decrease in fertilization rates and an increase in miscarriage rates. It can be easily estimated that administration of the aneuploidy inhibitor of the present invention to men will reduce aneuploidy in sperm and reduce aneuploidy in fertilized eggs produced by known in vitro fertilization methods such as sperm insemination (conventional in vitro fertilization) and intracytoplasmic sperm injection (ICSI).

[0065] The above-mentioned aneuploidy of oocytes can be described as a condition in which, in females, an excess or deficiency of chromosomes occurs in the oocyte, which begins as a diploid germ cell called an oogonia, undergoes somatic cell division to become a primary oocyte, and then undergoes meiosis and cell differentiation to form a haploid gamete. In humans, oocytes have 22 autosomes and an X sex chromosome, but it is believed that numerical chromosomal abnormalities (aneuploidy) characterized by an excess or deficiency of chromosomes occur due to errors in chromosome segregation during meiosis of the oocyte. Oocytes with such aneuploidy are considered to be a factor in infertility and pregnancy disorders, such as a decrease in fertilization rate, an increase in miscarriage rate, and an increased risk of developing various diseases caused by chromosomal abnormalities, and are more likely to cause diseases caused by the aforementioned aneuploidy. It is presumed that administration of the chromosomal aneuploidy inhibitor of the present invention to women will reduce the aneuploidy of fertilized eggs produced by in vitro fertilization.

[0066] As an example of the effect of improving chromosomal aneuploidy in the above-mentioned fibroblasts, the improvement in chromosomal aneuploidy that occurs when BJ cells, which are human fibroblasts established from the foreskin of neonatal males, are cultured for 80 passages can be cited as an example of improvement in aneuploidy in aging. When the chromosomal aneuploidy inhibitor of the present invention, which contains 5-ALA and SFC, is administered to cells, the proportion of chromosomal aneuploid cells is significantly reduced compared to when no administration is performed. Furthermore, when 5-ALA and SFC are cultured with NMN and / or resveratrol added, the proportion of chromosomal aneuploid cells can be further reduced compared to 5-ALA alone. These results suggest the possibility that chromosomal stability is enhanced through improved accuracy of chromosome segregation during cell division, suppression of cellular senescence, and improvement of mitochondrial function, and are useful findings from the perspective of aging prevention.

[0067] Regarding the improvement effect on ovarian reserve values ​​in the above-mentioned AMH (Anti-Mullerian Hormone) test, a significant improvement effect has been observed with the administration of the chromosomal aneuploidy improving agent or inhibitor of the present invention in the AMH test, which is used to determine how many eggs remain in the ovaries (ovarian reserve). In particular, when the chromosomal aneuploidy inhibitor of the present invention is administered to women showing DOR (Diminished ovarian reserve) with an AMH of less than 1, the values ​​increase significantly compared to before administration, for example, by more than 1.4 times after 3 months and / or more than 1.8 times after 6 months, compared to those who did not receive the drug. The above-mentioned AMH is a hormone secreted from follicles at the stage from primary follicle to preantral follicle, and the amount of secreted AMH is considered to be an indicator of ovarian reserve, with high values ​​when there are many developing follicles and low values ​​when there are few. The fact that administration of the present invention significantly increases AMH levels suggests its potential as a new intervention for age-related changes and functional decline of the ovaries, and represents useful findings that will contribute to expanding treatment options in infertility treatment.

[0068] The present invention will be described more specifically below with reference to examples, but the technical scope of the present invention is not limited to these examples.

[0069] [Example 1] The patient was a 39-year-old adult woman. There was nothing noteworthy in her medical history. Over a three-year period of infertility treatment, as shown in Table 1, she received ovulation-inducing drugs, human follicle-stimulating hormone and / or human postmenopausal gonadotropin, followed by administration of 5-ALA, and a total of 15 egg retrievals were performed. The length of each period (one cycle) from the start of drug administration to egg retrieval corresponds to the number of Clomid tablets in each cycle in Table 1. For example, if it says 23 Clomid tablets, it is 23 days.

[0070] The ovaries of the above-mentioned women were stimulated by orally administering Clomid® tablets 50 mg / (manufactured by Fuji Pharmaceutical Co., Ltd.) as an ovulation inducer, and by injecting 150 IU / vial of Gonal-f® (manufactured by Merck Biopharma), a recombinant human follicle-stimulating hormone (FSH) preparation, and / or HMG Ferring (manufactured by Ferring Pharma), a human postmenopausal pituitary gonadotropin preparation with a 1:1 ratio of FSH to luteinizing hormone (LH).

[0071] As a trigger for oocyte retrieval, a GnRH agonist nasal spray (Buserelin, manufactured by Fuji Pharmaceutical Co., Ltd.), a derivative of hypothalamic hormone (GnRH: Gonadotropin-releasing hormone), was used. As a chromosome aneuploidy inhibitor, tablets containing 50 mg of 5-ALA and 57 mg of ferrous sodium citrate per tablet (manufactured by NeoPharma Japan) (hereinafter also referred to as "ALA tablets") were used. The timing of oral administration, oocyte retrieval results, embryo transfer results, and PGT-A results for this case are shown in Table 1 below.

[0072]

[0073]

[0074] (Results) 1) As shown in Table 1, in the first and second attempts where PGT-A testing was not performed, one cleavage-stage embryo and three blastocysts were frozen and transferred, but implantation did not occur, resulting in missed miscarriage or chemical pregnancy loss. 2) In the third attempt, one embryo transferred without PGT-A testing resulted in a chemical pregnancy loss. The three embryos that underwent PGT-A testing were aneuploid.

[0075] 3) In the 4th to 10th egg retrievals, 22 blastocysts were tested for PGT-A. There was one euploid A embryo (5th time), but it resulted in a chemical pregnancy after transfer. There were four B embryos (mosaic embryos) and 17 C embryos showing aneuploidy.

[0076] 4) Starting from the 11th cycle, daily oral administration of 5-ALA tablets (50 mg / tablet / day) was initiated on the second day of treatment (fourth day of menstruation). Egg retrieval was performed 14 days after the start of 5-ALA administration. 5-ALA was taken continuously without interruption thereafter. In the 11th to 13th egg retrievals, a total of 6 blastocysts were frozen and tested for PGT-A. On day 12 after 5-ALA administration, there was one C embryo; on day 75, there were two C embryos; and on day 122, there were two A embryos and one C embryo. In other words, in the 11th to 13th cycles, there were two euploid A embryos and four aneuploid C embryos. Therefore, after starting 5-ALA administration, there was a one-third probability of obtaining euploid A embryos.

[0077] Furthermore, before 5-ALA administration, 4% (1 embryo) were rated A by PGT-A, 16% (4 embryos) were rated B, and 80% (20 embryos) were rated C. In contrast, 122 days after starting oral administration of 5-ALA, 66.7% (2 embryos) were rated A, and 33.3% (1 embryo) were rated C. As is clear from Figure 1, compared to before 5-ALA administration, it was confirmed that after 5-ALA administration, the number of embryos rated A significantly increased and the number of embryos rated C decreased (P < 0.05). It was confirmed that when 5-ALA was administered orally in combination with conventionally used drugs for infertility treatment, the proportion of aneuploid embryos significantly decreased. In addition, pregnancy and the birth of normal children were observed after the transfer of the obtained A-rated embryos.

[0078] As previously studied, it was confirmed that administration of 5-ALA significantly reduced the percentage of aneuploid embryos. Women were administered 5-ALA for four months, but fertilized eggs after egg retrieval were not given 5-ALA, so it can be said that the effect of 5-ALA is to improve aneuploidy of eggs.

[0079] (Improvement in semen parameters) In another case, a patient underwent in vitro fertilization and experienced two miscarriages. Chromosome analysis of the placenta after the second miscarriage revealed an extra copy of chromosome 10 (trisomy 10). After the second miscarriage, the husband took 5-ALA for six months, and his semen parameters improved as shown below, leading to the birth of a healthy child. It is estimated that 80% of aneuploidy in fertilized eggs originates from the egg, and 20% from the sperm. Therefore, this case appears to be a case in which the improvement in sperm aneuploidy due to the improvement in semen parameters by 5-ALA was confirmed. From the above, it can be inferred that administration of 5-ALA may have an effect on improving aneuploidy in both eggs and sperm.

[0080]

[0081] The results of PGT-A tests and drug dosages during the three-year infertility treatment period described above were further examined as follows.

[0082] (Gardner classification) Figure 2 shows the scores before (including up to 13 days after administration of 5-ALA) and after administration. Compared to before administration of 5-ALA, the Gardner classification score after administration decreased significantly from 4.3 ± 1.6 to 3.0 ± 0.7, confirming the effect of administering the chromosome aneuploidy inhibitor of the present invention.

[0083] Furthermore, as can be seen from Figure 11, which shows the morphological changes of embryos before and after 5-ALA administration, embryos before 5-ALA administration had fewer cells in both the TE and ICM. 75 days after the start of 5-ALA administration, the cell volume had increased in both the TE and ICM, but the embryos were determined to be aneuploid. However, 122 days after the start of 5-ALA administration, the cell volume of embryos had clearly increased in both the TE and ICM, and two out of three embryos were confirmed to be euploid (euploid) chromosomes.

[0084] (Clomid Dosage) Figure 3 shows the number of Clomid tablets administered before and after 5-ALA administration. The average number of Clomid tablets administered before 5-ALA administration was 16.6 ± 4.3 tablets / cycle, while the number of tablets administered after 5-ALA administration was 11.0 ± 2.0 tablets / cycle. This indicates that the required dose of ovulation-inducing drug to reduce chromosomal aneuploidy in fertilized eggs was significantly reduced by the concomitant administration of 5-ALA (P < 0.01).

[0085] (Number of Gonal-f® / HMG Ferring injections) Figure 4 shows the number of Gonal-f® (150 IU) and / or HMG Ferring (150 IU) injections administered before and after 5-ALA administration.

[0086] The number of injections of Gonal-f® and / or HMG Ferring before 5-ALA administration was 8.5 ± 3.7 vials / cycle, while the number of injections after 5-ALA administration was 5.325 ± 1.3 vials / cycle. This indicates that concomitant administration of 5-ALA significantly reduced the required dose of FSH and / or HMG to decrease chromosomal aneuploidy in fertilized eggs (P < 0.05).

[0087] (Serum Estradiol (E2) Levels) Figure 5 shows the serum estradiol (E2) levels at the time of egg retrieval decision before and after 5-ALA administration. Estradiol (E2: (8S,9S,13S,14S,17S)-13-methyl-6,7,8,9,11,12,14,15,16,17-decahydrocyclopenta[a]phenanthrene-3,17-diol) is a type of estrogen known as a female hormone, possessing strong physiological activity and produced in granule cells, theca cells, placenta, adrenal cortex, testicular interstitial cells, etc. It is said to be produced reversibly by a reaction with estrone or irreversibly from testosterone. However, compared to before 5-ALA administration, there was no significant difference in serum estradiol (E2) levels after 5-ALA administration, although there was a downward trend (Figure 5).

[0088] (Number of follicle punctures) Figure 6 shows the number of follicle punctures per egg retrieval before and after 5-ALA administration. No significant difference was observed in the number of follicle punctures after 5-ALA administration compared to before 5-ALA administration.

[0089] (Number of eggs retrieved) Figure 7 shows the number of eggs retrieved before and after 5-ALA administration. Compared to before 5-ALA administration, the number of eggs retrieved after 5-ALA administration showed a decreasing trend, but no statistically significant difference was observed.

[0090] (Number of frozen blastocysts) Figure 8 shows the number of frozen blastocysts before and after 5-ALA administration. Compared to before 5-ALA administration, the number of frozen blastocysts after 5-ALA administration showed a decreasing trend, but no significant difference was observed.

[0091] (Blastocyst size) Figure 9 shows the blastocyst size of blastocysts obtained from eggs retrieved from women who did not receive 5-ALA and blastocysts obtained from eggs retrieved from women who received 5-ALA. Compared to before 5-ALA administration, blastocyst size after 5-ALA administration showed a decreasing trend, but no significant difference was observed.

[0092] (Freezing time of blastocysts) Figure 10 shows the freezing time of blastocysts obtained from eggs retrieved from women who did not receive 5-ALA and blastocysts obtained from eggs retrieved from women who received 5-ALA. Compared to before 5-ALA administration, the freezing time of blastocysts after 5-ALA administration was significantly reduced from 144.5 ± 23.6 hours to 121.2 ± 2.0 hours (P < 0.05).

[0093] (Summary) Infertile women were given 5-ALA for four months, which reduced the rate of aneuploidy in fertilized eggs, clearly making it possible to reduce the dosage of ovulation-inducing drugs. By evaluating the number of chromosomes in embryos using PGT-A and removing blastocysts showing aneuploidy from the list of candidate embryos for transfer, a dramatic improvement in pregnancy rates can be expected in the future.

[0094] (Discussion) In humans, the pregnancy rate with blastocyst transfer is said to be 35%, but it has been reported that the selection of PGT-A fertilized embryos increases the pregnancy rate to 70% and dramatically improves the live birth rate to 60% [https: / / doi.org / 10.1007 / s10815-023-02926-5]. However, it is known that the acquisition rate of A embryos decreases to around 10% in older women over 40, to 5% in those over 43, and to about 3% in those over 45 [https: / / doi.org / 10.1007 / s10815-023-02926-5], and many eggs need to be retrieved to acquire A embryos. In addition, in older women, it is often not possible to retrieve eggs even with ovarian stimulation, or even if eggs are retrieved, they cannot be frozen. Furthermore, repeated egg retrieval leads to a decrease in AMH (amyoglobin), which indicates ovarian reserve, and a decline in ovarian responsiveness. As a result, the gradual decline in the blastocyst acquisition rate is a major problem. Against this backdrop, a method of ovarian activation by injecting platelet components into the ovaries through PRP (Platelet-Rich Plasma) therapy has been reported, and increases in AFC (Antral Follicle Count), oocyte retrieval number, and fertilized embryos have been reported [Front Endocrinol, 14 2023 | https: / / doi.org / 10.3389 / fendo.2023.1292168]. However, PRP is an invasive treatment, and its effects are temporary, lasting only 1-2 months after injection, and there are no reports of improvement in the acquisition of euploid embryos. In this case, administration of 5-ALA for 4 months made it possible to reduce the number of Clomid doses for ovarian stimulation and the amount of injections used. This is thought to reduce ovarian damage caused by repeated ovarian stimulation and oocyte retrieval in PGT-A, and increase the possibility of more efficient acquisition of euploid embryos. Furthermore, since most infertility cases are caused by chromosomal abnormalities in fertilized eggs, 5-ALA administration can be expected to dramatically improve pregnancy rates in general infertility treatments such as timed intercourse and artificial insemination, which have pregnancy rates of only a few percent, as well as in older women aged 40-45 and above. In addition, 3-5% of newborns have congenital disorders, 25% of which are chromosomal abnormalities, most of which are aneuploidy, so a preventive effect against these congenital disorders can also be expected.

[0095] [Example 2] In this study, a tablet containing 50 mg of 5-ALA (phosphate) and 57 mg of ferrous sodium citrate (SFC) (6 mg as iron) (hereinafter also referred to as "5-ALA (+SFC) 50 mg") was used as a chromosome aneuploidy inhibitor. This dosage, administered one tablet three times a day (hereinafter also referred to as "5-ALA (+SFC) 150 mg / day"), was increased compared to Example 1. Based on this, the drug was administered to three patients, and the post-administration evaluation was performed. As in Example 1, the length of each period (1 cycle) from the start of drug administration to egg retrieval corresponds to the number of Clomid tablets in each cycle in the table. For example, if it says 10 Clomid tablets, it is 10 days.

[0096] The administration schedules for the three cases described above are shown in Table 3 (Case 1), Tables 4-1 and 4-2 (Case 2), and Table 5 (Case 3). Case 1 was a 42-year-old woman, Case 2 was a 38-year-old woman, and Case 3 was a 41-year-old woman.

[0097]

[0098]

[0099]

[0100]

[0101] In Case 1, PGT-A was performed on 5 embryos before 5-ALA administration, and 1 embryo (20%) was an A embryo. After 5-ALA administration, PGT-A was performed on 6 embryos, and 2 embryos (33.3%) were A embryos. In Case 2, PGT-A was performed on 5 embryos before 5-ALA administration, and 1 embryo (20%) was an A embryo. After 5-ALA administration, PGT-A was performed on 11 embryos, and 3 embryos (27%) were A embryos and 3 embryos (27%) were B embryos. In Case 3, PGT-A was performed on 3 embryos before 5-ALA administration, but no A embryos were found. After 5-ALA administration, PGT-A was performed on 4 embryos, and 2 embryos (50%) were A embryos.

[0102] (Clomid Dosage) Figure 12 shows the number of Clomid tablets administered before and after administration of 150 mg / day of 5-ALA (+SFC). Before administration, the number of Clomid tablets administered was 16.7 ± 3.3 tablets / cycle, while after 5-ALA administration, it was 10.9 ± 0.8 tablets / cycle, indicating that the required dose of ovulation-inducing drug was significantly reduced by the concomitant administration of 5-ALA (P < 0.05).

[0103] (Number of injections of Gonal-f® / HMG "Asuka") Figure 13 shows the number of injections of Gonal-f® (150 IU) and / or HMG "Asuka" (150 IU) before and after administration of 5-ALA 150 mg / day.

[0104] The number of injections of Gonal-f® and / or HMG "Asuka" before administration of 5-ALA 150 mg / day was 19.9 ± 3.0 injections / cycle, while the number of injections after administration was 14.3 ± 2.7 injections / cycle. This indicates that the required dose of FSH and / or HMG to reduce chromosomal aneuploidy in fertilized eggs was significantly reduced by co-administration of 5-ALA (P < 0.05).

[0105] (Number of retrieved eggs) Figure 14 shows the number of retrieved eggs before and after administration of 5-ALA (+SFC) 150 mg / day. The number of retrieved eggs per oocyte was 6.9 ± 3.0 before 5-ALA administration, while it significantly increased to 10.7 ± 3.9 after administration (P < 0.05). In Example 1, no significant difference was observed in the number of retrieved eggs before and after 5-ALA administration, so it can be said that a remarkably superior effect was obtained by increasing the dose of 5-ALA from 50 mg / day to 150 mg / day.

[0106] (Number of frozen blastocysts) Figure 15 shows the number of frozen blastocysts before and after administration of 5-ALA (+SFC) 150 mg / day. The number of frozen blastocysts per oocyte retrieved before 5-ALA administration was 1.4 ± 0.8, while the number of frozen blastocysts after administration significantly increased to 3.2 ± 1.1 (P < 0.05). In Example 1, no significant difference was observed in the number of frozen blastocysts before and after 5-ALA administration, so this can be considered a remarkably superior effect due to the increased dose of 5-ALA.

[0107] (Eupoploid Embryo Rate) Figure 16 shows the change in the chromosomal euploid embryo rate before and after administration of 5-ALA 150 mg / day. The chromosomal euploid embryo rate per oocyte retrieved before administration was 13.3 ± 11.5%, while it significantly increased to 36.9 ± 11.8% after an average of 69.0 ± 40.3 days of 5-ALA administration (P < 0.05). This result suggests that continuous administration of 5-ALA improves chromosomal aneuploidy in embryos and significantly improves the acquisition rate of normal embryos (A embryos).

[0108] [Example 3] (Effects of combination with other components) The effects of combining 5-ALA (+SFC) with other components were investigated. Specifically, the following seven combinations were administered orally, followed by oocyte retrieval and PGT-A testing.

[0109] (Treatment Groups) (1) Negative control group: No 5-ALA administration, no other components administered (2) 5-ALA group: 5-ALA (+SFC) 150 mg / day administered (3) NMN group: NMN (Nicotinamide Mononucleotide) 400 mg once daily administered (4) Resveratrol group: Resveratrol 125 mg twice daily (total: 250 mg / day) administered (5) 5-ALA + NMN group: 5-ALA (+SFC) 150 mg / day + NMN 400 mg / day administered (6) 5-ALA + Resveratrol group: 5-ALA (+SFC) 150 mg / day + Resveratrol 250 mg / day administered (7) 5-ALA + NMN + Resveratrol group: 5-ALA (+SFC) 150 mg / day + NMN 400 mg / day + Resveratrol 250 mg / day

[0110] We compared 35 patients (5 from each of the seven treatment groups) described above. The subjects were women aged 35 to 43 years. Six months after the start of administration, oocyte retrieval was performed, and the rate of chromatinically chromatinized aneuploid embryos (A embryos) was calculated using PGT-A. The results are shown in Figure 17. This study made it possible to clarify the difference in A embryo acquisition rates between the 5-ALA monotherapy group and the group receiving 5-ALA in combination with other components, and to evaluate the contribution to improving chromosomal aneuploidy.

[0111] (Results) The percentage of chromatinized positive number embryos (A embryos) in each of the above treatment groups was as follows: (1) Negative control group: 25.5% ± 7.6%, (2) 5-ALA group: 45.5 ± 11.1%, (3) NMN group: 29.1% ± 7.6%, (4) Resveratrol group: 27.3 ± 7.6%, (5) 5-ALA + NMN group: 50.9 ± 17.7%, (6) 5-ALA + Resveratrol group: 49.1 ± 10.4%, (7) 5-ALA + NMN + Resveratrol group: 52.7 ± 10%.

[0112] (Comparison of Euploid Embryo Rates) Compared to the negative control group, the 5-ALA group showed a significantly increased rate of chromatic euploid embryos (A embryos) (P < 0.05). On the other hand, the NMN group and resveratrol group showed an increasing trend compared to the negative control group, but the difference was not statistically significant. Furthermore, the 5-ALA + NMN group, 5-ALA + resveratrol group, and 5-ALA + NMN + resveratrol group showed an even more significantly increasing trend compared to the 5-ALA group (P < 0.05), but there was no statistically significant difference among these three groups. These results indicate that 5-ALA monotherapy is effective in improving chromosomal aneuploidy, and suggest that the effect may be further enhanced by combining it with NMN or resveratrol. Since the difference between the combination groups was not statistically significant, it is thought that each combination may have a similar level of effectiveness.

[0113] [Example 4] (AMH test) Changes in AMH were examined 3 months and 6 months after administration of 5-ALA (+SFC) 150 mg / day in 63 patients aged 35 to 43 years with a DOR of less than 1 prior to administration. The results are shown in Figure 18.

[0114] (AMH results) AMH levels significantly increased from 0.51±0.06 ng / mL before 5-ALA administration to 0.76±0.05 ng / mL 3 months after administration and to 1.01±0.05 ng / mL 6 months after administration (P<0.01). Therefore, it was confirmed that administration of 150 mg / day of 5-ALA (+SFC) improved ovarian reserve.

[0115] [Example 5] (Effect on improving sperm chromosomal aneuploidy) Ten men with severe sperm dysplasia (severe OAT, oligozoospermia, asthenozoospermia, teratozoospermia), characterized by a sperm concentration of less than 5 million / mL, less than 10% progressively motile sperm, and less than 1% normal morphology, were administered 50 mg of 5-ALA (+SFC) twice daily for six months, and sperm chromosomal aneuploidy was checked. The results are shown in Figure 19. This study aimed to evaluate whether continuous administration of 5-ALA contributes to the improvement of sperm chromosomal abnormalities, particularly aneuploidy, and suggested the possibility of improved chromosomal stability even in cases with severe spermatogenesis disorders.

[0116] (Results) Administration of 5-ALA (+SFC) 50 mg twice daily significantly reduced the rate of aneuploidy in men with severe sperm abnormalities from 14.2 ± 0.6% before administration to 10.3 ± 0.6% after 6 months of administration (P < 0.001), indicating that administration of 5-ALA (+SFC) 100 mg improved sperm chromosomal aneuploidy.

[0117] [Example 6] (Improvement of aneuploidy in human fibroblast BJ cells) Using BJ cells (ATCC), which are human fibroblasts established from the foreskin of neonatal males that can be cultured for a long period of time, chromosomal aneuploidy was examined by long-term subculturing. After 80 subculturing in EMEM medium, the percentage of aneuploid cells increased to 79.3 ± 3.6%.

[0118] Next, BJ cells were cultured for 80 passages in a culture medium containing either 1 μM 5-ALA + 0.5 μM SFC, 0.5 μM NMN, or 1 μM resveratrol. In the medium supplemented with 5-ALA and SFC, the percentage of aneuploid cells was 53.1 ± 5.4%, a significant decrease (P > 0.01). In the medium supplemented with NMN, the percentage of aneuploid cells was 71.9 ± 4.2%, and in the medium supplemented with resveratrol, it was 76.6 ± 4.8%, showing a decreasing trend, but the decrease was not statistically significant. Furthermore, when 5-ALA and SFCs were combined with NMN; 5-ALA and SFCs with resveratrol; or 5-ALA and SFCs with NMN + resveratrol, the percentage of aneuploid cells was significantly reduced to 41.5±5.5%, 46.4±6.2%, and 37.5±2.9%, respectively (P>0.01). However, there was no significant difference among these three groups. From the above, it was confirmed that long-term culture of fibroblasts in a medium supplemented with 5-ALA and SFCs, along with NMN and / or resveratrol, improved aneuploidy in senescent fibroblasts (Figure 20).

[0119] [Example 7] (Anticumor Effect) The antitumor effect of culturing non-small cell lung cancer cells A549 in a medium containing 1% FCS + RPMI culture medium supplemented with 1 μM 5-ALA, or 1 μM 5-ALA + 0.5 μM SFC, was investigated. The antitumor effect was evaluated by counting using trypan blue staining, which allows for cell viability determination because the stain penetrates the cell membrane and stains the cytoplasm blue in dead cells. The results are shown in Figure 21.

[0120] (Results) The antitumor effect against A549 non-small cell lung cancer cells was evaluated, and in the medium supplemented with 5-ALA alone, IC ５０ The concentration was 95.3 ± 3.7 μM, but in the culture medium to which 5-ALA and SFC were added, IC ５０ The concentration was 83.1 ± 7.8 μM, and it was confirmed that the antitumor effect was significantly increased by combining 5-ALA and SFC (P < 0.05). ５０The (median inhibitory concentration) is an index that indicates the concentration at which 5-ALA and / or 5-ALA + SFC is predicted to inhibit the proliferation of 50% of the target A549 cells. A lower value indicates a higher antitumor effect of the drug.

[0121] [Example 8] (Effect of reducing chromosomal aneuploidy in non-small cell lung cancer cells) The above-mentioned non-small cell lung cancer cell line A549 is a cell line that exhibits chromosomal aneuploidy, and it is said that the most common cell type has 66 chromosomes. In this study, A549 cells were cultured for 30 passages in a culture medium supplemented with 1 μM 5-ALA + 0.5 μM SFC, and the number of chromosomes was checked. The results are shown in Figure 22. It was confirmed that when cells were subcultured in a culture medium supplemented with 1 μM 5-ALA + 0.5 μM SFC, chromosomal aneuploidy was significantly reduced (improved) compared to when cells were subcultured in a culture medium without the supplement (control).

[0122] (Discussion) When three tablets containing 50 mg of 5-ALA and sodium ferrous citrate (SFC, 57 mg, 6 mg as iron) were administered orally daily, the following excellent effects were observed. Specifically, the number of Clomid tablets and injections used for ovarian stimulation decreased, and effects such as an increase in the number of retrieved eggs and an increase in the number of frozen blastocysts were obtained. These effects are thought to be due to an increase in the proportion of oocytes with euploidy, which occurred when the dosage of 5-ALA and SFC was increased.

[0123] Furthermore, we were able to confirm that the administration of 5-ALA and SFC reduced the rate of aneuploidy in sperm.

[0124] Furthermore, we confirmed that the proportion of aneuploid cells decreased when 5-ALA and SFC, 5-ALA and SFC with NMN, 5-ALA and SFC with resveratrol, or 5-ALA and SFC with NMN and resveratrol were used in combination with senescent human fibroblasts (BJ cells) that had been cultured for a long period and showed an increased proportion of aneuploid cells.

[0125] Furthermore, when 5-ALA and SFC were added to the culture medium of non-small cell lung cancer cells A549, the viability of the cells decreased, confirming that 5-ALA and SFC have antitumor effects. In addition, it was confirmed that treating non-small cell lung cancer cells with 1 μM 5-ALA + 0.5 μM SFC improved the aneuploidy of chromosomes in non-small cell lung cancer cells A549.

[0126] (Summary) Based on the above, it is expected that administering increased doses of 5-ALA and SFC will increase the likelihood of obtaining normal euploid embryos more efficiently than before. Furthermore, since many of the main causes of infertility are due to chromosomal abnormalities in fertilized eggs, and sperm chromosomal abnormalities (aneuploidy) are one of the contributing factors, it is suggested that administration of 5-ALA and SFC may also be effective for male infertility. Moreover, it was confirmed that administration of 5-ALA and SFC improves chromosomal aneuploidy not only in germ cells but also in aging human fibroblasts and non-small cell lung cancer cells. These findings indicate that 5-ALA + SFC has the effect of enhancing chromosomal stability at the cellular level, suggesting potential applications not only in reproductive medicine but also in anti-aging medicine and cancer research.

[0127] This invention is useful in the fields of infertility treatment, prevention of congenital diseases caused by chromosomal abnormalities, anti-aging medicine, and chemoprevention of cancer. In particular, by improving chromosomal aneuploidy, it is possible to improve the acquisition rate of normal embryos, contributing to improved treatment outcomes for infertility and a reduction in the risk of miscarriage. Furthermore, since it contributes to enhancing anti-aging and antitumor effects by controlling chromosomal stability in senescent and cancer cells, it is also expected to be applied as a supplementary strategy in geriatric medicine and cancer treatment.

Claims

1. The following formula (I) (In the formula, R １ R represents a hydrogen atom or an acyl group. ２ A compound represented by () or a salt thereof is an orally administered chromosome aneuploidy inhibitor, in which case () represents a hydrogen atom, alkyl group, cycloalkyl group, aryl group, or aralkyl group.

2. The chromosomal aneuploidy inhibitor according to claim 1, characterized in that the cells whose chromosomal aneuploidy is suppressed are one or more selected from sperm, eggs, fertilized eggs, senescent cells, and tumor cells.

3. The chromosomal aneuploidy inhibitor according to claim 1, characterized in that the chromosomal aneuploidy of a fertilized egg is determined by PGT-A.

4. The chromosome aneuploidy inhibitor according to claim 1, further characterized by containing an iron compound.

5. The chromosome aneuploidy inhibitor according to claim 1, further characterized by the use of NMN and / or resveratrol in combination.

6. The chromosome aneuploidy inhibitor according to claim 1, characterized in that the oral dose is 1 mg to 500 mg / day in terms of 5-aminolevulinic acid, and is administered orally once or twice a day.

7. The chromosome aneuploidy inhibitor according to claim 1, characterized by being administered orally for 14 days or more.

8. A treatment for infertility in infertile men and women, comprising an aneuploidy inhibitor of fertilized eggs according to any one of claims 1 to 7.

9. The infertility treatment drug according to claim 8, characterized in that it is used in combination with one or more selected from ovulation-inducing agents, follicle-stimulating hormone preparations, luteinizing hormone preparations, and postmenopausal pituitary gonadotropin preparations.

10. The infertility treatment drug according to claim 8, characterized in that it enables a reduction in the dosage of ovulation-inducing agents, follicle-stimulating hormone preparations, luteinizing hormone preparations, or postmenopausal pituitary gonadotropin preparations.

11. A preventive agent for Patau syndrome, Edwards syndrome, Down syndrome, Turner syndrome, Triple X syndrome, or Klinefelter syndrome, comprising an aneuploidy inhibitor for fertilized eggs according to any one of claims 1 to 7.

12. An agent for improving ovarian reserve caused by chromosomal aneuploidy, comprising an inhibitor of chromosomal aneuploidy of a fertilized egg according to any one of claims 1 to 7.

13. An agent for improving aging and tumor development and progression caused by chromosomal aneuploidy, comprising an inhibitor of chromosomal aneuploidy of a fertilized egg according to any one of claims 1 to 7.

14. An agent for improving aging caused by chromosomal aneuploidy, comprising an inhibitor of chromosomal aneuploidy of a fertilized egg according to any one of claims 1 to 7.

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