New use of PQQ and derivative thereof

Abstract

A new use for PQQ and a derivative thereof. PQQ can effectively relieve or treat primary dysmenorrhea, secondary dysmenorrhea, and irregular menstruation. Following treatment with PQQ, the following effects can be achieved in patients: 1. the dysmenorrhea relief rate is 100%; 2. the average duration of the menstrual period is reduced from approximately 2 weeks to approximately 1 week, returning to the normal average duration of the menstrual period; 3. the volume of menstrual blood in each month is reduced by more than 30% on average, returning substantially to the normal average level of menstrual blood volume; and 4. two patients who had suffered years of infertility due to secondary dysmenorrhea became pregnant within a 3-month treatment period.

Description

New use of PQQ and derivative thereof Technical field The present invention relates to pyrroloquinoline quinone for a novel therapeutic use according to the appended claims. Background of the invention Dysmenorrhea is one of the most common gynecological symptoms, referring to lower abdominal pain, bloating, backache, or other discomfort before, during, or after menstruation. These symptoms can significantly impact quality of life. Dysmenorrhea can be divided into two categories: primary and secondary. Primary dysmenorrhea refers to dysmenorrhea without any organic lesions in the reproductive organs; secondary dysmenorrhea refers to dysmenorrhea caused by pelvic organ dysfunction. The causes of dysmenorrhea are not fully understood. It is generally believed that the pathogenesis and treatment plan for secondary dysmenorrhea differ from those for primary dysmenorrhea. Dysmenorrhea typically manifests in various ways, with different types of pain: lower abdominal pain, lower abdominal distension, anal pain, pain during sexual intercourse, and so on. Most mammals do not have regular menstrual cycles and primarily experience cryptomenorrhea, which is hardly comparable to the secondary indicators of menstrual pain in humans. Although some primates also menstruate, secondary dysmenorrhea is not observed. The lack of a practical animal model available for studying dysmenorrhea, which would allow for drug development, limits progress in this area. Existing studies also demonstrate that experimental results obtained in animals or cell models of dysmenorrhea are often ineffective when applied to humans. For example, Durak, Yildirim, et al. ("Effect of vitamin C on the growth of experimentally induced endometriotic cysts." Journal of Obstetrics and Gynaecology Research 39).7 (2013): 1253-1258) indicated that vitamin C supplementation significantly reduced the volume and weight of endometriotic cysts in a dose-dependent manner. However, it is well known that vitamin C supplementation has no palliative effect on human dysmenorrhea, let alone a therapeutic effect. Currently, there are no highly effective drugs for treating dysmenorrhea. Traditional treatments for dysmenorrhea primarily include hormonal medications. However, treatment with hormonal or hormone-like drugs is associated with serious side effects, including, but not limited to, infertility, which limits their use. Pyrroloquinoline quinone (PQQ) is a tricarboxylic acid quinone compound, CAS No. 72909-34-3, IUPAC name: 4,5-dioxo-1H-pyrrolo[2,3-f]quinoline-2,7,9-tricarboxylic acid. PQQ is widely present in various foods. The PQQ content in food is approximately 3.65–61 ng / g; in parsley and green peppers (vegetables), kiwifruit and papaya (fruits), green tea and oolong tea (beverages), and tofu (which people commonly consume), the PQQ content is approximately 30 ng / g. Previous studies have shown that PQQ can stimulate the growth rate of cells in microorganisms, plants, animals, and humans; eliminate excess free radicals in the body and protect it from oxidative damage; accelerate the oxidation of acetaldehyde to acetic acid to reduce the acetaldehyde content in the body, thus hopefully reducing the toxic liver damage caused by alcohol consumption.Document CN110870866A discloses the application of pyrroloquinoline quinone in the preparation of medications to prevent and treat acute altitude sickness and acute altitude hypoxia injury; document CN110151764A discloses that pyrroloquinoline quinone can reduce lipopolysaccharide-induced animal fibroblasts and intestinal inflammation; document CN106265730A discloses the application of pyrroloquinoline quinone (PQQ) to reverse tumor resistance to multiple drugs; document CN105963297A discloses the application of pyrroloquinoline quinone in adjuvant therapy after chemotherapy; document CN103191115A discloses the application of pyrroloquinoline quinone in the treatment and / or relief of diabetic foot ulcers. Document WO2020 / 262325 discloses the use of PQQ for the treatment of menstrual disorders related to irregularities in the ovulation cycle.Document WO2018 / 065076 discloses estetrol for use in the treatment of primary dysmenorrhea. Technical solutions The scope of protection of the present invention is defined in the accompanying set of claims. A first aspect of the present invention provides: Pyrroloquinoline quinone or derivatives thereof for use in a method of prevention, relief or treatment of a disease selected from: - primary dysmenorrhea; and - menstrual abnormalities selected from an abnormal increase in the amount of menstrual bleeding and / or an abnormal increase in the duration of menstrual bleeding, wherein said pyrroloquinoline quinone derivative is a salt, C2-C6 ester, amide, hydrate, crystal, cocrystal or solvate acceptable for pharmaceutical or food use. In some realizations, this abnormal increase in the amount of menstrual bleeding refers to the amount of menstrual bleeding being 50% greater than the amount of a healthy woman. In some embodiments, this abnormal increase in the duration of menstrual bleeding refers to a duration of menstrual bleeding of no less than 8 days. In some embodiments, the oral dose based on pyrroloquinoline quinone is: approximately 5 mg / day to approximately 10 mg / day for the prevention of primary dysmenorrhea; approximately 15 mg / day to approximately 20 mg / day for the relief or treatment of mild dysmenorrhea; approximately 20 mg / day to approximately 30 mg / day for the relief or treatment of moderate dysmenorrhea; approximately 25 mg / day to approximately 100 mg / day for the relief or treatment of severe dysmenorrhea; approximately 20 mg / day to approximately 50 mg / day for the relief or treatment of menstrual abnormalities. In some embodiments, this composition is a food, a nutraceutical, or a medicine. In some embodiments, this composition also includes excipients acceptable from a pharmaceutical or food point of view. In some embodiments, said excipient is selected from at least one of carriers, solvents, antioxidants, and preservatives. In some realizations, the patient achieves at least one of the following benefits after prevention, relief, or treatment: 1) ability to become pregnant; 2) relief of dysmenorrhea, preferably that the average Menstrual Dysmenorrhea Pain Index score decreases by more than 1 point or that the pain level decreases by one grade; 3) the amount of menstrual bleeding is reduced to no more than 50%, 40%, 30% of women's normal menstrual bleeding, preferably 10%, and more preferably reduced to the normal average menstrual bleeding; 4) the duration of menstrual bleeding is shortened to no more than 10 days, preferably to no more than 9 days, 8 days or 7 days. The pain index or pain level is determined according to WHO standards. Beneficial effect The inventors discovered that PQQ is effective in preventing, relieving, or treating patients with primary dysmenorrhea, secondary dysmenorrhea, and accidental menstrual abnormalities, wherein the treatment of secondary dysmenorrhea is mentioned for illustrative purposes only. In some implementations, after being treated with PQQ, patients experience at least one of the following effects: 1. the dysmenorrhea relief rate is 100%; 2. the average duration of the menstrual period is reduced from approximately 2 weeks to approximately 1 week, and returns to the normal average duration of the menstrual period; 3. the amount of menstrual blood in the menstrual period is reduced by more than 30% on average, and returns substantially to the normal average level; and 4. two patients who suffered years of infertility caused by secondary dysmenorrhea become pregnant within a 3-month treatment period. Brief description of the drawings Figure 1 shows the changes in the dysmenorrhea index (VAS score) in the treatment of secondary dysmenorrhea during treatment (not according to the claimed invention); Figure 2 shows the changes in the duration of menstruation in patients with abnormal menstruation (irregular menstruation) during treatment; Figure 3 shows the changes in the consumption of sanitary pads by patients with abnormal menstruation (irregular menstruation) during treatment. Detailed description of the achievements Acceptable pharmaceutical or food derivatives of the compound refer to simple derivatives thereof, especially lower esters, lower ethers, lower alkyl substituents, pharmaceutically acceptable salts, and lower amides having 1 to 6 carbon atoms, preferably 2 to 6, and a derivative obtained by condensation of a carboxylic acid, alcohol, or amine from 2 to 4 carbon atoms with the parent compound. In particular, the general formula of the pyrroloquinoline quinone derivative is as follows: In the formula, R1 to R3 are the same or different, and are selected from H, hydrocarbon groups C1 to C6, naturally occurring amino acid residues, Na, K, Li, and other pharmaceutically acceptable groups. The pyrroloquinoline quinone derivatives according to the invention are defined in the appended claims. Pharmaceutically acceptable salts of compounds can be synthesized from the parent compounds by conventional chemical methods, such as those described in Pharmaceutical Salts: Properties, Selection, and Use, P. Heinrich Stahl (Editor), Camille G. Wermuth (Editor), ISBN: 3-90639-026-8, Hardcover, 388 pages, August 2002. In general, these salts are prepared by reacting the free base and acid of the compound in water or an organic solvent or a mixture of both; non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are commonly used. Acid addition salts can be made with various acids (inorganic and organic acids). Acid addition salt realizations include a salt made by a compound reacting with an acid, said acid being selected from a group consisting of acetic acid, 2,2-dichloroacetic acid, adipic acid, alginic acid, ascorbic acid, L-aspartic acid, benzenesulfonic acid, benzoic acid, 4-acetylaminobenzoic acid, butyric acid, (+)-camphoric acid, camphorsulfonic acid, (+)-(1S)-camphor-10-sulfonic acid, capric acid, hexanoic acid, octanoic acid, cinnamic acid, citric acid, cyclamic acid, dodecyl sulfuric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, formic acid, fumaric acid, galactonic acid, gentisic acid, glucoheptonic acid, D-gluconic acid, glucuronic acid, and other acids. glutamic acid, alpha-ketoglutaric acid, glycolic acid, hippuric acid, hydrobromic acid, hydrochloric acid,hydriodic acid, isethionic acid, (+)-L-lactic acid, (±)-DL-lactic acid, lactobionic acid, maleic acid, malic acid, (-)-L-malic acid, malonic acid, (±)-DL-mandelic acid, methanesulfonic acid, naphthalene-2-sulfonic acid, naphthalene-1,5-disulfonic acid, 1-hydroxy-2-naphthoic acid, nicotinic acid, nitric acid, oleic acid, orotic acid, oxalic acid, palmitic acid, pamoic acid, phosphoric acid, propionic acid, L-pyroglutamic acid, salicylic acid, 4-aminosalicylic acid, sebacic acid, stearic acid, succinic acid, sulfuric acid, tannic acid, (+)-L-tartaric acid, sulfocyanic acid, p-toluenesulfonic acid undecylenic acid, pentanoic acid and acylated amino acid. In the study of PQQ, the inventors found that PQQ is effective in preventing, relieving, or treating patients with primary dysmenorrhea, secondary dysmenorrhea (not according to the claimed invention), and accidental menstrual abnormalities. In some studies, after treatment with PQQ, at least one of the following effects was achieved in patients: 1. the dysmenorrhea relief rate was 100%; 2. the average duration of the menstrual period was reduced from approximately 2 weeks to approximately 1 week, returning to the normal average duration of the menstrual period; 3. the amount of menstrual blood during the menstrual period was reduced by more than 30% on average, returning substantially to the normal average level; and 4. two patients who had suffered years of infertility due to secondary dysmenorrhea became pregnant within a 3-month treatment period. Details are as follows: Treatment of patients with primary dysmenorrhea: Experiment number: 100 people have been diagnosed with primary dysmenorrhea, 50 in the experimental group and 50 in the control group. Experimental method: oral administration of PQQ to patients in the experimental group, oral administration of placebo to patients in the control group. The duration of the experiment was 3 months, and menstrual pain was reported and recorded. The results of the experiment: Experimental group: the dysmenorrhea index decreased by 100% compared to the start of the experiment. Control group: the dysmenorrhea index decreased by less than 20%, compared to the start of the experiment, and the average degree of relief was less than that of the experimental group. Compared to the control group, the data from the experimental group showed that the drug is statistically significant for the treatment of primary dysmenorrhea. Treatment of patients with secondary dysmenorrhea (for illustrative purposes only): Experiment number: 100 people have been diagnosed with secondary dysmenorrhea, 50 in the experimental group and 50 in the control group. Experimental method: oral administration of PQQ to patients in the experimental group, and oral administration of placebo to patients in the control group. The experiment lasted 3 months, during which the presence of menstrual pain and pregnancy was recorded. The results of the experiment: Experimental group: the dysmenorrhea index decreased by 100% compared to the start of the experiment; 2 cases became pregnant. Control group: the dysmenorrhea index decreased by less than 5% compared to the start of the experiment, and the average degree of relief was much lower than that of the experimental group; no cases became pregnant. Compared to the control group, the data from the experimental group showed that the drug is statistically significant for the treatment of secondary dysmenorrhea. The dysmenorrhea index is determined based on the VAS scoring standard, meaning that patients self-assess the intensity of their pain and the degree of psychological distress they experience, including: 0 points: no pain; 1-3 points: mild pain; 4-6 points: moderate pain; 7-9 points: intense pain; 10 points: unbearable pain. Changes in the average dysmenorrhea index are shown in Figure 1. According to the figure, the dysmenorrhea index of the PQQ group decreased significantly, while the dysmenorrhea index of the control group did not change significantly. Secondary dysmenorrhea has been shown to be significantly relieved by oral administration of a PQQ preparation. Treatment of patients with abnormal menstruation: Experiment number: 100 people diagnosed with menstrual abnormalities, 50 in the experimental group and 50 in the control group. Experimental method: oral administration of PQQ to patients in the experimental group, oral administration of placebo to patients in the control group. The experiment lasted 3 months, during which menstrual conditions (duration of menstruation, consumption and weight of sanitary pads) were measured and recorded. The results of the experiment: The experimental results are shown in Figure 2 and Figure 3. As shown in Figure 2 and Figure 3, in the experimental group: menstrual duration: the average duration of monthly menstrual bleeding was reduced from approximately 2 weeks to approximately 1 week compared to the start of the experiment; amount of menstrual bleeding: the average amount of menstrual bleeding decreased by more than 30%; in the control group: compared to the start of the experiment, menstrual duration: there was no significant relief; amount of menstrual bleeding: there was no significant relief. Compared to the control group, the data from the experimental group showed that the drug is statistically significant for the treatment of menstrual abnormalities.

Claims

1. Pyrroloquinoline quinone or derivatives thereof for use in a method of preventing, relieving, or treating a disease selected from: - primary dysmenorrhea; and - menstrual abnormalities selected from an abnormal increase in the amount of menstrual bleeding and / or an abnormal increase in the duration of menstrual bleeding, wherein said pyrroloquinoline quinone derivative is a salt, C2-C6 ester, amide, hydrate, crystal, cocrystal, or solvate acceptable for pharmaceutical or food use.

2. Pyrroloquinoline quinone or derivatives thereof for use according to claim 1, wherein: said abnormal increase in the amount of menstrual bleeding refers to the amount of menstrual bleeding being greater than 50% of the normal amount of menstrual bleeding in women; and said abnormal increase in the duration of menstrual bleeding refers to a duration of menstrual bleeding of not less than 8 days. 3.Pyrroloquinoline quinone or derivatives thereof for use according to claim 1, wherein the oral dosage based on pyrroloquinoline quinone is: approximately 5 mg / day to approximately 10 mg / day for the prevention of primary dysmenorrhea; approximately 15 mg / day to approximately 20 mg / day for the relief or treatment of mild dysmenorrhea; approximately 20 mg / day to approximately 30 mg / day for the relief or treatment of moderate dysmenorrhea; approximately 25 mg / day to approximately 100 mg / day for the relief or treatment of severe dysmenorrhea; approximately 20 mg / day to approximately 50 mg / day for the relief or treatment of menstrual abnormalities.

4. Pyrroloquinoline quinone or derivatives thereof for use according to claim 1, wherein said composition is a food, a nutraceutical, or a medicament. 5.Pyrroloquinoline quinone or derivatives thereof for use according to claim 1, wherein said composition further comprises pharmaceutically or food-grade acceptable excipients.

6. Pyrroloquinoline quinone or derivatives thereof for use according to claim 5, wherein said excipient is selected from at least one of carriers, solvents, antioxidants, and preservatives.

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