BG4276U1 - Means for treatment of gynaecological adhesions and processes associated with ovarian aging - Google Patents

Abstract

The means for treatment of gynaecological adhesions and processes associated with ovarian aging according to the utility model finds application in human medicine and, in particular, in the treatment of women who have problems with ovarian aging and with adhesions of any nature and subsequent problems with the pregnancy. The means for treatment according to the utility model comprises Nicotinamide mononucleotide (NMN); Nicotinamide riboside; Quercetin, wherein it also comprises Ursolic acide or a combination of Nattokinase and Serrapeptase, which are contained in the following quantitative ratios by weight %: Nicotinamide mononucleotide (NMN) from 14.29% to 23.81%; Nicotinamide riboside from 7.14% to 11.90%; Quercetin from 17.86% to 29. 76%, wherein it also contains Ursolic acide from 35.72% to 59.52% or a combination of Nattokinase - from 8.93% to 14.89% and Serrapeptase from 26.78% to 44.64%. The means for treatment of gynaecological adhesions and processes associated with ovarian aging is taken orally. Successful treatment is achieved in patients with diagnosed female infertility, failed IVF procedures, surgical interventions in the pelvic area and poor egg quality in previous ovarian punctures. As a result of the treatment provided with the means, the subject of the utility model, pregnancy and birth of a healthy child is achieved.

Description

(54) TREATMENT OF GYNECOLOGICAL ADHESIONS AND PROCESSES ASSOCIATED WITH OAG AGING

Field of technique

The agent for the treatment of gynecological adhesions and processes related to aging of the ovum, according to the utility model, will find application in human medicine and in particular in the treatment of women who have problems with aging of the ovum and with adhesions of any nature and subsequent problem with pregnancy.

Prior art

Adhesions are known to cause problems for millions of women. They have a variety of manifestations, from blocked tubes associated with infertility, through the subtle adhesions that form at the site of ruptured ovarian follicles to chronic pelvic pain resulting from the attachment of one organ to another or to the omentum. Adhesions can be very extensive but relatively asymptomatic. The causes of adhesions are numerous, but the main ones are tissue irritation due to an inflammatory event or trauma (eg after surgery), which initiates the process of adhesion formation. Chronic irritation of pelvic tissues from common disease processes such as endometriosis can also cause adhesions.

Intra-abdominal adhesive disease is associated with 15% to 20% of all cases of infertility /1/.

Although a causal relationship with infertility is sometimes difficult to establish with certainty, pelvic adhesions are thought to restrict the free movement of the pelvic organs.

Ovarian aging, which occurs earlier than the aging of most other organs, is a continuous process, with the most significant feature of ovarian aging being the reduced and depleted ovarian reserve (ODR), ie. the deterioration of egg quality and quantity, which is also a major cause of infertility and failure in assisted reproductive technology (ART) (MayPanloup et al., 2016). In addition, ovarian aging is associated with an increased risk of diabetes, heart disease, cancer, and other age-related conditions. The importance of the ovary in maintaining health and prolonging life has also been well demonstrated in animal models. The free radical theory, a classical theory of aging, suggests that oxidative stress caused by increased intracellular levels of reactive oxygen species (ROS) is the most significant contributor to cellular senescence and aging in mammals. Based on these theoretical considerations, reducing ovarian oxidative stress is an important means of delaying ovarian aging.

A number of biologically active substances are known in the form of a combination of ready-made dosage forms, which are used to support these processes.

There is no known oral oral product, drug product model, medical device, or dietary supplement that can help reduce adhesions and subsequent infertility problems.

The remedy for the treatment of gynecological adhesions and delaying the aging of the ovaries and eggs according to the useful model contains the active substances Nattokinase, Serrapeptase, Ursolic acide, Nicotinamide mononucleotide (NMN), Nicotinamide riboside (NR ) and Quercetin / Quercetin. The activity of the enzymes Nattokinase / Nattokinase and Serrapeptase / Serrapeptase is accepted to be expressed in international units (UI) or fibrinolytic units (FU).

The individual effect of the individual biologically active substances in the complex of the product formula is known as follows:

Nattokinase / Nattokinase

Nattokinase is known to be a serine protease first isolated in 1987 from the Japanese food containing fermented soybeans called Natto. Natto has been used in Japan for more than 2,000 years in folk medicine for cardiovascular disease, to relieve fatigue, and as an anti-beriberi. Nattokinase is currently consumed as a dietary supplement and prophylactic in Japan, Europe and the USA.

For the first time, Nattokinase / Nattokinase was crystallized in 2010. It has 4 times greater thrombolytic ability than plasmin, which is the body's natural defense against clots. Nattokinase's potent activity comes from its ability to activate the formation of plasmin from plasminogen. Additionally, studies have shown that nattokinase is stable in the gut and has not shown side effects such as allergies, abdominal pain, or blood clotting disorders.

Serrapeptase / Serrapeptase (Serrapeptase/Serratiopeptidase)

Serrapeptase / Serratiopeptidase is a zinc-containing metalloprotease with a molecular weight of 45-60 kDa. It was originally obtained from Serratia marcescens isolated from the gut of the silkworm Bombyx mori L.

Serine protease has a higher affinity for cyclooxygenase (COX-I and COX-II), a key enzyme involved in the production of various inflammatory mediators, including interleukins (IL), prostaglandins (PG) and thromboxane (TX), etc.

Serrapeptase is a proteolytic enzyme with many therapeutic applications due to its caseinolytic (proteolytic) and fibrinolytic effects. It shows significant anti-inflammatory, anti-edema and analgesic effects in various fields, including surgery, orthopedics, otorhinolaryngology, gynecology and dentistry. The anti-inflammatory effect is related to the regulation of inflammatory cytokines and hence the appearance of chronic inflammation. Serrapeptase significantly modifies cell adhesion molecules that direct inflammatory cells to sites of inflammation. This supports wound healing and restoration of skin temperature at the target site of inflammation /2/.

Ursolic acid / Ursolic acide

IUPAC Name - (1S,2R,4aS,6aR,6aS,6bR,8aR,10S,12aR,14bS)-10-hydroxy-1,2,6a,6b,9,9,12aheptamethyl-2,3,4,5 ,6,6a,7,8,8a,10,11,12,13,14b-tetradecahydro-1H-picene-4a-carboxylic acid

Ursolic acid has been studied for more than two decades and pharmacological effects such as hepatoprotective, wound healing, antibacterial, anti-inflammatory, antitumor and antiviral properties combined with low toxicity have been described.

Ursolic acid has low solubility in water but high solubility in sodium hydroxide (NaOH) and glacial acetic acid. The chemical formula is C30H48O3, with a melting point of 283 285°C and a molecular weight of 456.7 g/mol.

It is a pentacyclic triterpenoid identified in the epicuticular waxes of apples as early as 1920 and is widely distributed in the skins or skins of some fruits (eg, apples, basil, blueberries, cranberries, elderberries, hawthorns, and prunes), as well as in herbs and spices such as rosemary, oregano, lavender, mint and thyme.

In vitro, ursolic acid inhibits the proliferation of various types of cancer cells and induces apoptosis. It reduces muscle atrophy, also showing potential cardioprotection. Ursolic acid ameliorates high-fat diet-induced cognitive impairment by blocking endoplasmic reticulum stress and IkB kinase β/nuclear factor-kB-mediated inflammatory pathway in mice. Studies on mice have shown a variety of positive health effects. Ursolic acid attenuates lipopolysaccharide-induced cognitive deficits by suppressing p38/NF-kB-mediated inflammatory pathways. Ursolic acid improves mouse liver regeneration after partial hepatectomy, increases skeletal muscle mass, has reduced expression of genes involved in the development of muscle atrophy, and reduced indicators of accumulated fatigue and exercise-induced stress. Improves hepatic steatosis induced by high-fat diets and ameliorates metabolic disturbances in high-fat-induced non-alcoholic fatty liver disease.

This effect is accompanied by inhibition of the focal adhesion signaling pathway, including changes in ICAM-1, VCAM-1, E-selectin, P-selectin, integrin α6β1, FAK, Src, paxillin and PTEN /3/.

Until now, the use of a combination of Ursolic acid and the proteolytic enzymes Nattokinase and Serrapeptase is not known.

Quercetin (3,3',4',5,7-Pentahydroxyflavone)

Quercetin is a flavonoid and is widely distributed in various foods and medicinal plants, such as apples, berries, Ginkgo biloba, Hypericum perforatum L., /4/. Recently, the use of quercetin in the treatment of ovarian aging has been increasingly considered.

Numerous in vitro studies have shown that the use of quercetin improves the viability of granulosa cells, reduces the deterioration of oocyte quality and improves the subsequent development of embryos /4/. Accordingly, quercetin has a protective role in the ovaries.

Nicotinamide mononucleotide / Nicotinamide mononucleotide (NMN)

Nicotinamide-1-ium-1-β-D-ribofUranoside 5'-phosphate

Nicotinamide mononucleotide (NMN), as a precursor of NAD+, effectively regulates mitochondrial metabolism. Taken orally, NMN is rapidly absorbed and converted to NAD+. In numerous studies, NMN supplementation increases NAD+ biosynthesis, suppresses age-related adipose tissue inflammation, enhances insulin secretion and insulin action, improves mitochondrial function, improves neuronal function in the brain. Although NMN occurs naturally in small amounts in fruits and vegetables such as avocados, broccoli, cabbage, soybeans and cucumbers, in mammals most NMN is synthesized from vitamin B3 in the form of nicotinamide.

NMN administration has been shown to have anti-aging and anti-inflammatory effects, along with improving cycle status and endocrine function in women. The present results show that NMN has the potential to stabilize the reduced ovarian reserve. One well-known consequence of poor egg quality as the mother ages is chromosomal segregation defects. It is possible that NAD+ deficiency with age impairs energy metabolism and therefore, NMN intake may reduce the rate of chromosomal defects and aneuploidy. (Keisuke Okabe, et al. Implications of altered NAD metabolism in metabolic disorders. Journal of Biomedical Science 2019; 26:34).

Nicotinamide riboside NR-1-(P-D-Ribofuranosyl) nicotinamide

Nicotinamide riboside (NR) is a vitamin B3-like pyridine nucleoside that functions as a precursor to nicotinamide adenine dinucleotide (NAD+).

Increasing ovarian NAD+ levels results in increased ovarian follicle number and ovulatory potential, as well as increased live birth rates. NR supplementation reduced reactive oxygen species (ROS) levels and reduced cell division abnormalities. In addition, NR supplementation improves the energy metabolism of ovarian mitochondria /5/.

Our data suggest that supplementation with NAD+ precursors (NMN and NR) may be a potential therapeutic approach to reduce age-related infertility of ovarian origin.

Adhesion disease is known to be a major cause of serious morbidity among women undergoing surgery. Traditionally, good surgical technique has been advocated as the primary way to prevent postoperative adhesions. This includes minimizing tissue trauma with meticulous hemostasis, minimizing ischemia, and preventing infections.

Currently, dextran solutions, gels with hyaluronic acid and its salts, as well as various cellulose networks are used as additional products. Many other experimental therapies are in progress, but they are all administered at the time of surgery.

The purpose of the utility model is to create an orally administered agent for treating gynecological adhesions and affecting oocyte aging.

Technical nature of the utility model

The task is solved by a means of treatment of gynecological adhesions and processes associated with aging of eggs according to the useful model. It consists of six active components - Nattokinase / Nattokinase; Serrapeptase / Serrapeptase; Nicotinamide mononucleotide / Nicotinamide mononucleotide (NMN); Nicotinamide riboside / Nicotinamide riboside (NR); Quercetin / Quercetin; Ursolic acid / Ursolic acide, included in two separate dosage forms of the "sachet" type, the total weight of each sachet being 2100 mg.

The composition of each sachet is shown in mg, converted to % by weight.

The morning sachet is intended to be taken in the morning on an empty stomach, i.e. 1 hour before or 2 hours after a meal.

The composition of the morning sachet is shown in mg and converted to weight. %.

Nattokinase - the amount in mg from 187.5 (3750 IU) to 312.5 (6250 IU), recalculated as weight % from 8.93 to 14.89.

Serrapeptase - the amount in mg from 562.5 (56250 IU) to 937.5 (93750 IU), recalculated as weight % from 26.78 to 44.64.

Nicotinamide mononucleotide / Nicotinamide mononucleotide (NMN) amount in mg from 300 to 500 mg, recalculated in weight % from 14.29 to 23.81.

NR (Nicotinamide riboside) amount in mg from 150 to 250, recalculated as weight % from 7.14 to 11.90.

Quercetin / Quercetin amount in mg from 375 to 625, recalculated as weight % from 17.86 to 29.76.

The evening sachet is intended to be taken in the evening up to 30 minutes after a meal.

Evening Sachet:

Ursolic acid / Ursolic acide - the amount in mg from 750 to 1250, recalculated in weight % from 35.72 to 59.52.

β-nicotinamide mononucleotide / Nicotinamide mononucleotide (MNM) - the amount in mg from 300 to 500, recalculated in weight % from 14.29 to 23.81.

Nicotinamide riboside / Nicotinamide riboside (NR) - the amount in mg from 150 to 250, recalculated in weight % from 7.14 to 11.90.

Quercetin / Quercetin - the amount in mg from 375 to 625, recalculated in weight % from 17.86 to 29.76.

The combination of the main active ingredients works synergistically by breaking down accumulated adhesions and preventing the formation of new ones and may be a potential therapeutic approach to reduce age-related infertility of ovarian origin.

Example implementations of the utility model

The agent for the treatment of gynecological adhesions and processes associated with aging of the ovum is illustrated by the following non-limiting examples.

The active substances are mixed in a dry manner in the proportions specified in the recipe. It is possible to add auxiliary substances to the dry substances to improve the fluidity of the powder, the taste and aroma of the finished mixture.

The composition of the sachets is shown in mg and converted to weight. %.

Empty sachets are filled using semi-automatic or automatic filling machines and packaged in a suitable manner to preserve the qualities of the substances and correct dosage.

Example 1.

The active substances are mixed in a dry manner in the specified proportions with a total weight of 2100 mg.

Morning Sachet:

Nattokinase / Nattokinase 250 mg (5000 FU) - 11.91%

Serrapeptase 750 mg (75,000 U) - 35.71%

Nicotinamide mononucleotide / Nicotinamide mononucleotide (NMN) - 400 mg - 19.05%

Nicotinamide riboside / Nicotinamide riboside (NR) - 200 mg - 9.52%

Quercetin - 500 mg - 23.81%

The evening sachet is intended to be taken in the evening up to 30 minutes after a meal.

Evening Sachet:

Ursolic acid / Ursolic acide 1000 mg - 47.62%

Nicotinamide mononucleotide / Nicotinamide mononucleotide (MNM) - 400 mg - 19.05%

Nicotinamide riboside / Nicotinamide riboside (NR) - 200 mg - 9.52%

Quercetin - 500 mg - 23.81%

The effectiveness of the remedy according to the useful model was verified by the application on a patient with the initials GG. 42 years old.

At the time of starting to take the remedy from example 1, the patient was diagnosed with "Female infertility of unspecified origin". She has had three unsuccessful IVF procedures. In the period before starting the nutritional supplement, there were 7 surgical interventions in the area of the small pelvis, of which 3 were laparoscopic. During the penultimate surgical intervention, adhesions were found that fixed the ovaries. Poor egg quality was also found in previous punctures. Reception of the treatment agent was started, strictly following the instructions for taking the morning sachet on an empty stomach, requirements that arise from the structure and biochemical characteristics of the substances. Three months later, during a repeat laparoscopic intervention, a serious reduction of the adhesions around the ovaries was found and IVF stimulation was started. After a successful puncture of good quality oocytes and 7 subsequent fertilizations, an embryo transfer was initiated. The pregnancy is successful and the delivery is due.

Example 2.

We mix the active ingredients according to the recipe, the basis of which is the reduction of Nattokinase in the morning sachet by 25% and Quercetin in the evening sachet by 25%. The total weight of the sachet remains 2100 mg.

The composition of the morning sachet looks like this:

Nattokinase 187.5 mg - 8.92%

Serrapeptase 765 mg - 36.43%

Nicotinamide mononucleotide / Nicotinamide mononucleotide (NMN) - 416.25 mg - 19.82%

Nicotinamide riboside / Nicotinamide riboside (NR) - 215 mg - 10.24%

Quercetin - 516.25 mg - 24.59%

Evening sachet

Ursolic acid / Ursolic acide 1045 mg - 49.76%

Nicotinamide mononucleotide / Nicotinamide mononucleotide (NMN) - 440 mg - 20.95%

Nicotinamide riboside / Nicotinamide riboside (NR) - 240 g - 11.43%

Quercetin - 375 mg - 17.86%

Example 3.

Example composition for a morning sachet with a 25% increase in Nattokinase / Nattokinase and a total weight of the sachet of 2100 mg:

Composition of the morning sachet:

Nattokinase 312.5 mg - 14.88%

Serrapeptase 735 mg - 35%

Nicotinamide mononucleotide / Nicotinamide mononucleotide (NMN) - 383.75 mg - 18.27%

Nicotinamide riboside / Nicotinamide riboside (NR) - 185 mg - 8.81%

Quercetin - 483.75 mg - 23.04%

Example composition for an evening sachet with a 25% increase in Quercetin and a total weight of 2100 mg

Ursolic acid / Ursolic acide - 955 mg - 45.48%

Nicotinamide mononucleotide / Nicotinamide mononucleotide (NMN) - 360 mg - 17.14%

Nicotinamide riboside / Nicotinamide riboside (NR) - 160 mg - 7.62%

Quercetin - 625 mg - 29.76%

Means for the treatment of gynecological adhesions and processes related to the aging of eggs according to the useful model are applied to patients with diagnosed female infertility, unsuccessful IVF procedures, surgical interventions in the area of the small pelvis and poor quality of eggs in previous ovarian punctures.

The advantages of the proposed formula are related to the reduction of already formed adhesions and the prevention of new ones, as well as the reduction of the effects of aging on the eggs in women 8 who are going through problems conceiving. This model makes it possible to reduce the negative effect of adhesions of any localization and improve the quality of the eggs, which is combined with minimal or absent toxicity and convenient oral intake, without additional interventions. Added to this are the additional health benefits that the respective substances bring together and individually.

Claims (1)

Means for the treatment of gynecological adhesions and processes related to the aging of the eggs, characterized in that it consists of Nicotinamide mononucleotide / Nicotinamide mononucleotide (NMN); Nicotinamide riboside / Nicotinamide riboside; Quercetin, which also contains Ursolic acid or a combination of Nattokinase and Serrapeptase