Field of the Invention

The present invention pertains to nutritional compositions comprising genistein, nutritional products comprising such compositions, and methods of treating patients suffering from the symptoms of perimenopause or menopause.

Background

The menopausal transition can be a challenging time frame in the lives of women, and typically starts in the mid-to-late forties and can last up to 10 years. Many women experience both physical and emotional symptoms during this time frame. For example, vasomotor symptoms (hot flashes and night sweats) are a hallmark of the menopausal transition. Additionally, it has been reported that the risk of depression is 2-4 times higher in women in the perimenopausal or early post-menopausal time frames. Sleep disruptions are also very common in this population, where over 1/3 of midlife women have reported sleep problems. Elevated cortisol, a marker of stress, has also been associated with menopausal symptoms. However, aside from hormone replacement therapy, there are few medical treatment options available that address both the physical and emotional symptoms of menopause, and many women are reluctant to take medications for symptoms that are perceived as a “normal” life transition.

Menopausal hot flashes are thought to be triggered by the sex hormone imbalances that are associated with the menopausal transition. In particular, a depletion in estrogen levels is associated with the onset of many menopausal symptoms. Isoflavones from soy are considered to be “phytoestrogens” because they have been shown to have weak estrogenic activity. Numerous clinical trials have shown that supplementation with soy-derived isoflavones can reduce the severity and duration of menopausal symptoms, including hot flashes. Several recent meta-analyses have found a statistically significant improvement in hot flash frequency and duration resulting from soy isoflavone supplementation. In particular, soy isoflavone extracts containing high levels of the single isoflavone genistein have been shown to be particularly effective, specifically at levels greater than or equal to 30 mg/day. See Williamson-Hughes, et al., “Isoflavone Supplements Containing Predominantly Genistein Reduce Hot Flash Symptoms: A Critical Review of Published Studies.” Menopause 13 (5): 831-39. 2006. (https://doi.org/10.1097/01.gme.0000227330.49081.9e). Lethaby, et al., “Phytoestrogens for Menopausal Vasomotor Symptoms.” The Cochrane Database of Systematic Reviews, no. 12 (December): CD001395 (2013) (https://doi.org/10.1002/14651858.CD001395.pub4).

Numerous studies have shown a statistically significant improvement in menopausal hot flash symptoms with the supplementation of genistein, either as a purified substance or as a major component of an isoflavone extract. Genistein has also been shown to be safe.

However, developing a nutritional composition comprising genistein has been challenging due to genistein’ s known poor water solubility. The format of such a nutritional composition can play a major role in adherence to such a regimen. Most of today’s menopause supplements are in the form of 2-piece capsules or tablets. However, this format may be problematic, as older individuals increasingly suffer from issues related to swallowing. In addition, today’s consumers increasingly prefer alternative formats, such as beverages, shots, or chews, to traditional “pill-based” supplement formats. A composition comprising genistein that allows for a wider array of delivery formats would be desirable.

The prior art has used customary thickening agents to reduce the sedimentation of genistein in a water-based genistein composition. While this does provide some degree of improvement, a composition that exhibits improved content uniformity and utility in a wide array of product formats would be desirable.

Summary

It was surprisingly found that the addition of a saffron extract can further improve the water solubility of genistein in a water-based nutritional composition. Suitable solubility of genistein was observed across a range of product formats, including beverages, shots, and gummies.

Increasing levels of pectin, in combination with saffron extract were found to improve the solubilization of genistein in beverages. In follow-up experiments, where the level of genistein was held constant at 0.05% of the formulation, increasing amounts of pectin alone did not improve solubilization, and in fact were found to decrease the amount of genistein detected in the decanted solution. Surprisingly, it was found that the addition of a saffron extract to the formulation increased the solubilization of genistein. In an embodiment, an orally consumable nutritional supplement comprises a thickening agent, genistein, and a saffron extract, wherein the weight ratio of genistein to the saffron extract is from about 2: 1 to about 1 :2 and the weight ratio of thickening agent to genistein is at least 2: 1. In an embodiment, the thickening agent comprises a hydrocolloid, such as pectin.

The compositions and methods disclosed herein may have numerous benefits over prior art compositions and methods. Such potential benefits include better content uniformity, reduced settling of genistein, improved product stability, improved product quality, a wider degree of suitable product formats, additional or improved health benefits, and reduced manufacturing complexity.

Brief Description of the Drawings

Fig. 1 is chart of genistein concentration (ppm) vs. pectin content associated with Example 1.

Description

In an embodiment, an orally consumable nutritional supplement comprises a thickening agent, genistein, and a saffron extract, wherein the weight ratio of genistein to the saffron extract is from about 2: 1 to about 1 :2.

The composition comprises genistein. Genistein is typically added as a powder. Genistein may be obtained from natural sources or be synthetically produced. A suitable genistein is geniVida™, obtainable from DSM Nutritional Products, Parsippany, NJ. The genistein typically has high purity, such as 98.5% purity.

The composition comprises a thickening agent, such as a hydrocolloid. There are numerous commercially available food-grade thickening agents that may be suitable in the instant compositions. In an embodiment, the thickening agent comprises a hydrocolloid. In an embodiment, the thickening agent consists of a hydrocolloid. In an embodiment, the hydrocolloid comprises starch, xanthan, guar gum, locust bean gum, gum karaya, gum tragacanth, gum Arabic, acacia, alginate, pectin, carrageenan, gelatin, gellan, agar, a cellulose derivative, or a mixture thereof. In an embodiment, the hydrocolloid is a pectin. In an embodiment, the pectin is a high-methoxyl pectin. The composition comprises a saffron extract. Saffron extracts may be obtained by hot water extraction of saffron or via solvent extraction. A hot water extract of saffron is an extract obtained using an extraction medium of majority hot water. In an embodiment, the saffron extract is an extract obtained using an extraction medium of at least 60 wt%, 70 wt%, 80 wt%, 85 wt%, 90 wt%, 95 wt% or 100 wt% water. Commercial examples of such saffron extracts are affron® from Gencor™ (100 wt% water extract) and Safr’Inside™ from Seppic (70:30 w/w water: ethanol). In an embodiment, the saffron extract is a solvent extract (obtained using an extraction medium of majority solvent). In an embodiment, the saffron extract is an extract obtained using an extraction medium of less than 30 wt%, 20 wt%, or 10 wt% of water. The solvent may be a low molecular weight alcohol, such as ethanol. An example of such a solvent extract is Saffir’ Activ® from SuanFarma (20:80 w/w water: ethanol). Water extracts of saffron of at least 60 wt% water as extraction medium are preferred. In an embodiment, the saffron extract comprises crocins, trans-crocetin, or safranal. By crocins it is meant crocin and crocin isomers. In an embodiment, the saffron extract comprises crocins, trans-crocetin, and safranal.

Although genistein and other soy isoflavones have been shown to address physical symptoms such as hot flashes and night sweats, there is no evidence that they address the concomitant emotional health symptoms that also occur during the menopausal transition.

The health benefits from the saffron extract may have additive benefits for women undergoing perimenopause or menopause in that a saffron extract may be beneficial to managing the emotional symptoms thereof while genistein may be beneficial to managing the physical symptoms thereof. Although genistein and other soy isoflavones have been shown to address physical symptoms such as hot flashes and night sweats, there is no evidence that they address the concomitant emotional health symptoms that also occur during the menopausal transition.

In Lopresti, et al., “The Effects of a Saffron Extract (Affron®) on Menopausal Symptoms in Women during Perimenopause: A Randomised, Double-Blind, Placebo- Controlled Study.” Journal of Menopausal Medicine 27: e8 (2001) (https://doi.org/10.6118/jmm.21002) it was found that supplementation of healthy perimenopausal women with 14 mg saffron extract twice daily resulted in statistically significant improvements in the Greene Climacteric Scale psychological score, and a decrease in PANAS negative affect score compared to placebo. However, no improvements in physical symptoms were observed. These results are also consistent with those of another study in which a different saffron extract was investigated for the treatment of major depressive disorder associated with menopausal hot flashes (Kashani, et al., “Efficacy of Crocus Sativus (Saffron) in Treatment of Major Depressive Disorder Associated with Post-Menopausal Hot Flashes: A Double-Blind, Randomized, Placebo-Controlled Trial.” Archives of Gynecology and Obstetrics 297 (3): 717-24 (2018) (https://doi.org/10.1007/s00404-018-4655-2). Hot flash and anxiety symptoms and sleep parameters have also been shown to be beneficially impacted by saffron supplementation.

Given the coexistence of both physical symptoms and emotional health symptoms during menopause, a composition comprising genistein and a saffron extract may be useful.

In an embodiment, the weight ratio of thickening agent to genistein is at least 2: 1. In an embodiment, the weight ratio of thickening agent to genistein is from 3: 1, 4: 1, 5: 1, 6:1, 7: 1, or 8: 1 to 16: 1, 15: 1, 14: 1, 13: 1, or 12: 1.

In an embodiment, the weight ratio of genistein to the saffron extract is from about 1.5:1 to about 1 : 1.5, from about 1.2: 1 to about 1 : 1.2, from about 1.1 : 1 to about 1 : 1.1, from about 1.2: 1 to about 1 : 1, or about 1 : 1.

In an embodiment, the composition comprises from 1 to 20 wt% of genistein, from 60 to 98 wt% of a hydrocolloid, and from 1 to 20 wt% of a saffron extract, based on the total weight of genistein, hydrocolloid, and saffron extract in the composition. In an embodiment, the genistein is present in an amount of from 2 to 18 wt%, 3 to 15 wt%, 2 to 10 wt%, or 5 to 10 wt%, based on the total weight of the genistein, hydrocolloid, and saffron extract in the composition. In an embodiment, the amount of hydrocolloid is present in an amount of from 64 to 96 wt%, from 70 to 94 wt%, from 80 to 96 wt%, or from 78 to 91 wt%, based on the total weight of the genistein, hydrocolloid, and saffron extract in the composition. In an embodiment, the amount of a saffron extract is from 2 to 18 wt%, 3 to 15 wt%, 2 to 10 wt%, or 4 to 12 wt%, based on the total weight of the genistein, hydrocolloid, and saffron extract in the composition.

The compositions may be particularly useful in forming nutritional beverages, shots, and/or gummies. The water content will differ depending on which product form is desired. In an embodiment, the composition comprises from 92 to 99 wt%, from 90 to 95 wt%, from 80 to 90 wt%, at least 80 wt%, at least 85 wt%, or at least 95 wt% of water, based on the total weight of the composition. In an embodiment, the composition comprises from 10, 15, or 20 wt% to 40, 35, or 30 wt% of water, based on the total weight of the composition.

Further additives, such as sweeteners and flavoring agents may be added.

The compositions and resulting products disclosed herein may show benefits in the management of physical and emotional symptoms of perimenopause and menopause. Thus, in an embodiment, a method of treating the physical and emotional symptoms of perimenopause and menopause comprises the steps of treating a patient in need thereof by administering the composition. In an embodiment, the composition is administered in two doses per day. In an embodiment, the total daily intake of genistein of from 25 to 35 mg. In an embodiment, the total daily intake of saffron extract is from 25 to 35 mg.

The following examples are included to better elucidate the instant inventions but, of course, should not be construed to limit their scope.

Examples

In preliminary experimentation, poor water solubility of genistein was observed as evidenced by sedimentation at the bottom of a beverage. Therefore, a standardized heating approach was employed to mimic pasteurization of a ready-to-drink beverage. Dry ingredients were pre-mixed in powder form. Water was heated to 80 °C in a water bath, and the dry ingredients were mixed into the beverage while stirring with a propeller at 400 RPM. The mixture was stirred continuously and held at 85 °C for 30 minutes. It was then cooled to room temperature (20 °C) in an ice bath. This protocol was used to prepare the beverages and shots that follow.

Pure genistein powder (98.5% purity, geniVida™) was obtained from DSM Nutritional Products, Parsippany, NJ. The pectin was a high-methoxyl pectin obtained from Cargill, Inc. (Minneapolis, MN; product code 64030).

A powdered saffron extract was obtained by hot water extraction of saffron (affron® from Gencor™). Its principal active components were characterized by HPLC. The saffron extract (25 mg) was dissolved into 12.5 ml of water, and vortexed for one minute and sonicated for an additional 10 minutes. Afterwards, 12.5 ml of methanol was added and vortexed for 1 min and sonicated for another 10 minutes. The sample was then filtered through a 0.2 pm FTPE filter paper and stored at -36 °C before analysis. High-performance liquid chromatography (HPLC) coupled with diode array detection (DAD) was used for the quantification of standards and saffron sample. The compounds were confirmed by analysis using high-resolution mass spectrometry analysis with Q-Exactive Orbitrap. Concentrations of the active components were obtained based on calibrations with serial dilutions of standard stock solutions with a concentration of 1 mg/mL of safranal, crocin and crocetin in 50/50 MeOH/water (v/v). Concentrations of total crocin isomers, trans-crocetin and safranal are shown in Table 1.

Table 1 - Composition of Saffron Extract by HPLC Analysis

Component Concentration (mg/g)

Total crocins 492.7 ± 11.2 mg/g

Trans-crocetin 0.083 ± 0.005 mg/g

Safranal 0.44 ± 0.01 mg/g

Example 1: Effect of Saffron and Hydrocolloid on Solubilization of Genistein in a Beverage

The beverage formulations shown in Example 1 were prepared. The amount of genistein was held constant while the amount of hydrocolloid (pectin) and saffron extract were modified. Each composition had a batch size of 200g, including water, 100 mg of which was genistein, and were used to prepare a 200 ml beverage using the procedure described previously.

After cooling to room temperature, the beverage was allowed to settle at room temperature for 30 minutes. The saffron extract imparted a yellow coloration, which was evenly distributed with no observed sedimentation of yellow particulate. However, sedimentation of white crystalline material was observed at the bottom of the beverages, particularly those with lower amounts of pectin. This was suspected to be genistein based on the known poor water solubility of genistein. A 50 ml sample of the solution was decanted and analyzed for genistein by HPLC using the method described in Hsieh, et al., “A Fast HPLC Method for Analysis of Isoflavones in Soybean,” Journal of Liquid Chromatography & Related Technologies, 27(2):315- 324 (2004). The compositions (in wt% based on the total weight of the composition) and measured genistein concentration in the decanted solutions are shown in Table 2.

Table 2: Example 1 Compositions

Fig. 1 shows a plot of genistein concentration (ppm) vs pectin content. A viscosity measurement was taken for Compositions 1, 2, 4, and 6. This is reported in Table 3.

Table 3: Example 1 Viscosity Measurements

Composition Viscosity (mPa-s)

Control (Composition 1) 4.87±0.08

Pectin 0.1% (Composition 2) 5.71±0.11

Pectin 0.5% (Composition 4) 9.04±0.09

Pectin 1.0% (Composition 6) 15.42±0.10

In formulations 1, 2, 4, and 6, the increasing amounts of pectin added to the formulations had no appreciable effect on increasing the solubility of genistein. However, in formulations 3, 5, and 7, the further addition of saffron improved the solubility of genistein, especially at higher concentrations of pectin where solubility was found to decrease. In formulation number 5, where saffron was added to the mixture in a 1 : 1 ratio with genistein, this combination with pectin was found to increase the solubility of genistein over 3-fold, compared to pectin alone. This effect was also more pronounced compared to the lower and higher concentrations of saffron extract. Comparative Example 1: Genistein Beverage without Hydrocolloid

A beverage containing 14 mg saffron extract and 15 mg of pure genistein in a standard 240 ml serving was formulated. The beverage was designed to be consumed twice daily to achieve a total daily intake of 28 mg saffron extract and 30 mg genistein. A 30% overage of each active ingredient was added to account for expected degradation of the active ingredients over shelf-life. The beverage composition included water, sugar for sweetening, citric acid and sodium citrate for pH adjustment, and a natural orange flavor. The formulation of the beverage is shown in Table 4. Table 4: Formulation of beverage for Comparative Example 1 :

The saffron extract imparted a yellow coloration to the beverage which was evenly distributed with no observed sedimentation of yellow particulate. However, sedimentation of white crystalline material was observed at the bottom of the beverage, which was suspected to be genistein based on the known poor water solubility of genistein. After 5 minutes of settling, a 50 ml sample of the beverage was decanted and sent for genistein analysis by HPLC. The remaining beverage was then decanted, and the last 50 ml was swirled and sampled for genistein analysis.

The expected concentration of genistein in the beverage was 81.3 ppm. The measured genistein concentration in the beverage sample was <10 ppm, below the limit of quantitation for the HPLC method. The measured genistein concentration in the sediment beverage sample was 47.9 ppm, also below the expected concentration. While the beverage samples were shaken prior to analysis, it’s possible that the crystalline material in the sediment was not evenly distributed in the analytical sample. These results confirmed that a beverage composition containing both saffron extract and geni stein was not successful.

Comparative Example 2: Genistein Beverage with Insufficient Hydrocolloid

A beverage containing 14 mg saffron extract and 15 mg of pure genistein in a standard 240 ml serving was formulated. As in Comparative Example 1, the beverage was designed to be consumed twice daily to achieve a total daily intake of 28 mg saffron extract and 30 mg genistein. A 30% overage of each active ingredient was added to account for expected degradation of the active ingredients over shelf-life. A hydrocolloid was added to the mixture in order to facilitate suspension of the genistein in the beverage and to reduce sedimentation. The beverage composition included water, sugar for sweetening, citric acid and sodium citrate for pH adjustment, pectin, and a natural orange flavor. The formulation of the beverage from Experiment 2 is shown in Table 5. The beverage was prepared in the same way as Comparative Example 1.

Table 5 - Formulation of beverage for Comparative Example 2:

Sedimentation of white crystalline material at the bottom of the beverage was observed, although to a lesser extent as in Comparative Example 1. After 5 minutes of settling, a 50 ml sample of the beverage was decanted and sent for genistein analysis by HPLC. The remaining beverage was then decanted, and the last 50 ml was swirled and sampled for genistein analysis.

The expected concentration of genistein in the beverage was 81.3 ppm. The measured genistein concentration in the beverage sample was <10 ppm, below the limit of quantitation for the HPLC method. The measured genistein concentration in the sediment beverage sample was 86.5 ppm, above the expected concentration. While the higher recovery of genistein in the sediment sample suggested that the addition of a small amount of hydrocolloid helped improve the content uniformity of genistein, these results again confirmed that a beverage composition containing both saffron extract and genistein was not successful due to issues with solubility and content uniformity of genistein.

Example 2: Genistein Shot

A more concentrated shot-style beverage containing 14 mg saffron extract and 15 mg of pure genistein in a smaller 50 ml serving was formulated from a batch size of 240 g. The shot was designed to be consumed twice daily to achieve a total daily intake of 28 mg saffron extract and 30 mg genistein, to achieve efficacy of each individual ingredient. A 30% overage of each active ingredient was added to account for expected degradation of the active ingredients over shelf-life. A larger amount of the pectin hydrocolloid ingredient was added to the mixture to better facilitate suspension of the genistein in the shot, and to reduce the occurrence of sedimentation. The shot composition included water, sugar for sweetening, citric acid and sodium citrate for pH adjustment, pectin, and a natural orange flavor. The formulation of the shot from in Table 6. The shot was prepared in the same way as the beverages of Comparative Examples 1 and 2.

Table 6 - Composition of Shot of Example 2

The viscosity was found to be 9.7±0.1 mPa-s (average±SEM), consistent with a visibly thicker texture, but still well within the range expected of a shot. Compared to the beverages in comparative experiments 1 and 2, the shot had a darker yellow coloration due to the saffron extract, but the yellow color was evenly distributed with no observed sedimentation of yellow particulate. It was again observed, although to a much lesser extent, sedimentation of white crystalline material at the bottom of the shot, which was again assumed to be geni stein. After 5 minutes of settling, a 50 ml sample of the shot was decanted and sent for genistein analysis by HPLC. The remaining shot was then decanted, and the last 50 ml was swirled and sampled for genistein analysis.

The expected concentration of genistein in the shot was 390 ppm. In the decanted shot sample, the genistein concentration was 59.8 ppm, which was a 15% recovery compared to the expected concentration. This finding was somewhat surprising, as it suggested that the hydrocolloid may be having an effect of stabilizing the genistein in solution. In the sediment beverage sample, the concentration of genistein was 1170 ppm, far above the expected concentration. The higher recovery of genistein in both the decanted and sediment samples of the shot suggested that the addition of a larger amount of hydrocolloid helped to improve the content uniformity of genistein even further. However, content uniformity of the shot formulation was still an issue, as the genistein was not evenly distributed between the decanted sample and the sediment sample of the shot.

Example 3: Genistein Gummy

A more concentrated product form compared to the shot-style beverage was formulated with and without a saffron extract. The targeted dose was 15 mg of pure genistein and (if present) 14 mg saffron extract in a 6 g gummy serving. The gummy was formulated in a batch size of 400 g. The 6 g gummy was designed to be consumed twice daily to achieve a total daily. Again, a 30% overage of each active ingredient was added to account for expected degradation of the active ingredients over shelf-life. The gummy composition included water, sugar for sweetening, citric acid and sodium citrate for pH adjustment, pectin, and a natural orange flavor. High-DE corn syrup was also added to the formulation to impart additional sweetness and texture. Betacarotene (cold water soluble; DSM Nutritional Products, Parsippany, NJ) was added to this formulation to impart an orange color.

The pectin, sodium citrate and 10% of the sugar were pre-mixed in powder form. Water was heated to 80 °C in a water bath, and the dry ingredients were mixed while stirring with a propeller at 400 RPM. The mixture was stirred continuously and held at 80 °C for 30 minutes. The remaining sugar and corn syrup were boiled to 110 °C and the pectin solution was added to the com syrup sugar mixture and heated until Brix reached 78%. The remaining powdered ingredients were then added to a slurry and added to the mixture, and final Brix level was 80%. The finished mixture was then deposited into silicone molds and polished with carnauba wax after setting for 24 hours. The formulations of the gummies are shown in Table 7.

Table 7 - Formulation of Example 3 Gummies

Compared to the beverages and shots, the gummy had a darker yellow coloration due to the saffron extract, but the yellow color was again evenly distributed with no observed sedimentation of yellow particulate. Sedimentation of the genistein during the production process was not observed. Gummy samples were sent for analysis of genistein to determine genistein recovery in the finished product. The results are shown in Table 8.

Table 8 - Example 3 Results

While both gummies likely have sufficient genistein recovery to be commercially suitable, improved recovery was observed with the addition of saffron extract.

The following non-limiting list of exemplary embodiments is included to further elucidate certain embodiments of the invention. Additional Description of Certain Exemplary Embodiments

1. An orally consumable nutritional supplement comprising a thickening agent, genistein, and a saffron extract, wherein the weight ratio of genistein to the saffron extract is from about 2: 1 to about 1 :2.

2. An orally consumable nutritional supplement comprising a thickening agent, genistein, and a saffron extract, wherein the weight ratio of genistein to the saffron extract is from about 2: 1 to about 1 :2 and the weight ratio of thickening agent to genistein is at least 2: 1.

3. The composition according to any one of the preceding exemplary embodiments, wherein the thickening agent comprises a hydrocolloid.

4. The composition according to any one of the preceding exemplary embodiments, wherein the thickening agent consists of a hydrocolloid.

5. An orally consumable nutritional supplement comprising a hydrocolloid, genistein, and a saffron extract, wherein the weight ratio of genistein to the saffron extract is from about 2: 1 to about 1 :2.

6. An orally consumable nutritional composition comprising: a. from 2 to 20 wt% of genistein; b. from 60 to 94 wt% of a hydrocolloid; and c. from 2 to 20 wt% of a saffron extract, wherein the weight ratio of genistein to the saffron extract is from about 2: 1 to 1 :2, and wherein the wt% is based on the total weight of genistein, hydrocolloid, and saffron extract in the composition.

7. An orally consumable nutritional composition comprising: a. from 90 to 99.89 wt% of water; b. from 0.005 to 0.05 wt% of genistein; c. from 0.1 to 1.0 wt% of a hydrocolloid; and d. from 0.005 to 0.05 wt% of a saffron extract, wherein the weight ratio of genistein to the saffron extract is from about 2: 1 to 1 :2, and wherein the wt% is based on the total weight of the composition.

8. An orally consumable nutritional composition comprising: a. from 80 to 90 wt% of water; b. from 0.01 to 0.1 wt% of geni stein; c. from 0.1 to 1.0 wt% of a hydrocolloid; and d. from 0.01 to 0.1 wt% of a saffron extract, wherein the weight ratio of genistein to the saffron extract is from about 2: 1 to 1 :2, and wherein the wt% is based on the total weight of the composition.

9. The composition according to any one of the preceding exemplary embodiments, wherein the weight ratio of genistein to the saffron extract is from about 1.5: 1 to about 1 : 1.5.

10. The composition according to any one of the preceding exemplary embodiments, wherein the weight ratio of genistein to the saffron extract is from about 1.2: 1 to about 1 : 1.2.

11. The composition according to any one of the preceding exemplary embodiments, wherein the weight ratio of genistein to the saffron extract is from about 1.1 : 1 to about 1 : 1.1.

12. The composition according to any one of the preceding exemplary embodiments, wherein the weight ratio of genistein to the saffron extract is from about 1.2: 1 to about 1 : 1.

13. The composition according to any one of the preceding exemplary embodiments, wherein the weight ratio of genistein to the saffron extract is about 1 : 1.

14. The composition according to any one of the preceding exemplary embodiments, wherein the weight ratio of thickening agent to genistein is at least 3: 1, 4: 1, 5:1, 6: 1, 7: 1, or 8: 1.

15. The composition according to any one of the preceding exemplary embodiments, wherein the weight ratio of thickening agent to genistein is at most 16: 1, 15: 1, 14: 1, 13: 1, or 12: 1.

16. The composition according to any one of the preceding exemplary embodiments, wherein the composition comprises: a. from 1 to 20 wt% of genistein; b. from 60 to 98 wt% of a hydrocolloid; and c. from 1 to 20 wt% of a saffron extract, wherein the wt% is based on the total weight of genistein, hydrocolloid, and saffron extract in the composition.

17. The composition according to any one of the preceding exemplary embodiments, wherein the composition comprises: a. from 2 to 18 wt% of genistein; b. from 64 to 96 wt% of a hydrocolloid; and c. from 2 to 18 wt% of a saffron extract, wherein the wt% is based on the total weight of genistein, hydrocolloid, and saffron extract in the composition.

18. The composition according to any one of the preceding exemplary embodiments, wherein the composition comprises: a. from 3 to 15 wt% of genistein; b. from 70 to 94 wt% of a hydrocolloid; and c. from 3 to 15 wt% of a saffron extract, wherein the wt% is based on the total weight of genistein, hydrocolloid, and saffron extract in the composition.

19. The composition according to any one of the preceding exemplary embodiments, wherein the composition comprises: a. from 2 to 10 wt% of genistein; b. from 80 to 96 wt% of a hydrocolloid; and c. from 2 to 10 wt% of a saffron extract, wherein the wt% is based on the total weight of genistein, hydrocolloid, and saffron extract in the composition. 0. The composition according to any one of the preceding exemplary embodiments, wherein the composition comprises: a. from 5 to 10 wt% of genistein; b. from 78 to 91 wt% of a hydrocolloid; and c. from 4 to 12 wt% of a saffron extract, wherein the wt% is based on the total weight of genistein, hydrocolloid, and saffron extract in the composition. 21. The composition according to any one of the preceding exemplary embodiments, wherein the composition comprises: a. from 90 to 99.89 wt% of water; b. from 0.005 to 0.05 wt% of genistein; c. from 0.1 to 1.0 wt% of a hydrocolloid; and d. from 0.005 to 0.05 wt% of a saffron extract, wherein the wt% is based on the total weight of the composition.

22. The composition according to any one of the preceding exemplary embodiments, further comprising water.

23. The composition according to any one of the preceding exemplary embodiments, further comprising at least 80 wt%, 85 wt%, or 90 wt% of water.

24. The composition according to any one of the preceding exemplary embodiments, wherein the composition comprises from 92 to 99 wt% of water, based on the total weight of the composition.

25. The composition according to any one of the preceding exemplary embodiments, wherein the composition comprises from 90 to 95 wt% of water, based on the total weight of the composition.

26. The composition according to any one of the preceding exemplary embodiments, wherein the composition comprises from 80 to 90 wt% of water, based on the total weight of the composition.

27. The composition according to any one of the preceding exemplary embodiments, wherein the composition comprises from 10, 15, or 20 wt% to 40, 35, or 30 wt% of water, based on the total weight of the composition.

28. The composition according to any one of the preceding exemplary embodiments, wherein the composition comprises at least 80 wt% of water, and 0.05 to 2 wt% of a hydrocolloid, based on the total weight of the composition.

29. The composition according to any one of the preceding exemplary embodiments, wherein the composition comprises at least 80 wt% of water, and 0.05 to 2 wt% of a hydrocolloid, based on the total weight of the composition. The composition according to any one of the preceding exemplary embodiments, wherein the composition comprises at least 85 wt% of water, and 0.1 to 1.5 wt% of a hydrocolloid, based on the total weight of the composition. The composition according to any one of the preceding exemplary embodiments, wherein the composition comprises at least 90 wt% of water, and 0.1 to 1.5 wt% of a hydrocolloid, based on the total weight of the composition. The composition according to any one of the preceding exemplary embodiments, wherein the hydrocolloid comprises starch, xanthan, guar gum, locust bean gum, gum karaya, gum tragacanth, gum Arabic, acacia, alginate, pectin, carrageenan, gelatin, gellan, agar, a cellulose derivative, or a mixture thereof. The composition according to any one of the preceding exemplary embodiments, wherein the hydrocolloid is present in an amount of from 0.05 or 0.1 to 3.0 or 2.0 wt%, based on the total weight of the composition. The composition according to any one of the preceding exemplary embodiments, wherein the hydrocolloid comprises a pectin. The composition according to any one of the preceding exemplary embodiments, wherein the hydrocolloid consists of a pectin. The composition according to any one of the preceding exemplary embodiments, wherein the pectin comprises a high-methoxy pectin. The composition according to any one of the preceding exemplary embodiments, wherein the pectin consists of a high-methoxy pectin. The composition according to any one of the preceding exemplary embodiments, wherein the saffron extract comprises crocins, trans-crocetin, or safranal. The composition according to any one of the preceding exemplary embodiments, wherein the saffron extract comprises crocins, trans-crocetin, and safranal. The composition according to any one of the preceding exemplary embodiments, wherein the saffron extract is a water extract of saffron. The composition according to any one of the preceding exemplary embodiments, wherein the saffron extract is a hot water extract of saffron. 42. The composition according to any one of the preceding exemplary embodiments, wherein the saffron extract is an extract obtained using an extraction medium of least 60 wt%, 70 wt%, 80 wt%, 85 wt%, 90 wt%, 95 wt% or 100 wt% water.

43. The composition according to any one of the preceding exemplary embodiments, wherein the saffron extract is a solvent extract of saffron.

44. The composition according to any one of the preceding exemplary embodiments, wherein the saffron extract is an extract obtained using an extraction medium of less than 30 wt%, 20 wt%, or 10 wt% of water.

45. The composition according to any one of the preceding exemplary embodiments, wherein the saffron extract is an extract obtained using an extraction medium comprising a low molecular weight alcohol, such as ethanol.

46. The composition according to any one of the preceding exemplary embodiments, wherein the saffron extract is a water extract of saffron of at least 60 wt% water as extraction medium.

47. The composition according to any one of the preceding exemplary embodiments, wherein the saffron extract is a hot water extract of saffron of at least 60 wt% hot water as extraction medium.

48. The composition according to any one of the preceding exemplary embodiments, further comprising a sweetener and a flavoring agent.

49. The composition according to any one of the preceding exemplary embodiments for the management of physical and emotional symptoms of perimenopause and menopause.

50. A beverage comprising the composition according to any one of the previous exemplary embodiments.

51. A water-based nutritional shot comprising the composition according to any one of the previous exemplary embodiments.

52. A gummy comprising the composition according to any one of the previous exemplary embodiments.

53. Use of the composition of any one of the preceding claims for the management of physical and emotional symptoms of perimenopause and menopause. 54. A method of treating the physical and emotional symptoms of perimenopause and menopause comprising the steps of treating a patient in need thereof by administering a composition according to any one of the preceding exemplary embodiments.

55. The method according to any one of the preceding exemplary embodiments, wherein the composition is administered in one dose per day.

56. The method according to any one of the preceding exemplary embodiments, wherein the composition is administered in two doses per day.

57. The method according to any one of the preceding exemplary embodiments, wherein the composition achieves a total daily intake of saffron extract of from 25 to 35 mg.

58. The method according to any one of the preceding exemplary embodiments, wherein the composition achieves a total daily intake of genistein of from 25 to 35 mg.

59. The method according to any one of the preceding exemplary embodiments, wherein the composition is the form of a beverage or a water-based nutritional shot.

60. The method according to any one of the preceding exemplary embodiments, wherein the composition is the form of a beverage or a gummy.

The use of the terms “a” and “an” and “the” and similar referents in the context of describing the invention (especially in the context of the following claims) are to be construed to cover both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context. The terms “comprising,” “having,” “including,” and “containing” are to be construed as open-ended terms (i.e., meaning “including, but not limited to,”) unless otherwise noted. Recitation of ranges of values herein are merely intended to serve as a shorthand method of referring individually to each separate value falling within the range, unless otherwise indicated herein, and each separate value is incorporated into the specification as if it were individually recited herein. The use of any and all examples, or exemplary language (e.g., “such as”) provided herein, is intended merely to better illuminate the invention and does not pose a limitation on the scope of the invention unless otherwise claimed. No language in the specification should be construed as indicating any non-claimed element as essential to the practice of the invention.

Preferred embodiments of this invention are described herein, including the best mode known to the inventors for carrying out the invention. Variations of those preferred embodiments may become apparent to those of ordinary skill in the art upon reading the foregoing description. The inventors expect skilled artisans to employ such variations as appropriate, and the inventors intend for the invention to be practiced otherwise than as specifically described herein. Accordingly, this invention includes all modifications and equivalents of the subject matter recited in the claims appended hereto as permitted by applicable law. While certain optional features are described as embodiments of the invention, the description is meant to encompass and specifically disclose all combinations of these embodiments unless specifically indicated otherwise or physically impossible.