TREATMENT OF PREMENSTRUAL SYNDROME AND/OR MENSTRUAL DISCOMFORT WITH A COMPOSITION COMPRISING VICENIN-2

Technical field

The present invention relates to compositions that are useful in the treatment of female subjects suffering from premenstrual syndrome and/or menstrual discomfort. Furthermore, the invention relates to the prevention, curing and/or alleviation of at least one symptom associated with premenstrual syndrome and/or menstrual discomfort using the compositions of the invention.

Background of the Invention

Premenstrual syndrome, known as PMS, is a very common problem that affects millions of young women during their reproductive lives, disrupting their emotional and physical well-being. It is widely recognized as a recurrent, cyclical disorder related to the latter half of the menstrual cycle, subsiding with the onset of menses. The syndrome is characterized by a complex group of signs and symptoms that may include depression, mood swings, irritability, fatigue, abdominal discomfort and changes in appetite. The central element seems to be a change in capillary permeability accompanied by the formation of an interstitial tissular oedema mainly in the breasts (mastalgia), the brain (neuropsychological manifestations), and the abdominopelvic cavity (abdominopelvic disorders). Although many women experience only mild symptoms, as many as 30-50% suffer from troublesome symptoms. Surveys indicate that approximately 5% of North American women consider their symptoms to be severe enough to have a substantially negative impact on their health and social well-being. It has been suggested that women in this latter group be defined as having Premenstrual Dysphoric Disorder (PMDD).

The causes of the premenstrual syndrome have not yet been clearly understood, but have been attributed to hormonal and neuronal imbalance, diet and lifestyle. Hyperprolactinemia seems to be an important factor which is considered to be part of the endocrine disorder. Animal studies suggest actions of gonadal hormones on the mesolimbic dopamine system.

There is no single established therapy for PMS. A variety of treatments have been proposed over the years including lifestyle and dietary modifications, herbal remedies, hormonal therapies and pharmacologic interventions. The majority have proven to be ineffective or only temporarily effective, while other treatments have proven scientific efficacy. Some popular methods of treatment that have failed scientifically rigorous evaluation include progesterone therapy, monoamine oxidase inhibitors, bromocriptine and evening primrose oil. Proven treatments of PMS include calcium supplementation, selective serotonin receptor reuptake inhibitors (SSRIs) and gonadotropin releasing hormone agonists. For some women, it is not acceptable that a natural biological process such as the menstrual cycle necessitates lifestyle changes or a daily pharmacologic regimen.

The symptoms of premenstrual syndrome can be divided into three main categories, notably breast symptoms, psychological/mental symptoms and abdominopelvic symptoms. Breast symptoms can be a simple mastodynia but with really painful and tense breasts. Psychological/mental symptoms include irritability, anxiety and depression. Abdominopelvic symptoms can consist of more or less pronounced bloating, potentially associated with transit issues and/or weight gain. Other symptoms may include food craving.

The defining criteria for diagnosis of premenstrual syndrome according to the American College of Obstetricians and Gynaecologists include at least one moderate to severe mood symptom and one physical symptom ( Rapkin A. A review of treatment of premenstrual syndrome and premenstrual dysphoric disorder. Psychoneuroendocrinology. 2003 Aug;28 Suppl 3:39-53. Review).

Discomfort experienced during menses is not the same as the discomfort felt during premenstrual syndrome, although the symptoms of both disorders can sometimes be experienced as a continuous process. Many women suffer from both PMS and menstrual discomfort. The condition referred to as ‘menstrual discomfort’, involves a variety of physical and mental symptoms, which symptoms typically peak during menses of a woman's cycle. Said symptoms include for example abdominal pain, back pain, cramps, breast tenderness, mood changes, headaches, nausea and/or dizziness. The severity of these symptoms ranges from mild to incapacitating. Increased menstrual discomfort is the most common medical reason reported for copper IUD removal.

To date, there is a strong felt need for effective management of premenstrual syndrome and/or menstrual discomfort. Dietary supplements effective in preventing, treating and/or alleviating symptoms of PMS and/or menstrual discomfort would be a particularly attractive solution. In general, treatments based on dietary supplements taken orally, typically on a daily basis, are not perceived as burdensome and treatment compliance/adherence is generally good. Another factor to be considered in this regard is the general attitude towards the use of dietary supplements, which is often better if the supplement is perceived as‘natural’.

It is an objective of the present invention to provide compositions, in particular in the form of dietary supplements, that can be used effectively in the treatment of female subjects suffering from and/or at risk of suffering from PMS and/or menstrual discomfort. It is a further object of the invention to provide treatments based on the administration of said compositions.

Summary of the Invention

In accordance with the present invention, it has been found that vicenin-2 and composition comprising vicenin-2 can be used effectively in the treatment of female subjects suffering from and/or at risk of suffering from premenstrual syndrome and/or menstrual discomfort. In accordance with the invention, the treatment of female subjects with a dietary supplement comprising vicenin-2 results in the prevention, treatment or alleviation of one or more symptoms associated with premenstrual syndrome and/or menstrual discomfort, as can be assessed using prospective diaries (COPE, Calendar of Premenstrual Events) or similar self-assessment protocols.

The invention thus resides in the use of vicenin-2 as an active ingredient for use in a treatment of premenstrual syndrome and/or menstrual discomfort. Accordingly, the invention provides compositions, especially pharmaceutical and/or nutraceutical formulations, comprising vicenin-2 as a pharmacologically and/or physiologically active ingredient. The present invention also provides methods of treatment of subjects in need thereof using vicenin-2 and compositions comprising vicenin-2. The invention accordingly also provides vicenin-2 and compositions comprising vicenin-2 for use in the treatment of subjects in need thereof.

So far the literature describes that vicenin-2 has an anti-cancer, anti-inflammatory, antinociceptive, antispasmodic or prokinetic effect. To the understanding of the present inventors, its use in the treatment of premenstrual syndrome and/or of menstrual discomfort is new.

Particularly good results are attained when the treatment comprises the administration of compositions comprising, besides vicenin-2, one or more further pharmacologically and/or physiologically active ingredients. The present invention thus provides compositions, especially pharmaceutical and/or nutraceutical formulations, comprising vicenin-2 in association with one or more further ingredients. The present invention also provides methods of treatment of subjects in need thereof using compositions comprising vicenin-2 in association with one or more further ingredients. The invention accordingly also provides compositions comprising vicenin-2 in association with one or more further ingredients for use in the treatment of subjects in need thereof.

These and other aspects of the invention will become apparent to those skilled in the art on the basis of the following description. Detailed description of the Invention

The compositions

A first aspect of the invention provides compositions comprising vicenin-2, such as pharmaceutical formulations and/or food supplement products comprising vicenin-2 in association with one or more further ingredients, typically one or more further active ingredients and/or one or more excipients.

Vicenin-2

Vicenin-2 is a naturally occurring apigenin glycoside. It has CAS Registry Number 23666-13-9. The systematic (lUPAC) name is 5,7-dihydroxy-2-(4-hydroxyphenyl)-6,8- bis[(2S,3R,4R,5S,6R)-3,4,5-trihydroxy-6 (hydroxymethyl)oxan-2-yl]chromen-4-one). Common synonyms include apigenin-6,8-di-C-b-D-glycoside; apigenin-6,8-di-C-b-D- glucopyranoside; and 5,7,4'-trihydroxyflavone-6,8-di-C-glucoside. Vicenin-2 has the following molecular structure:

Vicenin-2

Vicenin-2 occurs naturally in various plants, such as plants in the genera artemisia, perilla, urtica, passiflora, camelia, cayaponia, colocasia, desmodium, hordeum, origanum, ocimum, jatropha, parkinsonia, peperomia, piheranthos, centaurea, indigo, bomba, lychnophera, asplenium, chinotto, citrus, viola, trigonella, lamiacea, labiatae, lavandula, nipponanthemum, abrus, santalum, oryza, scleropyrum, tulsi, indigofera, bombax, glinus, lychnophora, urticaceae, rosales, malpighiales, thymus, prunus, camellia, olea, brassica, apium, petroselinum, matricaria, chamaemelum, and chrystanthemum. For example, vicenin-2 may be found in vitex agnus-castus, petroselinum crispum, apium graveolens, citrus paradisi, citrus maxima, perilla frutescens, Matricaria chamomilla, chrysanthemum morifolium and chamaemelum nobile. Plants of particular interest as a vicenin-2 source are plants in the perilla genus, such as perilla frutescens.

Vicenin-2 may be obtained by extraction or isolation from a natural source or by chemical synthesis. In a preferred embodiment, the compositions of the invention comprise vicenin-2 in the form of an extract. In a preferred embodiment, the compositions of the invention comprise vicenin-2 in the form of an extract from a plant material derived from a plant species in a genus selected from the group consisting of artemisia, perilla, urtica, passiflora, camelia, cayaponia, colocasia, desmodium, hordeum, origanum, ocimum, jatropha, parkinsonia, peperomia, piheranthos, centaurea, indigo, bomba, lychnophera, asplenium, chinotto, citrus, viola, trigonella, lamiacea, labiatae, lavandula, nipponanthemum, abrus, santalum, oryza, scleropyrum, tulsi, indigofera, bombax, glinus, lychnophora, urticaceae, rosales, malpighiales, thymus, prunus, camellia, olea, brassica, apium, petroselinum, matricaria, chamaemelum, and chrystanthemum, preferably the compositions of the invention comprise vicenin-2 in the form of an extract from a plant material derived from a plant species in a genus selected from the group consisting of thymus, prunus, camellia, olea, brassica, apium, petroselinum, matricaria, chamaemelum and chrystanthemum. In a more preferred embodiment, the compositions of the invention comprise vicenin-2 in the form of an extract from plant material derived from vitex agnus- castus, petroselinum crispum, apium graveolens, citrus paradisi, citrus maxima, perilla frutescens, Matricaria chamomilla, chrysanthemum morifolium or chamaemelum nobile.

The plant material preferably comprises or consists of seed. In a particularly preferred embodiment of the invention, the composition comprises vicenin-2 in the form of a Perilla extract, preferably a Perilla seed extract, more preferably a Perilla frutescens (L.) Britton extract, most preferably a Perilla frutescens (L.) Britton seed extract. In preferred embodiments said Perilla extract is made from sun-dried seeds which were harvested in autumn.

Suitable extracts can be produced with polar solvents, such as with water, methanol, ethanol and mixtures thereof. In preferred embodiments the extract is produced with a solvent having a relative polarity of more than 0.5, such as more than 0.6 or more than 0.7. Relative polarity values are known to the skilled person, preferably the relative polarity is determined as a normalized value from measurements of solvents shifts of adsorption spectra, wherein water has a relative polarity value of 1 , as explained in Christian Reichardt, Solvents and Solvent Effects in Organic Chemistry, Wiley-VCH Publishers, 3rd ed., 2003.

Preferred extracts can be produced with water, with alcohols, in particular methanol, ethanol, propanol or mixtures thereof, or with mixture of water and alcohol, preferably mixtures with a level of alcohol within the range of 10-95 %(v/v), 30-90 %(v/v) or 60-80 %(v/v) as the extraction solvent. In preferred embodiments the extract is produced with water, methanol, ethanol, water-ethanol or water-methanol mixtures. In more preferred embodiments, the extract is produced with water, ethanol, or water-ethanol mixtures. Highly preferred extracts can be produced with water as the sole/main extraction solvent, since some volatile, allergenic compounds like perillaldehyde, methyleugenol and myristicin, which may occur in the plant material containing vicenin-2 can be eliminated by (hot) water extraction.

Hence, in accordance with a preferred embodiment of the invention, the composition comprises vicenin-2 in the form of an aqueous extract, preferably an extract obtained using water as the sole extraction solvent (referred to herein as a‘100% water extract’), of a vicenin-2 comprising plant material as described above. In an embodiment of the invention, a composition as defined herein is provided comprising an aqueous extract, preferably a 100% water extract, of a vicenin-2 comprising plant material.

In accordance with a preferred embodiment of the invention, the composition comprises vicenin-2 in the form of an aqueous extract, preferably a 100% water extract, from Perilla, preferably fromPerilla seed, more preferably from Perilla frutescens (L.) Britton, most preferably from Perilla frutescens (L.) Britton seed, wherein the extraction was performed at a temperature of more than 60°C, preferably more than 80°C, most preferably more than 95°C.

In accordance with a preferred embodiment of the invention, the composition comprises vicenin-2 in the form of an extract, preferably an aqueous extract, more preferably a 100% water extract, wherein the extract comprises less than 0.1 wt.% myristicine, based on the total weight of the plant derived components, preferably less than 0.01 wt.% myristicine.

Aqueous, preferably 100% water vicenin-2 containing plant extracts may typically comprise one, two, three, four or five additional active ingredients selected from the group consisting of perilloside A, perilloside E, trihydroxyflavones, scutellarin, caffeic acid, prunasin, luteolin, chrysoeriol, apigenin, shisonin, scutellarein, coumaroyl tartaric acid, linolenic acid, linoleic acid, oleic acid, stearic acid, rosmarinic acid and palmitic acid.

In a preferred embodiment of the invention, the composition comprises a vicenin- 2 containing plant extract having a vicenin-2 level of at least 0.1 wt.%, based on the total weight of the plant derived components or based on total dry solids weight, e.g. at least 0.5 wt.%, at least 1 wt.%, at least 2 wt.%, at least 3 wt.%, at least 4 wt.% or at least 5 wt.%. In a preferred embodiment of the invention, the composition comprises a vicenin- 2 containing plant extract obtainable by aqueous extraction, preferably extraction with water as the sole extraction solvent, performed in such a way that an extract is produced that, excluding any extraction solvent, is from 1/6 - 1/4 of the (dry) weight of the plant material before extraction.

In a preferred embodiment of the invention, the composition comprises a vicenin- 2 containing plant extract obtainable by a method comprising the steps of:

a) providing Perilla plant material, preferably Perilla frutescens (L.) Britton seed; b) macerating or grinding the plant material provided in step a);

c) performing an aqueous, preferably a 100% water extraction, preferably at a temperature of more than 95°C;

d) concentrating the extract, preferably at a temperature not exceeding 95°C, preferably not exceeding 85°C; and

e) drying, preferably spray-drying, the concentrated extract.

Vicenin-2 containing extracts suitable for use in the context of the present invention, and the production thereof, have been described in the prior art, e.g. in:

• Islam, Md Nurul, et al. "Vicenin 2 isolated from Artemisia capillaris exhibited potent anti-glycation properties." Food and chemical toxicology 69 (2014): 55-62;

• Marrassini, Carla, et al. "Vicenin-2, a potential anti-inflammatory constituent of Urtica circularis." Journal of natural products 74.6 (2011): 1503-1507.

Vicenin-2 containing extracts suitable for use in the context of the present invention are available commercially, e.g. from the company“EURL Natural” in France under the reference“Perilla seed extract 4/1 (aldehyde chemotype)”.

Rosmarinic acid

In particularly preferred embodiments of the invention, compositions as defined herein are provided, further comprising rosmarinic acid. Rosmarinic acid is a naturally occurring compound belonging to the class of phenolic acids. It has CAS Registry Number 20283-92-5. The systematic (lUPAC) name is 3,4-dihydroxy-a-[[3-(3,4-dihydroxyphenyl)- 1-oxo-2-propenyl7-oxy7-phenyl-propionic acid. Rosmarinic acid has the following molecular structure: Rosmarinic acid

Rosmarinic acid occurs naturally in various plants, such as plants in the families Lamiaceae, Boraginaceae, and Marantaceae. It is, for example, found in plants of the genera ocimum, melissa, rosmarinus, origanum, salvia, thymus, prunella, stachys, heliotropium, maranta, thalia, perilla, mentha, celastrus etc. For example, rosmarinic acid may be found in ocimum basilicum, ocimum tenuiflorium, melissa officinalis, rosmarinus officinalis, origanum majorana, salvia officinalis, thymus vulgaris, mentha x piperita, prunella vulgaris, stachys sylvatica, heliotropium foertherianum, maranta leuconeura, maranta depressa, thalia geniculata, anthoceros agrestis, perilla fruescens, salvia officialis, mentha arvense, celastrus hindsii etc.

Rosmarinic acid may be obtained by extraction or isolation from a natural source or by chemical synthesis. In a preferred embodiment, the compositions of the invention comprise rosmarinic acid in the form of an extract. In a preferred embodiment, the compositions of the invention comprise rosmarinic acid in the form of an extract from a plant material derived from a plant species in a genus selected from the group consisting of ocimum, melissa, rosmarinus, origanum, salvia, thymus, prunella, stachys, heliotropium, maranta, thalia, perilla, mentha and celastrus. In a preferred embodiment, the compositions of the invention comprise rosmarinic acid in the form of an extract from a plant material derived from ocimum basilicum, ocimum tenuiflorium, melissa officinalis, rosmarinus officinalis, origanum majorana, salvia officinalis, thymus vulgaris, mentha x piperita, prunella vulgaris, stachys sylvatica, heliotropium foertherianum, maranta leuconeura, maranta depressa, thalia geniculata, anthoceros agrestis, perilla fruescens, salvia officialis, mentha arvense and celastrus hindsii. The plant material preferably comprises or consists of whole plants, preferably leaves, flowers and/or stem, more preferably leaves and/or flowers, most preferably leaves. In a particularly preferred embodiment of the invention, the composition comprises rosmarinic acid in the form of a Perilla extract, preferably a Perilla seed extract, more preferably a Perilla frutescens (L.) Britton extract, most preferably a Perilla frutescens (L.) Britton seed extract. Suitable extracts can be produced with polar solvents, such as with water, methanol, ethanol and mixtures thereof. In preferred embodiments the extract is produced with a solvent having a relative polarity of more than 0.5, such as more than 0.6 or more than 0.7.

Preferred extracts can be produced with water, methanol, ethanol, propanol or mixtures thereof, preferably with a level of alcohol within the range of 10-95 %(v/v), 30-90 %(v/v) or 60-80 %(v/v) as the extraction solvent. In preferred embodiments the extract is produced with water, methanol, ethanol or water-ethanol or water-methanol mixtures. In more preferred embodiments, the extract is produced with water, ethanol, or water-ethanol mixtures. Most preferably, the extract is produced with a water-ethanol mixture.

In embodiments the extract is produced with a water-ethanol mixture with a level of ethanol within the range of 20-90 %(v/v), preferably within the range of 40-90 %(v/v), preferably within the range of 60-80 %(v/v), preferably within the range of 65-75 %(v/v).

Highly preferred extracts can be produced with water as the sole/main extraction solvent, referred to as a 100 % water extract, since some volatile, allergenic compounds like perillaldehyde, methyleugenol and myristicin, which may occur in the plant material can be eliminated by (hot) water extraction.

Hence, in accordance with a preferred embodiment of the invention, the composition comprises rosmarinic acid in the form of an aqueous extract, preferably a 100% water extract of a rosmarinic acid comprising plant material as described above. In an embodiment of the invention, a composition as defined herein is provided comprising an aqueous extract, preferably a 100% water extract, of a rosmarinic acid comprising plant material.

In accordance with a preferred embodiment of the invention, the composition comprises rosmarinic acid in the form of an aqueous extract, preferably a 100% water extract, from Perilla, preferably from Perilla seed, more preferably from Perilla frutescens (L.) Britton, most preferably from Perilla frutescens (L.) Britton seed, wherein the extraction was performed at a temperature of more than 60°C, preferably more than 80°C, most preferably more than 95°C.

In accordance with a preferred embodiment of the invention, the composition comprises rosmarinic acid in the form of an extract, preferably an aqueous extract, more preferably a 100% water extract, wherein the extract comprises less than 0.1 wt.% myristicine, based on the total weight of plant derived component or based on total dry solids weight, preferably less than 0.01 wt.% myristicine.

Rosmarinic acid containing plant extracts may typically comprise one, two, three, four or five additional active ingredients selected from the group consisting of vicenin-2, perilloside A, perilloside E, trihydroxyflavones, scutellarin, caffeic acid, prunasin, luteolin, chrysoeriol, apigenin, shisonin, scutellarein, coumaroyl tartaric acid, linolenic acid, linoleic acid, oleic acid, stearic acid, and palmitic acid.

In a preferred embodiment of the invention, the composition comprises a rosmarinic acid containing plant extract, having a rosmarinic acid level of at least 0.01 wt.%, based on the weight of the rosmarinic acid containing plant extract essentially free of extraction solvent, e.g. at least 0.05 wt.%, at least 0.1 wt.%, at least 0.5 wt.%, or at least 2 wt.%. A suitable way to determine the rosmarinic acid content is by high performance liquid chromatography (HPLC) using a Develosil HG-5 column (Nomura Chemical Co., Ltd., Aichi, Japan) with solvents A (0.1 % v/v trifluoroacetic acid [TFA] in distilled water) and B (0.1 % v/v TFA in acetonitrile) under the following conditions: 10%-50% linear gradient of A in B; flow rate of 0.8 ml/min; and detection at 280 nm.

In a preferred embodiment of the invention, the composition comprises a rosmarinic acid containing plant extract obtainable by aqueous extraction, preferably by extraction with water as the sole extraction solvent, referred to herein as‘100% water extraction’, performed in such a way that an extract is produced that, excluding any extraction solvent, is from 1/6 - 1/4 of the (dry) weight of the plant material before extraction.

In a preferred embodiment of the invention, the composition comprises a rosmarinic acid containing plant extract obtainable by a method comprising the steps of: a) providing Perilla plant material, preferably Perilla frutescens (L.) Britton seed; b) preferably macerating or grinding the plant material provided in step a);

c) performing an aqueous, preferably a 100% water extraction, preferably at a temperature of more than 95°C;

d) concentrating the extract, preferably at a temperature not exceeding 95°C, preferably not exceeding 85°C; and

e) drying, preferably spray-drying, the concentrated extract.

Rosmarinic acid containing extracts suitable for use in the context of the present invention, and the production thereof, have been described in the prior art, e.g. in

• Chen M-L, Wu C-H, Hung L-S, Lin B-F. Ethanol Extract of Perilla frutescens Suppresses Allergen-Specific Th2 Responses and Alleviates Airway Inflammation and Hyperreactivity in Ovalbumin-Sensitized Murine Model of Asthma. Evidence-based Complementary and Alternative Medicine : eCAM. 2015;2015:324265. doi: 10.1155/2015/324265;

• Jun, Hyun-ll, et al. "Structural characterization of phenolic antioxidants from purple perilla (Perilla frutescens var. acuta) leaves." Food chemistry 148 (2014): 367-372. Rosmarinic acid containing extracts suitable for use in the context of the present invention are available commercially, e.g. from the company“EURL Natural” in France under the reference“Perilla seed extract 4/1 (aldehyde chemotype)”.

As will be evident to those skilled in the art, on the basis of the present teachings, preferred embodiments are provided wherein an extract, such as the Perilla extracts as defined herein, is incorporated in the composition as a source of both vicenin-2 as well as rosmarinic acid.

Clerodane diterpenoids

In particularly preferred embodiments of the invention, compositions as defined herein are provided, further comprising one or more clerodane diterpenoids, preferably one or more clerodadienols.

Clerodadienols are naturally occurring diterpenes which have a cleroda-x, 14-dien- 13-ol skeleton. The clerodadienol skeleton has the following molecular structure:

Clerodadienols occur naturally in plants and herbs, such as Vitex agnus-castus, also known as the chastetree.

Clerodadienols may be obtained by extraction or isolation from a natural source or by chemical synthesis. In a preferred embodiment, the compositions of the invention comprise one or more clerodadienols in the form of an extract. In a preferred embodiment, the compositions of the invention comprise one or more clerodadienols in the form of an extract from a plant material derived from Vitex Agnus-Castus. The plant material preferably comprises or consists of fruit, leaves, flowers and/or seeds preferably fruit and/or leaf, most preferably fruit. In a particularly preferred embodiment of the invention, the composition comprises one or more clerodadienols in the form of a Vitex Agnus- Castus extract, preferably a Vitex Agnus-Castus fruit extract. Suitable extracts can be produced with polar solvents, such as with water, with alcohols, such as methanol, ethanol and mixtures thereof, or with water-alcohol mixtures. In preferred embodiments the extract is produced with a solvent having a relative polarity of more than 0.5, such as more than 0.6 or more than 0.7.

Preferred extracts can be produced with water, alcohol, such as methanol, ethanol, propanol or mixtures thereof, or water-alcohol mixtures, preferably with a level of alcohol within the range of 10-95 %(v/v), 30-90 %(v/v) or 60-80 %(v/v) as the extraction solvent. In preferred embodiments the extract is produced with water, methanol, ethanol or water- ethanol or water-methanol mixtures. In more preferred embodiments, the extract is produced with water, ethanol, or water-ethanol mixtures. Most preferably, the extract is produced with a water-ethanol mixture.

In some embodiments the extract is produced with a water-ethanol mixture with a level of ethanol within the range of 20-90 %(v/v), preferably within the range of 40-90 %(v/v), preferably within the range of 60-80 %(v/v), preferably within the range of 65-75 %(v/v).

Highly preferred extracts can be produced with water as the sole/main extraction solvent.

Hence, in accordance with a preferred embodiment of the invention, the composition comprises one or more clerodadienols in the form of an aqueous extract, preferably a 100% water extract of a clerodadienol comprising plant material as described above. In an embodiment of the invention, a composition as defined herein is provided comprising an aqueous extract, preferably a 100% water extract of a clerodadienol comprising plant material.

In accordance with a preferred embodiment of the invention, the composition comprises one or more clerodadienols in the form of an aqueous extract, preferably a 100% water extract which is a Vitex agnus-castus extract, preferably a Vitex agnus-castus fruit extract, wherein the extraction was performed at a temperature of more than 60°C, preferably more than 80°C, most preferably more than 95°C.

Clerodadienol containing plant extracts may typically comprise one, two, three, four or five additional active ingredients selected from the group consisting of limolene, cineole, pinene, sabinene, aucubin, agnoside, casticin, kaempferol, quercetagetin, orientin, isovitexin, oileic acid, linolenic acid, palmitic acid and stearic acid.

In a preferred embodiment of the invention, the composition comprises a clerodadienol containing plant extract, having a clerodadienol level of at least 0.001 wt.%, based on total essential oil weight, e.g. at least 0.005 wt.%, at least 0.01 wt.%, at least 0.05 wt.%, at least 0.1 wt.%, at least 0.5 wt.% or at least 1 wt.%. In a preferred embodiment of the invention, the composition comprises a clerodadienol containing plant extract obtainable by aqueous extraction, preferably by extraction with water as the sole extraction solvent (referred to herein as a‘100% water extraction’), performed in such a way that an extract is produced that, excluding any extraction solvent, is from 1/5 - 1/3 of the (dry) weight of the plant material before extraction.

In a preferred embodiment of the invention, the composition comprises a cloredadienol containing plant extract obtainable by a method comprising the steps of: a) providing Vitex agnus-castus plant material, preferably Vitex agnus-castus fruit; b) macerating or grinding the plant material provided in step a);

c) performing an aqueous, preferably a 100% water extraction, preferably at a temperature of more than 95°C;

d) concentrating the extract, preferably at a temperature not exceeding 95°C, preferably not exceeding 85°C; ande) drying, preferably spray-drying, the concentrated extract.

Extracts suitable for use in the context of the present invention, and the production thereof, have been described in the prior art, e.g. in

• Hoberg et al, 1999 (Am J Physiol 1989; R276-80. Hoberg E, Orjala J, Meier B, Sticher O. Diterpenoids from the fruits of Vitex agnus castus.)

• Chen S-N, Friesen JB, Webster D, et al. Phytoconstituents from Vitex agnus- castus fruits. Fitoterapia. 2011 ;82(4):528-533.

Clerodadienol containing extracts suitable for use in the context of the present invention are available commercially, e.g. from the company“Plantex S.A.” in France under the reference“Chaste tree dry extract PR449”.

Crocin

In particularly preferred embodiments of the invention, compositions as defined herein are provided further comprising crocin.

Crocin is a naturally occurring compound belonging to the class of carotenoids. It has CAS Registry Number 42553-65-1. The Systematic (lUPAC) name is Bis[(2S,3R,4S,5S,6R)-3,4,5-trihydroxy-6-({[(2R,3R,4S,5S,6R)- 3,4,5-trihydroxy-6- (hydroxymethyl)tetrahydro-2H-pyran-2-yl]oxy}methyl)tetrahydr o-2H-pyran-2-yl]

(2E,4E,6E,8E,10E,12E,14E)-2,6,11 ,15-tetramethyl-2,4,6,8,10,12,14- hexadecaheptaenedioate). Crocin has the following molecular structure: Crocin is the diester formed from the disaccharide gentiobiose and the dicarboxylic acid crocetin. Other monoglycosyl or diglycosyl esters of crocetin are known and often found together with crocin. The group of monoglycosyl or diglycosyl esters of crocetin are referred to as“crocins”.

Crocins occur naturally in various plants and herbs, such as Gardenia jasminoides and crocus sativus. Crocin is a non-volatile organic compound contributing to the red colour of saffron, which are stigma of crocus sativus. Together, the monoglycosyl or diglycosyl esters of crocetin constitute about 10% of saffron.

For the purposes of the present invention, crocins may be obtained by extraction or isolation from a natural source or by chemical synthesis. In a preferred embodiment, the compositions of the invention comprise one or more crocins, preferably crocin in the form of an extract. In a preferred embodiment, the compositions of the invention comprise one or more crocins, preferably crocin in the form of an extract from a plant material derived from Gardenia jasminoides or crocus sativus, preferably from crocus sativus, more preferably from Crocus sativus (L.) Iridaceae. The plant material may consist of the entire plant, but preferably comprises or consists of the plant devoid of root, preferably comprises or consists of leaves and flowers, preferably comprises or consists of flowers, preferably comprises or consists of stigma.

In a particularly preferred embodiment of the invention, the composition comprises one or more crocins, preferably crocin in the form of a Crocus sativus extract, preferably a Crocus sativus leaf or flower extract, more preferably a Crocus sativus flower extract, most preferably a Crocus sativus stigma extract such as a Crocus sativus (L.) Iridaceae stigma extract. In an embodiment of the invention, the composition comprises one or more crocins, preferably crocin in the form of a Gardenia jasminoides extract, preferably a Gardenia jasminoides fruit extract.

Suitable extracts can be produced with polar solvents, such as with water, methanol, ethanol, acetonitrile, diethylether and mixtures thereof. In embodiments the extract is produced with a solvent having a relative polarity of more than 0.5, such as more than 0.6 or more than 0.7.

In preferred embodiments the extract is produced with water, methanol, ethanol, a water-ethanol mixture or a water-methanol mixture. In more preferred embodiments, the extract is produced with water, water-ethanol, or water-methanol mixtures. Most preferably, the extract is produced with water-ethanol or water-methanol mixtures.

In embodiments the extract is produced with a water-methanol or a water-ethanol mixture with a level of alcohol within the range of 10-60 %(v/v), preferably within the range of 20-40 %(v/v), preferably within the range of 25-35 %(v/v), preferably within the range of 28-32 %(v/v).

In embodiments the extract is produced using 30-70 gram plant material per liter extraction solvent, preferably 40-60 g/l, most preferably 45-55 g/l.

In embodiments the extract is produced using microsimultaneous hydro distillation- extraction (MSDE) and/or ultrasound-assisted extraction (USE). In embodiments, the extract is produced with supercritical carbon dioxide.

In preferred embodiments, the plant material is heated prior to extraction, for example at a temperature above 50°C, preferably above 70°C, such as 80°C for at least 1 minute, preferably at least 20 minutes, preferably at least 1 hour.

Hence, in accordance with a preferred embodiment of the invention, the composition comprises one or more crocins, preferably crocin in the form of a water- alcohol extract of a crocin comprising plant material. In an embodiment of the invention, a composition as defined herein is provided comprising a water, a water-ethanol or a water- methanol extract, preferably a water-ethanol extract of a crocin containing plant material.

In accordance with a preferred embodiment of the invention, the composition comprises crocin in the form of a water-ethanol extract produced with a water-ethanol mixture with a level of alcohol within the range of 10-60 %(v/v), preferably within the range of 20-40 %(v/v), preferably within the range of 25-35 %(v/v), preferably within the range of 28-32 %(v/v), from Crocus sativus, preferably from Crocus sativus leaf or flower, more preferably from Crocus sativus flower, most preferably from Crocus sativus stigma, such as from Crocus sativus (L.) Iridaceae stigma. In accordance with a preferred embodiment of the invention, the composition comprises crocin in the form of a water-ethanol extract wherein the extraction was performed at a temperature of less than 90°C, preferably less than 60°C, most preferably less than 40°C.

The one or more crocins, preferably crocin containing plant extracts may typically comprise one, two, three, four or five additional compounds selected from the group consisting of safranal, picrocrocin, kaempherol, further crocins, crocetin, pinene, cineol, riboflavin, quercetin, lycopene, alpha carotene, beta carotene, zeaxanthin, phytoene, and phytofluene.

In a preferred embodiment of the invention, the composition comprises one or more crocins, preferably a crocin containing plant extract having a total crocins content of at least 0.1 wt.%, based on total weight of the extract after solvent evaporation, e.g. at least 0.5 wt.%, at least 1 wt.% or at least 2 wt.% determined using UHPLC, preferably determined using UHPLC performed using a binary gradient of solvents A and B, wherein solvent A consists of formic acid in acetonitrile, solvent B consists of formic acid in water, and using detection at 440 nm, on a sample prepared by stirring the crocin containing plant extract in a 60%(v/v) ethanol in water solution for at least an hour.

In a preferred embodiment of the invention, the composition comprises a crocin containing plant extract obtainable by water-ethanol extraction employing a water-ethanol mixture with a level of alcohol within the range of 10-60 %(v/v), preferably within the range of 20-40 %(v/v), preferably within the range of 25-35 %(v/v), preferably within the range of 28-32 %(v/v) as the extraction solvent, wherein the extraction is performed in such a way that an extract is produced that, excluding any extraction solvent, is from 1/6 - 1/4 of the (dry) weight of the plant material before extraction.

In a preferred embodiment of the invention, the composition comprises a crocin containing plant extract obtainable by a method comprising the steps of:

a) providing Crocus sativus plant material, preferably a Crocus sativus leaf or flower, more preferably Crocus sativus flower, most preferably Crocus sativus stigma such as a Crocus sativus (L.) Iridaceae stigma;

b) preferably macerating or grinding the plant material provided in step a);

c) performing an extraction with a water-ethanol mixture with a level of alcohol within the range of 10-60 %(v/v), preferably within the range of 20-40 %(v/v), preferably within the range of 25-35 %(v/v), preferably within the range of 28-32 %(v/v), preferably at a temperature of less than 90°C, preferably less than 60°C, most preferably less than 40°C.; d) concentrating the extract, preferably at a temperature not exceeding 70°C, preferably not exceeding 60°C, preferably not exceeding 45°C; and

e) drying, preferably freeze-drying, the concentrated extract. Extracts suitable for use in the context of the present invention, and the production thereof, have been described in the prior art, e.g. in

• Li, N., Lin, G., Kwan, Y.W., Min, Z.D., 1999. Simultaneous quantification of five major biologically active ingredients of saffron by high-performance liquid chromatography. J. Chromatogr. A 849, 349-355.

• Alonso, G.L., Salinas, M.R., Garijo, J., Sanchez-Fernandez, M.A., 2001. Composition of crocins and picrocrocin from Spanish saffron (Crocus sativus L). J. Food Qual. 24, 219-233.

• Alam, Pravej & F Elkholy, Shereen & Hosokawa, Munetaka & A Mahfouz, Sabry & A Sharaf-eldin, Mahmoud. (2016). Simultaneous extraction and rapid HPLC based quantification of crocin and safranal in Saffron (Crocus sativus L.). International Journal of Pharmacy and Pharmaceutical Sciences. 8. 224-227;

• Tarantilis, Petros A., Moschos Polissiou, and Michel Manfait. "Separation of picrocrocin, cis-trans-crocins and safranal of saffron using high-performance liquid chromatography with photodiode-array detection." Journal of Chromatography A 664.1 (1994): 55-61 ;

• Hadizadeh, F., S. A. Mohajeri, and M. Seifi. "Extraction and purification of crocin from saffron stigmas employing a simple and efficient crystallization method." Pakistan Journal of Biological Sciences 13.14 (2010): 691.

Crocin containing extracts suitable for use in the context of the present invention are available commercially, e.g. from the company“Activ’lnside” in France under the reference“Safr’inside PR-0033”.

Safranal

In particularly preferred embodiments of the invention, compositions as defined herein are provided further comprising safranal.

Safranal is a naturally occurring cyclical terpenic aldehyde. It has CAS Registry Number 116-26-7. The Systematic (lUPAC) name is 2,6,6-trimethyl-1 ,3-cyclohexadiene- 1-carboxaldehyde. Safranal has the following molecular structure:

safranal Safranal occurs naturally in various plants, such as aspalathus linearis, camellia sinensis, crocus sativus, ficus carica and lyceum chinense, cuminum cyminum, centaurea sibthorpii, centaurea amanicola, centaurea consanguinea, erodium cicutarium, calycopteris floribunda, sambucus nigra, citrus limon, achillea distans. Safranal is the most abundant chemical in saffron essential oil and accounts for 60-70% of the volatile fraction.

For the purposes of the present invention, safranal may be obtained by extraction or isolation from a natural source or by chemical synthesis. In a preferred embodiment, the compositions of the invention comprise safranal in the form of an extract. In a preferred embodiment, the compositions of the invention comprise safranal in the form of an extract from a plant material derived from one or more of the plant species recited here above, preferably from the group consisting of as aspalathus linearis, camellia sinensis, crocus sativus, ficus carica and lyceum chinense, preferably from Crocus sativus more preferably from Crocus sativus (L.) Iridaceae. The plant material may consist of the entire plant, but preferably comprises or consists of the plant devoid of root, preferably comprises or consists of leaves and flowers, preferably comprises or consists of flowers, preferably comprises or consists of stigma. In a particularly preferred embodiment of the invention, the composition comprises safranal in the form of a Crocus sativus extract, preferably a Crocus sativus leaf or flower extract, more preferably a Crocus sativus flower extract, most preferably a Crocus sativus stigma extract such as a Crocus sativus (L.) Iridaceae stigma extract. Suitable extracts can be produced with polar solvents, such as with water, methanol, ethanol, acetonitrile and mixtures thereof. In embodiments the extract is produced with a solvent having a relative polarity of more than 0.5, such as more than 0.6 or more than 0.7.

In preferred embodiments the extract is produced with water, methanol, ethanol or water-ethanol or water-methanol mixtures. In more preferred embodiments, the extract is produced with water, water-ethanol, or water-methanol mixtures. Most preferably, the extract is produced with water-ethanol or water-methanol mixtures.

In embodiments the extract is produced with a water-methanol or a water-ethanol mixture with a level of alcohol within the range of 10-60 %(v/v), preferably within the range of 20-40 %(v/v), preferably within the range of 25-35 %(v/v), preferably within the range of 28-32 %(v/v).

In embodiments the extract is produced using 30-70 gram plant material per liter extraction solvent, preferably 40-60 g/l, most preferably 45-55 g/l.

In embodiments the extract is produced using microsimultaneous hydro distillation- extraction (MSDE) and/or ultrasound-assisted extraction (USE). In embodiments, the extract is produced with supercritical carbon dioxide. In preferred embodiments, the plant material is heated prior to extraction, for example at a temperature above 50°C, preferably above 70°C, such as 80°C for at least 1 minute, preferably at least 20 minutes, preferably at least 1 hour.

Hence, in accordance with a preferred embodiment of the invention, the composition comprises safranal in the form of a water-alcohol extract of a safranal comprising plant material. In an embodiment of the invention, a composition as defined herein is provided comprising a water, a water-ethanol or a water-methanol extract, preferably a water-ethanol extract of a safranal containing plant material.

In accordance with a preferred embodiment of the invention, the composition comprises safranal in the form of a water-ethanol extract produced with a water-ethanol mixture with a level of alcohol within the range of 10-60 %(v/v), more preferably within the range of 20-40 %(v/v), still more preferably within the range of 25-35 %(v/v), most preferably within the range of 28-32 %(v/v), from Crocus sativus, preferably from Crocus sativus leaf or flower, more preferably from Crocus sativus flower, most preferably from Crocus sativus stigma, such as Crocus sativus (L.) Iridaceae stigma. In accordance with a preferred embodiment of the invention, the composition comprises safranal in the form of a water-ethanol extract produced, wherein the extraction was performed at a temperature of less than 90°C, preferably less than 60°C, most preferably less than 40°C.

The safranal containing plant extracts may typically comprise one, two, three, four or five additional compounds selected from the group consisting of picrocrocin, kaempherol, crocins such as crocin, crocetin, pinene, cineol, riboflavin, quercetin, lycopene, alpha carotene, beta carotene, zeaxanthin, phytoene, and phytofluene.

In a preferred embodiment of the invention, the composition comprises a safranal containing plant extract, having a safranal content of at least 0.1 %, based on total volatiles content, e.g. at least 1 %, at least 5 %, at least 10 %, at least 30 %, at least 50 % or at least 60 %. A suitable method to determine the safranal content based on total volatiles content is using gas chromatography-mass spectrometry, for example using the method described in Eleonora Urbani, Francesca Blasi, Claudia Chiesi, Angela Maurizi & Lina Cossignani (2015) Characterization of Volatile Fraction of Saffron from Central Italy (Cascia, Umbria), International Journal of Food Properties, 18: 10, 2223-2230.

In a preferred embodiment of the invention, the composition comprises a safranal containing plant extract, having a safranal content of at least 0.1 wt.%, based on total weight of the extract after solvent evaporation, e.g. at least 0.5 wt.%, at least 1 wt.% or at least 1.5 wt.% wherein the safranal content is determined in accordance with ISO 3632- 2:2010. In a preferred embodiment of the invention, the composition comprises a safranal containing plant extract obtainable from a water-ethanol extraction employing a water- ethanol mixture with a level of alcohol within the range of 10-60 %(v/v), preferably within the range of 20-40 %(v/v), preferably within the range of 25-35 %(v/v), preferably within the range of 28-32 %(v/v) as the extraction solvent, wherein the extraction is performed in such a way that an extract is produced that, excluding any extraction solvent, is from 1/6 - 1/4 of the (dry) weight of the plant material before extraction.

In a preferred embodiment of the invention, the composition comprises a safranal containing plant extract obtainable by a method comprising the steps of:

a) providing Crocus sativus plant material, preferably a Crocus sativus leaf or flower, more preferably Crocus sativus flower, most preferably Crocus sativus stigma such as a Crocus sativus (L.) Iridaceae stigma;

b) preferably macerating or grinding the plant material provided in step a);

c) performing an extraction with a water-ethanol mixture with a level of alcohol within the range of 10-60 %(v/v), preferably within the range of 20-40 %(v/v), preferably within the range of 25-35 %(v/v), preferably within the range of 28-32 %(v/v), preferably at a temperature of less than 90°C, preferably less than 60°C, most preferably less than 40°C; d) concentrating the extract, preferably at a temperature not exceeding 70°C, preferably not exceeding 60°C, preferably not exceeding 45°C; and

e) drying, preferably freeze-drying, the concentrated extract.

Extracts suitable for use in the context of the present invention, and the production thereof, have been described in the prior art, e.g. in

• M. Kosar, B. Demirci, F. Goger, I. Kara & K.H.C. Baser (2017) Volatile composition, antioxidant activity, and antioxidant components in saffron cultivated in Turkey, International Journal of Food Properties, 20:sup1 , S746-S754

• A.V Loskutov, C.W Beninger, G.L Hosfield, K.C Sink, Development of an improved procedure for extraction and quantitation of safranal in stigmas of Crocus sativus L. using high performance liquid chromatography, Food Chemistry, Volume 69, Issue 1 , 2000, Pages 87-95;

• Alam, Pravej & F Elkholy, Shereen & Hosokawa, Munetaka & A Mahfouz, Sabry & A Sharaf-eldin, Mahmoud. (2016). Simultaneous extraction and rapid HPLC based quantification of crocin and safranal in Saffron (Crocus sativus L.). International Journal of Pharmacy and Pharmaceutical Sciences. 8. 224-227;

• Tarantilis, Petros A., Moschos Polissiou, and Michel Manfait. "Separation of picrocrocin, cis-trans-crocins and safranal of saffron using high-performance liquid chromatography with photodiode-array detection." Journal of Chromatography A 664.1 (1994): 55-61 ;

• Kanakis, Charalabos D., et al. "Qualitative determination of volatile compounds and quantitative evaluation of safranal and 4-hydroxy-2, 6, 6-trimethyl-1 -cyclohexene- 1 - carboxaldehyde (HTCC) in Greek saffron." Journal of agricultural and food chemistry 52.14 (2004): 4515-4521.

• Lozano, P., et al. "A non-destructive method to determine the safranal content of saffron (Crocus sativus L.) by supercritical carbon dioxide extraction combined with high- performance liquid chromatography and gas chromatography." Journal of Biochemical and Biophysical Methods 43.1-3 (2000): 367-378.

Safranal containing extracts suitable for use in the context of the present invention are available commercially, e.g. from the company“Activ’lnside” in France under the reference“Safr’inside PR-0033”.

As will be evident to those skilled in the art, on the basis of the present teachings, preferred embodiments are provided wherein an extract, such as the safranal extracts as defined herein, is incorporated in the composition as a source of both crocin as well as safranal.

As will be evident to those skilled in the art, on the basis of the present teachings, preferred embodiments are provided wherein an extract, such as the Crocus sativus extracts as defined herein, is incorporated in the composition as a source of both crocin as well as safranal.

Apigenin

In particularly preferred embodiments of the invention, compositions as defined herein are provided comprising apigenins.

Apigenin, 4',5,7-trihydroxyflavone is naturally occurring compound belonging to the class of flavones. Apigenin has the CAS Registry Number 520-36-5 and systematic (lUPAC) name 5,7-Dihydroxy-2-(4-hydroxyphenyl)-4H-1-benzopyran-4-one. Common synonyms include Apigenine; Chamomile; Apigenol; Spigenin; Versulin; 4', 5, 7- Trihydroxyflavone and C.l. Natural Yellow 1. Apigenin has the following molecular structure: Apigenin In natural conditions, apigenin predominantly occurs in the form of an apigenin glycoside, wherein apigenin is bound to a sugar through a glycosidic bond. As used herein, the term “apigenin” refers to the aglycone of apigenin glycosides. The plural form, i.e.“apigenins”, is used herein to generically denote apigen and the apigenin glycosides, as will be understood by those skilled in the art.

Apigenin and apigenin glycosides occur naturally in various plants, such as plants in the genera artemisia, perilla, urtica, passiflora, camelia, cayaponia, colocasia, desmodium, hordeum, origanum, ocimum, jatropha, parkinsonia, peperomia, piheranthos, centaurea, indigo, bomba, lychnophera, asplenium, chinotto, citrus, viola, trigonella, lamiacea, labiatae, lavandula, nipponanthemum, abrus, santalum, oryza, scleropyrum, tulsi, indigofera, bombax, glinus, lychnophora, urticaceae, rosales, malpighiales, thymus, prunus, camellia, olea, brassica, apium, petroselinum, matricaria, chamaemelum, and chrystanthemum.

Plants of particular interest as an apigenin or apigenin glycoside source are vitex agnus-castus, petroselinum crispum, apium graveolens, citrus paradisi, citrus maxima, perilla frutescens, Matricaria chamomilla, chrysanthemum morifolium and chamaemelum nobile, and in particular matricaria recutita (also known as Matricaria chamomilla); chamaemelum nobile; and chrysanthemum morifolium. Apigenin or apigenin glycosides are particularly abundant in the flowers of chamomile plants, constituting up to 68% of total flavonoids. In most camomille plant varieties, apigenin-7-O-glucoside is the dominant form and is present in about 100-500mg/100g flowers, while apigenin is present in an amount of about 5-25mg/100g flowers.

In preferred embodiments, the compositions of the invention comprise apigenin or an apigenin glycoside, preferably an apigenin glycoside selected from the group consisting of apigenin 7-O-apioglucoside (apiin), apigenin 7-O-glucoside (apigetrin), apigenin 8-C- glucoside (vitexin), apigenin 6-C-glucosid (isovitexin), apigenin 7-O-neohesperidoside (rhoifolin), or apigenin 6-C-glucoside 8-C-arabinoside (schaftoside), preferably apigenin 7-O-apioglucoside (apiin) or apigenin 7-O-glucoside (apigetrin), most preferably apigenin 7-O-glucoside.

In natural conditions, the apigenin or apigenin glycoside commonly exists in an acetylated form, such as a monoacetylated or diacetylated form. In embodiments, the compositions and extracts described herein comprise acetylated apigenin or apigenin glycoside.

Apigenin and/or apigenin glycosides may be obtained by extraction or isolation from a natural source or by chemical synthesis.

In a preferred embodiment, the compositions of the invention comprise apigenin or an apigenin glycoside in the form of an extract. In a preferred embodiment, the compositions of the invention comprise apigenin or an apigenin glycoside in the form of an extract from a plant material derived from a plant species in a genus selected from the group consisting of artemisia, perilla, urtica, passiflora, camelia, cayaponia, colocasia, desmodium, hordeum, origanum, ocimum, jatropha, parkinsonia, peperomia, piheranthos, centaurea, indigo, bomba, lychnophera, asplenium, chinotto, citrus, viola, trigonella, lamiacea, labiatae, lavandula, nipponanthemum, abrus, santalum, oryza, scleropyrum, tulsi, indigofera, bombax, glinus, lychnophora, urticaceae, rosales, malpighiales, thymus, prunus, camellia, olea, brassica, apium, petroselinum, matricaria, chamaemelum, and chrystanthemum, preferably the compositions of the invention comprise apigenin or an apigenin glycoside in the form of an extract from a plant material derived from a plant species in a genus selected from the group consisting of thymus, prunus, camellia, olea, brassica, apium, petroselinum, matricaria, chamaemelum and chrystanthemum. In a preferred embodiment, the compositions of the invention comprise apigenin or an apigenin glycoside in the form of an extract from plant material derived from vitex agnus-castus, petroselinum crispum, apium graveolens, citrus paradisi, citrus maxima, perilla frutescens, Matricaria chamomilla, chrysanthemum morifolium or chamaemelum nobile, preferably the compositions of the invention comprise apigenin or an apigenin glycoside in the form of an extract from plant material derived from matricaria recutita (also known as Matricaria chamomilla), chamaemelum nobile, or chrysanthemum morifolium.

The plant material preferably comprises or consists of leaves and flowers, preferably flowers, preferably the ray florets.

Hence, in preferred embodiments the extract is a flower extract, preferably an extract of the flowers, preferably the ray florets of matricaria recutita (also known as Matricaria chamomilla), chamaemelum nobile, or chrysanthemum morifolium, preferably an extract of the flowers, preferably the ray florets of matricaria recutita (also known as Matricaria chamomilla). Suitable extracts can be produced with polar solvents, such as with water, methanol, ethanol and mixtures thereof. In embodiments the extract is produced with a solvent having a relative polarity of more than 0.5, such as more than 0.6 or more than 0.7 or more than 0.8.

Preferred extracts can be produced with water, methanol, ethanol, propanol or mixtures thereof, preferably with a level of alcohol within the range of 10-60 %(v/v), preferably within the range of 20-40 %(v/v), preferably within the range of 25-35 %(v/v), preferably within the range of 28-32 %(v/v). In preferred embodiments the extract is produced with water, methanol, ethanol or water-ethanol or water-methanol mixtures. In more preferred embodiments, the extract is produced with water, ethanol, or water- methanol mixtures. Most preferably, the extract is produced with water-ethanol mixtures.

In embodiments the extract is produced with a water-ethanol mixture with a level of ethanol within the range 10-60 %(v/v), preferably within the range of 20-40 %(v/v), preferably within the range of 25-35 %(v/v), preferably within the range of 28-32 %(v/v).

Hence, in accordance with a preferred embodiment of the invention, the composition comprises apigenin or an apigenin glycoside in the form of a water, methanol, ethanol, propanol or mixtures thereof of an apigenin or an apigenin glycoside comprising plant material, preferably a water-ethanol extract. In an embodiment, of the invention, a composition as defined herein is provided comprising a water, methanol, ethanol or water- ethanol or water-methanol extract of an apigenin or an apigenin glycoside containing plant material, preferably a water-ethanol extract.

In embodiments, the extract is rich in apigenin-7-O-glucoside and contains more apigenin-7-O-glucoside than apigenin. In embodiments the extract is rich in apigenin-7-O- glucoside and more than 20%, preferably more than 30%, more than 50%, more than 70% of the apigenin and apigenin-glycoside content is apigenin-7-O-glucoside. Such apigenin- 7-O-glucoside rich extracts can be produced with water, ethanol or methanol as the extraction medium, preferably water or ethanol.

In embodiments the extract is rich in apigenin and contains more apigenin than apigenin-7-O-glucoside. In embodiments the extract is rich in apigenin and more than 10%, preferably more than 20%, more than 50%, more than 70% of the apigenin and apigenin-glycoside content is apigenin. Such apigenin rich extracts can be produced with water-ethanol or water-methanol mixtures, preferably water-ethanol mixtures, preferably with a level of alcohol lower than 50 %(v/v), preferably lower than 40 %(v/v), preferably lower than 30 %(v/v). Although the flavonoid yield of such extracts rich in apigenin may be lower than the flavonoid yield of extracts rich in apigenin-7-O-glucoside, the relative increase of apigenin content may be desirable since apigenin is believed to be more physiologically active than apigenin glycosides.

In accordance with a preferred embodiment of the invention, the composition comprises apigenin or apigenin-glycoside in the form of a water-ethanol extract produced with a water-ethanol mixture with a level of alcohol within the range of 10-60 %(v/v), preferably within the range of 20-40 %(v/v), more preferably within the range of 25-35 %(v/v), most preferably within the range of 28-32 %(v/v), from a flower, preferably a ray floret, of matricaria recutita (also known as Matricaria chamomilla), chamaemelum nobile, or chrysanthemum morifolium, preferably of matricaria recutita.

The apigenin or apigenin-glycoside containing plant extracts, may typically comprise one, two, three, four or five additional active ingredients selected from the group consisting of hyperoside, herniarin, umbelliferone, chlorogenic acid, caffeic acid, luteolin, luteolin-7-O-glucoside, quercetin, rutin, and naringenin.

The apigenin or apigenin-glycoside containing plant extracts, may typically be prepared by milling, crushing or grinding plant material as described herein earlier, and suspending the plant material in the extraction medium, for example at a concentration of 0.01-50 %(w/v) of fresh plant material, preferably 0.1-20 %(w/v), preferably 0.5-10 %(w/v), preferably 1-7 %(w/v), preferably 2-6 %(w/v).

In a preferred embodiment of the invention, the composition comprises an apigenin or apigenin-glycoside containing plant extract, having a total amount of apigenin and apigenin-glycosides of at least 0.1 wt.%, based on the weight of the apigenin or apigenin- glycoside containing plant extract essentially free of extraction solvent, e.g. at least 0.5 wt.%, at least 1 wt.%, at least 1.5 wt.%, at least 2 wt.% or at least 5 wt.%, preferably as determined in accordance with the method described in the USP chamomile monograph.

In a preferred embodiment of the invention, the composition comprises an apigenin or apigenin-glycoside containing plant extract obtainable by a method comprising the steps of:

a) providing Matricaria recutita (also known as Matricaria chamomilla), plant material, preferably Matricaria recutita flowers, preferably Matricaria recutita ray florets;

b) preferably macerating or grinding the plant material provided in step a);

c) performing an extraction with a water-ethanol mixture with a level of alcohol within the range of 10-60 %(v/v), preferably within the range of 20-40 %(v/v), preferably within the range of 25-35 %(v/v), preferably within the range of 28-32 %(v/v), preferably at a temperature of less than 90°C;

d) concentrating the extract, preferably at a temperature not exceeding 70°C, preferably not exceeding 60°C, preferably not exceeding 45°C; and e) drying, preferably spray-drying, the concentrated extract.

Extracts suitable for use in the context of the present invention, and the production thereof, have been described in the prior art, e.g. in

• Srivastava JK, Gupta S. Extraction, Characterization, Stability and Biological Activity of Flavonoids Isolated from Chamomile Flowers. Molecular and cellular pharmacology. 2009; 1 (3): 138;

• EP2444061A1 ;

• EP0496230A1

• EP0330240A1 ;

• Chamomile: Industrial Profiles - Rolf Franke, Heinz Schilcher (2005).

Apigenin containing extracts suitable for use in the context of the present invention are available commercially, e.g. from the company“Evear extraction soilutions” in France under the reference“Chamomile dry extract 5% apigenin E2423A5”.

Vitamin D

In a preferred embodiment of the invention, the composition further comprises vitamin D. Vitamin D is a fat soluble vitamin that is rarely found naturally in food. It is not a true vitamin, but is a steroid prohormone that is produced in the skin by ultraviolet sunlight and converted by a series of hydroxylations to a biologically active steroid hormone metabolite. An active metabolite of vitamin D is calcitriol. As used herein,“vitamin D” comprises a group of, but not limited to, ergocalciferol (D2), cholecalciferol (D3), calcidiol (25 hydroxy vitamin D), or calcitriol (1 ,25 di hydroxy vitamin D). Because vitamin D is lipid soluble and potentially toxic, oral intakes of vitamin D greater than 1000 IU have not been advised. In a highly preferred embodiment of the invention, the composition further comprises vitamin D3.

Magnesium

In a preferred embodiment of the invention, the composition further comprises magnesium. Suitable magnesium sources may comprise any pharmaceutically acceptable inorganic or organic compound containing magnesium such as magnesium carbonate, magnesium hydroxide, magnesium gluconate, magnesium oxide, magnesium citrate or magnesium lactate; preferably magnesium carbonate or magnesium hydroxide, most preferably magnesium carbonate. Magnesium carbonate is preferably provided in the form of the dypingite mineral. Current guidelines in the US provide a recommended daily amount of magnesium of 300 - 400 mg (for adult women). It has been well established that magnesium contributes to increased hepatic metabolism. The present inventors believe that the increased hepatic effect of magnesium increases the sympathetic effects of the vicenin-2, as well as rosmarinic acid and allows for increased adsorption. Hence, in a highly preferred embodiment of the invention, the composition comprises magnesium in the form of magnesium carbonate.

Magnesium sources suitable for use in the context of the present invention are available commercially, e.g. from the company “Magnesia” in Germany under the reference“Magnesia 81811”.

It is to be understood that many or most of the pharmacologically and/or physiologically active ingredients as described herein can exist in the form of a pharmaceutically acceptable salt or solvate. Such forms will typically be equally suitable for use in the present invention. It is to be understood that it is within the scope of the present invention to include pharmaceutically acceptable salt forms, solvates or esters of any of the active ingredients recited herein in the compositions in addition to or instead of the corresponding ingredient in free acid or unsolvated form. Whenever, in this document, the amount of a certain ingredient is quantified, this refers to the amount of the active ingredient as such, excluding the weight of any counterion or solvated compounds that may be present (e.g. in a given extract), unless a specific salt is explicitly referred to (as is e.g. the case for magnesium carbonate).

In accordance with preferred embodiments of the invention compositions as defined herein are provided comprising:

• a combination of vicenin-2 and one or more further ingredients selected from the group consisting of rosmarinic acid, a clerodadienol, crocin, safranal, apigenin, apigenin-7-O- glucoside, vitamin D, and a magnesium source;

• a combination of vicenin-2, rosmarinic acid and one or more further ingredients selected from the group consisting of a clerodadienol, crocin, safranal, apigenin, apigenin-7-O-glucoside, vitamin D, and a magnesium source;

• a combination of vicenin-2, rosmarinic acid, a clerodadienol and one or more further ingredients selected from the group consisting of crocin, safranal, apigenin, apigenin- 7-O-glucoside, vitamin D, and a magnesium source;

• a combination of vicenin-2, rosmarinic acid, a clerodadienol, crocin and one or more further ingredients selected from the group consisting of safranal, apigenin, apigenin- 7-O-glucoside, vitamin D, and a magnesium source; • a combination of vicenin-2, rosmarinic acid, a clerodadienol, crocin, safranal and one or more further ingredients selected from the group consisting of apigenin, apigenin-7- O-glucoside, vitamin D, and a magnesium source;

• a combination of vicenin-2, rosmarinic acid, a clerodadienol, crocin, safranal, apigenin and one or more further ingredients selected from the group consisting of apigenin-7- O-glucoside, vitamin D, and a magnesium source;

• a combination of vicenin-2, rosmarinic acid, a clerodadienol, crocin, safranal, apigenin apigenin-7-O-glucoside and one or more further ingredients selected from the group consisting of vitamin D, and a magnesium source; or

• a combination of vicenin-2, rosmarinic acid, a clerodadienol, crocin, safranal, apigenin apigenin-7-O-glucoside, vitamin D, and a magnesium source.

Furthermore, in accordance with preferred embodiments of the invention, compositions as defined herein are provided comprising:

• a combination of Perilla frutescens seed extract and one or more further ingredients selected from the group consisting of Vitex agnus-castus fruit extract, Crocus sativus stigma extract, Matricaria chamomilla flower extract, vitamin D, and a magnesium source;

• a combination of Perilla frutescens seed extract and Vitex agnus-castus fruit extract and one or more further ingredients selected from the group consisting of Crocus sativus stigma extract, Matricaria chamomilla flower extract, vitamin D, and a magnesium source;

• a combination of Perilla frutescens seed extract, Vitex agnus-castus fruit extract, Crocus sativus stigma extract and one or more further ingredients selected from the group consisting of Matricaria chamomilla flower extract, vitamin D, and a magnesium source;

• a combination of Perilla frutescens seed extract, Vitex agnus-castus fruit extract, Crocus sativus stigma extract, Matricaria chamomilla flower extract and one or more further ingredients selected from the group consisting of vitamin D and a magnesium source; or

• a combination of Perilla frutescens seed extract, Vitex agnus-castus fruit extract, Crocus sativus stigma extract, Matricaria chamomilla flower extract, vitamin D, and a magnesium source.

In a preferred embodiment of the pharmaceutical compositions described herein, the weight to weight ratio of said Perilla extract to said Vitex agnus-castus extract is 50:1 to 1 :50, determined based on extract weights essentially free of extraction solvent, preferably 25:1 to 1 :25, more preferably 15:1 to 1 :15, most preferably 5:1 to 1 :1. In a preferred embodiment of the pharmaceutical composition described herein, the weight to weight ratio of said Perilla extract to said Crocus sativus extract is 50: 1 to 1 :50, determined based on extract weights essentially free of extraction solvent, preferably 25: 1 to 1 :25, more preferably 15:1 to 1 : 15, most preferably 5:1 to 1 : 1.

In a preferred embodiment of the pharmaceutical composition described herein, the weight to weight ratio of said Perilla extract to said Matricaria chamomilla extract is 50: 1 to 1 :50, determined based on extract weights essentially free of extraction solvent, preferably 25:1 to 1 :25, more preferably 10: 1 to 1 :10, most preferably 2: 1 to 1 :2.

The (unit) dosage forms

Compositions as defined herein are preferably provided in the form of a pharmaceutical formulation or a nutraceutical formulation, which may also be referred to as a food supplement or food supplement formulation. In preferred embodiments, the invention provides a pharmaceutical or nutraceutical formulation in the form of a so-called ‘unit dosage form’, in particular a unit dosage form that is suitable for oral administration. The term "unit dosage form" refers to a physically discrete unit of the pharmaceutical or nutraceutical formulation comprising a fixed, pre-determined dose of the pharmaceutically and/or physiologically active ingredient(s) in a form suitable for administration to a subject in need thereof.

In accordance with a preferred embodiment of the invention, a unit dosage form comprises vicenin-2 in an amount of 0.005 mg or more, preferably 0.01 mg or more, preferably 0.05 mg or more and/or in an amount of 10 mg or less, preferably 5 mg or less, preferably 1 mg or less.

In accordance with a preferred embodiment of the invention, a unit dosage form comprises rosmarinic acid in an amount of 0.005 mg or more, preferably 0.01 mg or more, preferably 0.05 mg or more and/or in an amount of 10 mg or less, preferably 5 mg or less, preferably 1 mg or less.

In accordance with a preferred embodiment of the invention, a unit dosage form comprises a clerodadienol in an amount of 0.005 mg or more, preferably 0.01 mg or more, preferably 0.05 mg or more and/or in an amount of 10 mg or less, preferably 5 mg or less, preferably 1 mg or less.

In accordance with a preferred embodiment of the invention, a unit dosage form comprises crocin in an amount of 0.01 mg or more, preferably 0.1 mg or more, preferably 0.4 mg or more and/or in an amount of 5 mg or less, preferably 3 mg or less, preferably 1.5 mg or less. In accordance with a preferred embodiment of the invention, a unit dosage form comprises safranal in an amount of 0.01 mg or more as determined in accordance with ISO 3632-2:2010, preferably 0.1 mg or more, preferably 0.2 mg or more and/or in an amount of 5 mg or less as determined in accordance with ISO 3632-2:2010, preferably 3 mg or less, preferably 1.5 mg or less.

In accordance with a preferred embodiment of the invention, a unit dosage form comprises apigenin or an apigenin glycoside in an amount of 0.1 mg or more as determined in accordance with the method described in the USP chamomile monograph, preferably 0.5 mg or more, preferably 1.5 mg or more and/or in an amount of 15 mg or less in accordance with the method described in the USP chamomile monograph, preferably 10 mg or less, preferably 4 mg or less.

In accordance with a preferred embodiment of the invention, a unit dosage form comprises vitamin D, preferably vitamin D3 in an amount of 0.01 mg or more, preferably 0.1 mg or more, preferably 1 mg or more and/or in an amount of 20 mg or less, preferably 10 mg or less, preferably 2 mg or less. In accordance with a more preferred embodiment of the invention, a unit dosage form comprises vitamin D, preferably vitamin D3 in an amount of 0.1 pg or more, preferably 0.6 pg or more, preferably 1 pg or more and/or in an amount of 40 pg or less, preferably 15 pg or less, preferably 4 pg or less. In accordance with a more preferred embodiment of the invention, a unit dosage form comprises vitamin D, preferably vitamin D3 in an amount corresponding to 4 IU or more, preferably 24 IU or more, preferably 40 IU or more and/or in an amount corresponding to 1200 IU or less, preferably 600 IU or less, preferably 160 I U or less.

In accordance with a preferred embodiment of the invention, a unit dosage form comprises a magnesium compound, preferably magnesium carbonate, preferably magnesium carbonate in the form of the dypingite mineral in an amount of 10 mg or more, preferably 100 mg or more, preferably 550 mg or more and/or in an amount of 2000 mg or less, preferably 1000 mg or less, preferably 650 mg or less.

In a particularly preferred embodiment of the invention a composition as defined herein is provided in unit dosage form comprising:

• Perilla frutescens seed extract in an amount of 5 mg or more, preferably 20 mg or more, preferably 30 mg or more and/or in an amount of 150 mg or less, preferably 75 mg or less, preferably 55 mg or less, such as 30 mg, 35 mg, 40 mg, 45 mg or 50 mg;

• Vitex agnus-castus fruit extract in an amount of 0.5 mg or more, preferably 2 mg or more, preferably 10 mg or more and/or in an amount of 100 mg or less, preferably 50 mg or less, preferably 20 mg or less, such as 5 mg, 10 mg, 13 mg, 15 mg or 17 mg; • Crocus sativus stigma extract in an amount of 0.5 mg or more, preferably 2 mg or more, preferably 5 mg or more and/or in an amount of 80 mg or less, preferably 30 mg or less, preferably 15 mg or less, such as 3 mg, 6 mg, 8 mg, 9 mg or 1 1 mg;

• Matricaria chamomilla flower extract in an amount of 5 mg or more, preferably 20 mg or more, preferably 30 mg or more and/or in an amount of 150 mg or less, preferably 75 mg or less, preferably 60 mg or less, such as 30 mg, 35 mg, 40 mg, 45 mg or 55 mg;

• vitamin D, preferably vitamin D3 in an amount of 0.01 mg or more, preferably 0.1 mg or more, preferably 1 mg or more and/or in an amount of 20 mg or less, preferably 10 mg or less, preferably 2 mg or less; and

• a magnesium compound, preferably magnesium carbonate, preferably magnesium carbonate in the form of the dypingite mineral in an amount of 10 mg or more, preferably 100 mg or more, preferably 550 mg or more and/or in an amount of 2000 mg or less, preferably 1000 mg or less, preferably 650 mg or less.

In a particularly preferred embodiment of the invention, said composition comprises the vitamin D, preferably vitamin D3, in an amount of 0.1 pg or more, preferably 0.6 pg or more, preferably 1 pg or more and/or in an amount of 40 pg or less, preferably 15 pg or less, preferably 4 pg or less.

Pharmaceutical and/or nutraceutical (unit-dosage) formulations as defined herein are preferably provided in a form suitable for oral administration. Examples of oral formulations include tablets, capsules, lozenges as well as particulates, such as granulates and powders, typically contained in a unit dosage packaging, such as a sachet. Embodiments are also envisaged, wherein the pharmaceutical and/or nutraceutical formulation is a liquid suitable for oral administration, such as a syrup, elixir or the like, e.g. contained in a (unit dosage) vial or ampoule or in a bottle or flask (from which a single unit dose must be drawn). In particularly preferred embodiments though, the unit dosage form is a solid oral unit dosage formulation, more preferably a tablet or capsule suitable for oral administration. Regarding general techniques of manufacturing oral solid dosage forms that can suitably be used in accordance with the present invention, reference is made to Remington, The Science and Practice of Pharmacy, 22 ^nd edition, 2012, chapter 45 "Oral solid dosage forms". Most preferably, the unit dosage form is a tablet for oral administration.

Tablets that can suitably be used for the purposes of the present invention typically comprise a core, comprising a combination of pharmacologically and/or physiologically active components as specified herein elsewhere in conjunction with one or more conventional excipients needed to (e.g.) facilitate processing of said combination into a tablet core that remains intact during processing, storing and distribution, that is convenient for a patient to self-administer and swallow and that disintegrates in the patient’s gastrointestinal tract at the appropriate rate, e.g. as quickly as possible. Typically, the tablet core comprises, besides the combination of pharmacologically and/or physiologically active ingredients, one or more of a bulking agent, such as sorbitol or microcrystalline cellulose, anti-caking agents, such as colloidal silicon, lubricants, such as glyceryl behenate, binders, fillers, disintegrants, preservatives, emollients, humectants, sweetening-agents, plasticizers, film-forming agents, hardness-increasing agents, flavours, etc.

The tablet core can suitably be produced by direct compression of a (free-flowing) mixture or blend of the combination of pharmacologically and/or physiologically active ingredients and the excipients or by the formation of a granulate comprising the combination of pharmacologically and/or physiologically active ingredients and the excipients, optionally using a granulation liquid, which granulate is subsequently compressed into a tablet (core).

In preferred embodiments of the invention, the tablets comprise a coating surrounding the core as defined here above. It is conventional in the art to apply a coating on a tablet formulation, in particular in order to improve the visual appearance of the tablet, in order to facilitate swallowing of the tablet, in order to mask unpleasant taste of tablet components, in order to confer a distinctive and recognizable appearance and/or in order to control disintegration of the tablet and release of the active ingredients from the tablet. In accordance with the present invention, a coating is applied using conventional coating compositions and techniques, e.g. using coatings comprising film-forming agents, thickener, anticaking agent, lubricant and colorants.

Kit of parts

In preferred embodiments of the invention, multiple unit dosage forms are combined and provided as a kit of parts. The invention thus provides a kit of parts comprising two or more unit dosage forms as defined herein, optionally provided with instructions for use of the unit dosage forms in a treatment regimen as defined herein. In accordance with the invention, such a kit may comprise a plurality of unit dosage forms, such as 5, 10, 15, 20, 25, 30, 40, 50, 60, 70, 75, 80, 90 or 100 unit dosage forms, said unit dosage forms preferably being adapted for daily administration of 1 , 2, 3 or 4 unit dosage forms. Advantageously, the kit contains a packaging and/or a leaflet reflecting said schedule of administration. In one particularly preferred embodiment kit packet comprises 60 unit dosage forms for once daily administration of 2 unit dosage forms over a period of 30 days.

In preferred embodiments, said kit of parts further comprises printed instructions for using the product in the treatment a subject as defined herein, by administering unit dosage forms contained in the kit according to the regimens defined herein.

Medical uses

A further aspect of the invention is directed to, stated generally, the prophylactic or curative treatment of a medical or non-medical condition in a subject in need thereof, using the compositions as defined herein before. Based on the information provided for the first time herein, it is contemplated that the compositions of the invention are useful for treatment of medical and non-medical conditions, especially conditions that may benefit from the administration of compositions as described herein, such as premenstrual syndrome and/or menstrual discomfort. The treatment comprises administering to the subject an effective amount of a composition as described herein elsewhere.

The term “premenstrual syndrome” (also referred to as ‘PMS’) as used herein encompasses conditions associated with the female menstrual cycle involving a variety of physical and mental symptoms, which symptoms typically peak during the late luteal phase (i.e. after ovulation) of a woman's cycle and abate with the beginning of menstrual blood loss. The severity of symptoms associated with PMS range from mild to incapacitating and it has been estimated that up to 90% of women who menstruate suffer from some degree of PMS, while 20-40% suffer symptoms severe enough to lead to physical or mental incapacitation. The severity of symptoms can vary from month to month or year to year for a particular woman.

Symptoms associated with PMS typically include depression, anger, irritability, anxiety, bloating, weight gain, abdominal pain, muscles and/or joint pain, breast pain and swelling, headache, fatigue, difficulty sleeping, difficulty concentrating, confusion, food cravings, lack of sexual interest and/or decreased efficiency.

The term “menstrual discomfort”, as used herein encompasses conditions associated with the female menstrual cycle involving a variety of physical and mental symptoms, which symptoms typically peak during menses of a woman's cycle. Said symptoms include for example abdominal pain, back pain, cramps, breast tenderness, mood changes, headaches, nausea and/or dizziness. The severity of these symptoms ranges from mild to incapacitating.

In one embodiment, the invention provides compositions as defined herein, for use in the treatment, in particular the prophylactic or curative treatment, of a subject in need thereof, especially a subject suffering from premenstrual syndrome and/or menstrual discomfort. In one embodiment, said method comprises the treatment, prevention or alleviation of a symptom associated with premenstrual syndrome and/or menstrual discomfort.

In one embodiment, the invention provides compositions as defined herein, for use in the treatment, in particular the prophylactic or curative treatment, of a condition, especially a condition selected from premenstrual syndrome and menstrual discomfort, in a subject in need thereof.

In one embodiment, the invention provides compositions as defined herein, for use in the treatment, in particular the prophylactic or curative treatment, of a symptom associated with a condition, especially premenstrual syndrome and/or menstrual discomfort, in a subject in need thereof.

In one embodiment, the invention provides compositions as defined herein, for use in the prevention, treatment or alleviation of a symptom associated with a condition, especially premenstrual syndrome and/or menstrual discomfort, in a subject in need thereof.

In one embodiment, the invention provides a method of treatment, in particular the prophylactic or curative treatment, of a subject in need thereof, especially a subject suffering from premenstrual syndrome and/or menstrual discomfort, said treatment comprising the administration of a composition as defined herein. In one embodiment, said method comprises the treatment, prevention or alleviation of a symptom associated with a condition selected from premenstrual syndrome and menstrual discomfort.

In one embodiment, the invention provides a method of treatment, in particular the prophylactic or curative treatment, of a condition, especially premenstrual syndrome and/or menstrual discomfort, in a subject in need thereof, said method comprising the administration of a composition as defined herein.

In one embodiment, the invention provides a method of treatment, in particular the prophylactic or curative treatment, of a symptom associated with a condition, especially premenstrual syndrome and/or menstrual discomfort, in a subject in need thereof, said method comprising the administration of a composition as defined herein.

In one embodiment, the invention provides a method of preventing, treating and/or alleviating a symptom associated with a condition, especially premenstrual syndrome and/or menstrual discomfort, in a subject in need thereof, said method comprising the administration of a composition as defined herein.

Main symptoms of premenstrual symptoms and/or menstrual discomfort to be treated, alleviated and/or prevented in accordance with the invention disclosed herein can be divided in three main categories, notably breast symptoms, psychological/mental symptoms and abdominopelvic symptoms. In preferred embodiments of the invention, the symptom associated with premenstrual syndrome and/or menstrual discomfort is a breast symptom, preferably a symptom selected from painful breast, tense breast, mastodynia, and combinations thereof. In preferred embodiments of the invention, the symptom associated with premenstrual syndrome and/or menstrual discomfort is a psychological symptom, preferably a psychological symptom selected from irritability, anxiety, depression, and combinations thereof. In preferred embodiments of the invention, the symptom associated with premenstrual syndrome and/or menstrual discomfort is an abdominopelvic symptom, preferably an abdominopelvic symptom selected from bloating, cramps, transit problems, and combinations thereof. As will be understood by those skilled in the art, embodiments are envisaged wherein a combination of two or more symptoms as recited here is treated.

In accordance with the embodiments as defined here above, the term "curative treatment", in relation a given condition, includes, but is not limited to, arresting the development of the condition; relieving the condition, causing regression of the condition; or relieving a symptom caused by or resulting from the condition.

In accordance with the embodiments as defined here above, the term "prophylactic treatment" in relation to a given condition means preventing the onset of development of the condition if none had occurred, or preventing the condition from occurring in a subject that may be predisposed to the condition but has not yet been diagnosed as having the condition.

The subject to be treated

The term "subject" as used herein refers to an animal, in particular a human, that is treatable by the method of the invention. The term "subject" refers to both the male and female gender unless one gender is specifically indicated. Where the invention is directed specifically to the treatment of premenstrual syndrome and/or menstrual discomfort and/or symptoms thereof and/or conditions associated therewith, it will be understood that the subject is a female. In accordance with the invention, the subject is a human subject.

In accordance with preferred embodiments of the invention, the subject in need thereof is a subject suffering from or at risk of suffering from any one of the conditions as defined here above. Hence, in accordance with embodiments of the invention, the subject in need thereof is a subject suffering from or at risk of suffering from premenstrual syndrome and/or menstrual discomfort. In accordance with preferred embodiments of the invention, the human subject can be a juvenile, an adolescent, an adult or an elderly subject. In preferred embodiments of the invention the human subject is at least 18 years of age, preferably at least 25 years, at least 30 years, at least 35 years, at least 40 years or at least 45 years. Human subjects treated in accordance with the invention will typically be less than 65 years of age, less than 60 years of age or less than 55 years of age.

In embodiments of the invention, the methods as described herein comprise the step of identifying a subject that is in need of receiving treatment with the compositions of the invention and/or identifying a subject suffering from or at risk of suffering from any of the conditions as described here above and/or a subject meeting any of the above- described physiological characteristics as described here above.

In one embodiment such method of treatment is carried out for non-medical or non- therapeutic reasons. Such treatment of healthy subjects for non-medical reasons will typically rely on the use of the same compositions and products and the same routes of administration and the same dosage regimens as defined here above in relation to medical treatments. In an embodiment of the invention, the subject is a healthy subject.

Treatment regimens

The methods as described herein, comprise the administration to the subject in need thereof of a composition or product as described herein in an amount effective to prevent or treat one or more of the conditions or pathologies as defined herein.

In accordance with a preferred embodiment of the invention, the treatment comprises the administration of vicenin-2 in an average daily dose of 0.01 mg or more, preferably 0.02 mg or more, preferably 0.1 mg or more and/or in an amount of 20 mg or less, preferably 10 mg or less, preferably 2 mg or less.

In accordance with a preferred embodiment of the invention, the treatment comprises the administration of rosmarinic acid in an average daily dose of 0.01 mg or more, preferably 0.02 mg or more, preferably 0.1 mg or more and/or in an amount of 20 mg or less, preferably 10 mg or less, preferably 2 mg or less.

In accordance with a preferred embodiment of the invention, the treatment comprises the administration of Perilla frutescens seed extract in an average daily dose of 10 mg or more, preferably 40 mg or more, preferably 60 mg or more and/or in an amount of 300 mg or less, preferably 150 mg or less, preferably 110 mg or less, such as 60 mg, 70 mg, 80 mg, 90 mg or 100 mg.

In accordance with a preferred embodiment of the invention, the treatment comprises the administration of a clerodadienol in an average daily dose of 0.01 mg or more, preferably 0.02 g or more, preferably 0.1 mg or more and/or in an amount of 20 mg or less, preferably 10 mg or less, preferably 2 mg or less.

In accordance with a preferred embodiment of the invention, the treatment comprises the administration of Vitex agnus-castus fruit extract in an average daily dose of 1 mg or more, preferably 4 mg or more, preferably 20 mg or more and/or in an amount of 200 mg or less, preferably 100 mg or less, preferably 40 mg or less, such as 10 mg, 20 mg, 26 mg, 30 mg or 34 mg.

In accordance with a preferred embodiment of the invention, the treatment comprises the administration of crocin in an average daily dose of 0.01 mg or more, preferably 0.1 mg or more, preferably 0.4 mg or more and/or in an amount of 5 mg or less, preferably 3 mg or less, preferably 1.5 mg or less.

In accordance with a preferred embodiment of the invention, the treatment comprises the administration of safranal in an average daily dose of 0.02 mg or more as determined in accordance with ISO 3632-2:2010, preferably 0.2 mg or more, preferably 0.4 mg or more and/or in an amount of 10 mg or less as determined in accordance with ISO 3632-2:2010, preferably 6 mg or less, preferably 3 mg or less.

In accordance with a preferred embodiment of the invention, the treatment comprises the administration of Crocus sativus stigma extract in an average daily dose of extract of 1 mg or more, preferably 4 mg or more, preferably 10 mg or more and/or in an amount of extract of 160 mg or less, preferably 60 mg or less, preferably 30 mg or less, such as 6 mg, 12 mg, 16 mg, 18 mg or 22 mg.

In accordance with a preferred embodiment of the invention, the treatment comprises the administration of apigenin or an apigenin glycoside in an average daily dose of 0.2 mg or more as determined in accordance with the method described in the USP chamomile monograph, preferably 1 mg or more, preferably 3 mg or more and/or in an amount of 30 mg or less in accordance with the method described in the USP chamomile monograph, preferably 20 mg or less, preferably 8 mg or less.

In accordance with a preferred embodiment of the invention, the treatment comprises the administration of Matricaria chamomilla flower extract in an average daily dose of 10 mg or more, preferably 40 mg or more, preferably 60 mg or more and/or in an amount of 300 mg or less, preferably 150 mg or less, preferably 120 mg or less, such as 60 mg, 70 mg, 80 mg, 90 mg or 110 mg.

In accordance with a preferred embodiment of the invention, the treatment comprises the administration of vitamin D, preferably vitamin D3 in an amount of 0.02 mg or more, preferably 0.2 mg or more, preferably 2 mg or more and/or in an amount of 40 mg or less, preferably 20 mg or less, preferably 4 mg or less. In accordance with a particularly preferred embodiment of the invention, the treatment comprises the administration of vitamin D, preferably vitamin D3, in an amount of 0.2 pg or more, preferably 0.12 pg or more, preferably 2 pg or more and/or in an amount of 80 pg or less, preferably 30 pg or less, preferably 8 pg or less.

In accordance with a preferred embodiment of the invention, the treatment comprises the administration of a magnesium compound, preferably magnesium carbonate, preferably magnesium carbonate in the form of the dypingite mineral in an amount of 20 mg or more, preferably 200 mg or more, preferably 1100 mg or more and/or in an amount of 4000 mg or less, preferably 2000 mg or less, preferably 1300 mg or less.

In a particularly preferred embodiment of the invention, the treatment comprises the daily administration of:

• Perilla frutescens seed extract in an amount of 60 mg or more and in an amount of 1 10 mg or less;

• Vitex agnus-castus fruit extract in an amount of 20 mg or more and in an amount of 40 mg or less;

• Crocus sativus stigma extract in an amount of 10 mg or more and in an amount of 30 mg or less;

• Matricaria chamomilla flower extract in an amount of 60 mg or more and in an amount of 120 mg or less;

• vitamin D, preferably vitamin D3 in an amount of 2 mg or more and in an amount of 4 mg or less;

• a magnesium compound, preferably magnesium carbonate, preferably magnesium carbonate in the form of the dypingite mineral in an amount of 1100 mg or more and in an amount of 1300 mg or less; and

• optionally fatty acid glycerides, preferably a diester formed from glycerol and a C20- C24 saturated fatty acid, preferably glycerol dibehenate in an amount of 12 mg or more and in an amount of 20 mg or less.

In an even more preferred embodiment of the invention, the treatment comprises the daily administration of:

• Perilla frutescens seed extract in an amount of 60 mg or more and in an amount of 1 10 mg or less;

• Vitex agnus-castus fruit extract in an amount of 20 mg or more and in an amount of 40 mg or less;

• Crocus sativus stigma extract in an amount of 10 mg or more and in an amount of 30 mg or less; • Matricaria chamomilla flower extract in an amount of 60 g or more and in an amount of 120 mg or less;

• vitamin D, preferably vitamin D3 in an amount of 2 pg or more and in an amount of 8 pg or less;

• a magnesium compound, preferably magnesium carbonate, preferably magnesium carbonate in the form of the dypingite mineral in an amount of 1100 mg or more and in an amount of 1300 mg or less; and

• optionally fatty acid glycerides, preferably a diester formed from glycerol and a C20- C24 saturated fatty acid, preferably glycerol dibehenate in an amount of 12 mg or more and in an amount of 20 mg or less.

Typically, the treatments entail the administration of the composition in the form of a‘unit dosage form’ as defined herein before. Unit dosage forms of the composition are preferably administered at least once a week, preferably at least once every 3 days, at least once every other day or at least once daily, most preferably once daily. In preferred embodiments of the invention, the treatment comprises the daily administration of one, two, three or four unit dosage forms, preferably one, two or three unit dosage forms, more preferably one or two. If more than one unit dosage form is administered per day, they may be taken simultaneously or consecutively at the same moment or they may be taken at intervals during the day, the former being preferred over the latter.

In accordance with the invention, the treatment as defined herein before, is continued for a period of at least two weeks, preferably at least 3 weeks, at least 4 weeks, at least 1 month, at least two months, at least three months, at least 4 months, at least 5 months, or at least 6 months.

In preferred embodiments the treatment comprises the daily oral administration of one or two unit dosage forms, preferably the daily oral administration of two unit dosage forms, more preferably the daily oral administration of two unit dosage forms simultaneously or consecutively at the same moment, wherein the treatment is continued for a period of at least 3 months.

Miscellaneous

Unless otherwise defined, all terms used in disclosing the invention, including technical and scientific terms, have the meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. By means of further guidance, term definitions are included to better appreciate the teaching of the present invention.

As used herein, the following terms have the following meanings: "A", "an", and "the" as used herein refer to both singular and plural forms unless the context clearly dictates otherwise. By way of example, "a compartment" refers to one or more than one compartment.

"About" as used herein referring to a measurable value such as a parameter, an amount, a temporal duration, and the like, is meant to encompass variations of +/-10% or less, more preferably +1-5% or less, even more preferably +/- 1 % or less of and from the specified value, in so far such variations are appropriate to perform in the disclosed invention. However, it is to be understood that the value to which the modifier "about" refers is itself also specifically disclosed.

"Comprise," "comprising," "comprises" and "comprised of" as used herein are synonymous with "include", "including", "includes" or "contain", "containing", "contains" and are inclusive or open-ended terms that specifies the presence of what follows e.g. component and do not exclude or preclude the presence of additional, non-recited components, features, element, members, steps, known in the art or disclosed therein.

The recitation of numerical ranges by endpoints includes all numbers and fractions subsumed within that range, as well as the recited endpoints. The skilled person will appreciate that the present invention can incorporate any number of the specific features described above.

Advantages of the invention will become apparent from the following examples, which are given below as mere illustrations, and are non-limitative.

Examples

Example 1 - Formulation according to the invention

In a most preferred embodiment of the invention, a composition in tablet form is prepared according to the ingredient list provided in Table 1.

In one embodiment a first blend comprising chasteberry fruit extract, vitamin D and magnesium citrate passed through a mesh screen is prepared by blending until uniformly mixed. A second blend is prepared comprising Perilla frutescens leaf extract, saffron stigmates extract and calcium carbonate. A third blend is made with chamomile and vitamin D. The ingredients used are selected to provide a per tablet amount as indicated in Table 1. All blends are passed through a mesh screen. The blends are combined and mixed long enough to ensure content uniformity as is commonly known and practiced in the art. The tableting mixture is discharged. Capsule shaped tablets with a target weight of 1410 mg (+/- 5%) are compressed with a target hardness of 8-12 kP.

Tablets prepared according to the composition provided in Table 1 may optionally be coated with a layer. Alternatively, the tablets are coated (Aquapolish F pink) using a conventional pan coating process.

Table 1 : pharmaceutical composition according to an embodiment of the invention

*Aquapolish F pink 044.147 MS

Example 2 Pilot study

A single blind pilot study to evaluate the safety, efficacy and tolerability of the formulation described in example 1 (‘study product’) in PMS is carried out at one study centre.

The trial objectives are:

(1) To determine the efficacy of the study product in ameliorating PMS (Premenstrual syndrome) symptoms as measured by the Calendar of Premenstrual Experiences which is a diary of 22 physcial and behavioral symptoms of PMS;

(2) To determine the tolerability of the study product in PMS;

(3) To determine the safety of the study product in PMS; and

(4) To establish a dose range which can be used in a later double blind trial.

Twenty subjects are recruited that meet the criteria for inclusion in the study. After screening, subjects undergo a one month assessment period with prospective diaries (COPE, Calendar of Premenstrual Events).

All subjects then enter the single-blind placebo treatment period and the subjects' outcome at the end of this cycle acts as their baseline assessment. Subjects are then treated with the study product (starting with 2 tablets a day) for the next three cycles and assessed using the COPE.

During this three month period, subjects may have a sequential increase in dose at monthly intervals from 2 to 3 tablets a day to optimize response. Provisions are made for dose decreases in case of tolerability concerns.

Subjects are aware that they receive three months of the study product and one month of placebo but are unaware of when the placebo is administered. The primary outcome measure is the mean change from the end of the placebo period in luteal phase total COPE score after three menstrual cycles of active treatment. Secondary efficacy measures include; mean change from the end of the placebo period in luteal phase total COPE score; mean change from end of the placebo period in luteal phase physical COPE symptoms; mean change from the end of the luteal phase behavioral symptoms; mean change from end of the placebo period in follicular phase total COPE score; CGI improvement score at each of the three menstrual cycles.

Total COPE score is significantly reduced in the majority of patients treated with the study formulation. The study product is well tolerated.

Example 3 - efficacy study

A study to evaluate the efficacy of the formulation described in example 1 (‘study product’) in treating PMS is carried out. 50 female patients aged 15-40 years which are not using hormonal contraception are treated with the study product (840 mg tablets as described in example 1). The administration regimen was two tablets per day for three months, taken orally (simultaneously or consecutively) with a large glass of water before breakfast.

The efficacy of the study product is evaluated by self-assessment of the study participants at the start of treatment and after 3 months using the form shown as Table 2. The participants use the form by allocating a severity score (light, moderate or severe) to each of the 18 criteria. Table 2: self-assessment form

An overall assessment score is calculated as follows:

(4 x number of ‘very important’ assessments) + (3 x number of ‘important’ assessments) + (2 x number of ‘moderate’ assessments) + (number of light assessments) = overall assessment score

Women benefiting from the product continue the treatment for another 3 months and provide another self-assessment after a total of 6 months of treatment.

The study product is well-tolerated and efficacious in improving one or more of the symptoms in the evaluation form of Table 2 after 3 months of treatment. Furthermore, the study product decreases the overall assessment score after 3 months of treatment by more than 4 in a large portion of individuals compared to the overall assessment score at the start of treatment, when administered orally at a dosage of two tablets per day.