WO2020144588A1 - Compositions for treatment of the menopause, osteopenia and osteoporosis, and menopause/related metabolic and vascular disorders - Google Patents
Compositions for treatment of the menopause, osteopenia and osteoporosis, and menopause/related metabolic and vascular disorders Download PDFInfo
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- WO2020144588A1 WO2020144588A1 PCT/IB2020/050111 IB2020050111W WO2020144588A1 WO 2020144588 A1 WO2020144588 A1 WO 2020144588A1 IB 2020050111 W IB2020050111 W IB 2020050111W WO 2020144588 A1 WO2020144588 A1 WO 2020144588A1
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- menopause
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Definitions
- the present invention relates to compositions useful for treatment of the symptoms of the menopause, comprising extracts of plants with oestrogenic activity optionally combined with other medicinal plant extracts, vitamins and oligoelements.
- the symptoms associated with the menopause which may be neurovegetative (hot flushes, sweating, headache) or psychiatric (irritability, depression, sleep disorders), and osteoporosis, which frequently arises during the menopause, are known to be attributable to oestrogen deficiency. Hormone replacement therapy is therefore an effective therapeutic remedy.
- phytoestrogens i.e. heterocyclic compounds contained in legumes and cereals which have a structure resembling that of oestradiol
- Diet supplementation with soya derivatives or administration of phytoestrogens derived from soya consequently represents a promising alternative to oestrogen administration.
- Soya is the main oestrogen source currently used; soya isoflavones have a well- established oestrogen-like activity, which is particularly effective against osteoporosis, due to its inhibiting action on tyrosine kinase which in turn inhibits osteoclastic activity, with a consequent increase in bone mineral density, and against post-menopausal symptoms, especially in reducing hot flushes, nervousness, headaches and palpitations.
- Cimicifuga racemosa black cohosh
- the roots and rhizome of Cimicifuga contain formononetin, an oestrogen, in addition to triterpene glycosides.
- the extract generally titrated in triterpene glycosides with values ranging between 0.5 and 30%, has proved effective in the treatment of menopause-related neurovegetative disorders and dysmenorrhoea [E. Ducker et al, Planta Med., 57 (1991) 420]
- EP1200107 and EP0847755 disclose the use of Cimicifuga extracts as alternatives to hormone replacement therapy.
- US6267994 discloses the use of the extract, combined with compounds having anti-oestrogen activity, especially tamoxifen, for the treatment of oestrogen-dependent tumours.
- WO 201307807 describes the use of Cimicifuga racemosa extracts for the prevention and treatment of osteoporosis.
- KR20020037292 discloses phytoestrogen compositions based on Ferula tenuisecta extract.
- Cimicifuga racemosa extract reduces the classic symptoms of the menopause, such as hot flushes, sweating, insomnia and anxiety, as from the first administrations.
- Said combination has surprisingly exhibited a synergic effect between the two ingredients, with a considerably greater activity than that obtained from the simple sum of the individual ingredients.
- the invention therefore provides compositions containing a Cimicifiiga racemosa extract and a Ferula sp extract.
- Water-alcohol extracts available on the market from a number of sources, are preferred.
- a further aspect of the invention also relates to the use of the compositions to treat pre-menopause, menopause and post-menopause symptoms.
- the Ferula species which can be used according to the invention comprise Ferula sumbul (also known as Ferula moschata ), Ferula hermonis and Ferula communis.
- Ferula sumbul extract is particularly preferred.
- the weight ratio of Cimicifuga racemosa extract to Ferula sumbul extract can range from 1 :2 to 1 : 10, preferably from 1 :3 to 1 :7, and is more preferably 1 :5.
- the unit doses in oral compositions typically range from 10 to 100 mg for the Cimicifuga extract and 20 to 1000 mg for the Ferula extract.
- compositions according to the invention can be administered orally in the form of tablets or cellulose or gelatin capsules, or topically, using suitable excipients.
- the compositions according to the invention are prepared by conventional techniques, such as those described in Remington’s Pharmaceutical Handbook, Mack Publishing Co., N.Y., USA.
- the Ferula extracts contain substances which interact with the oestrogen receptors and inhibit the proliferation of ovarian and breast cancer cells, while the Cimicifuga racemosa extracts contain both bisdesmosidic saponins with oestrogenic activity (cimigenol glucosides) and other saponins which, after elimination of the glucoside residue from the C22 position, give rise to the formation of compounds with a spirostane structure having progestinic activity.
- the Cimicifuga racemosa extracts also contain vitamin K2, which plays an important part in osteogenesis, together with vitamin D (Abstracts of Papers, 253rd ACS National Meeting & Exposition, San Francisco, CA, USA, April 2-6, 2017 (2017), CHED-526).
- Vitamin K2 regulates the calcium metabolism responsible, and contributes to maintaining the bone mass.
- the Cimicifuga and Ferula extracts can be advantageously combined with oligoelements, vitamins, in particular vitamin D and vitamin B complex, lipoic acid and/or one or more phytotherapeutic extracts, as additional ingredients to supplement the beneficial properties of the compositions.
- Vaccinium myrtillus or Vaccinium macrocarpon extracts containing pentacyclic triterpenes and procyanidins A and B, improve the vascular function of menopausal women suffering from cardiovascular damage associated with excess weight, characteristic of the menopause, and from problems associated with the symptoms of metabolic syndrome and type 2 diabetes; the intake of antioxidants and alpha-glucosidase and alpha amylase enzyme inhibitors in the intestine gives rise, in addition to body weight modulation, to an improvement in endothelial function and normalisation of the lipid parameters, with a particular increase in HDL cholesterol and a reduction in blood glucose levels.
- compositions according to the invention may also contain Citrus bergamia and Cynara cardunculus var sylvestris extracts, described in IT RM2007A000515; EP 2364158; and WO 2010 554920.
- Examples of other extracts useful for the purposes of the invention are Olea europaea, Ginkgo biloba, Citrus aurantium var. bergamia, Citrus reticulata var clementine, Salvia officinalis, Vitis vinifera (seed) and Berberis aristata extracts.
- Said extracts have a high content of polyphenols which perform a powerful action against free radicals, as well as inhibiting enzymes such as alpha-amylase, glucosidase and lipase in the intestine.
- the lipophilic diterpenes present in Salvia officinalis extract such as carnosol, carnosic acid and the like, cross the blood-brain barrier, wherein they exert an anti- inflammatory and neuroprotective activity with favourable effects on the neurovegetative and vascular disorders frequent in the menopause.
- Olea europaea leaf extracts contribute to the reduction of osteopenia and osteoporosis as a result of synergic effects between verbascoside, oleuropein and the pentacyclic triterpenes ursolic and oleanolic acid.
- adaptogenic plant extracts can be added.
- the preferred adaptogenic plant extract is Withania somnifera , which contains withanolides, active ingredients having a powerful inhibitory effect on acetyl and butyryl cholinesterase, enzymes involved in the brain function.
- the products were administered to normal women and those at the start of surgical menopause after cessation of the menstrual cycle, the patients being monitored in a randomised trial according to the methods and criteria of conventional protocols such as the Greene scale.
- the patients were treated for 1 month with two capsules a day, morning and evening, containing 20 mg of Cimicifuga racemosa water-alcohol extract, 100 mg of Ferula sumbul , or a combination of the two in the same quantitative ratio.
- Table 1 shows the data relating to the doses normally used for Cimicifuga racemosa and Ferula sumbul extracts, with the results expressed as the total scores obtained on the Greene scale.
- Table 2 shows the data produced with the Greene scale referring to the scores of
- Example 1 Soft gelatin capsules containing Cimicifuga racemosa and Ferula 1:5 extracts
- Example 2 Hard gelatin capsules containing Cimicifuga racemosa and
- Example 3 Tablets containing Cimicifuga racemosa and Ferula 1:5 extracts for the treatment of osteoporosis
- Example 4 Tablets containing Cimicifuga racemosa and Ferula 1:5 extracts for the treatment of cognitive impairment
- Example 5 Tablets containing Cimicifuga racemosa and Ferula 1:5 extracts for the treatment of metabolic and cardiovascular disorders.
- the Ferula extract (0.1-10 uM; 20% ferutinin), incubated with neurones co-cultured with human astrocytes according to the scheme shown in Figure 1, stimulates constitutive nitric oxide synthase (cNOS) in astroglial cells and increased expression of the enzyme glutamine synthase, and this effect is followed by glutamate release from the neurones and astrocytes (Table 1). Surprisingly, this effect was three times greater when the Ferula extract (10 uM) was added to the co-cultures ( Figure 2, Table 3). In fact, Cimicifuga alone did not influence cNOS or glutamate release from the cell culture.
- cNOS constitutive nitric oxide synthase
- Cimicifuga unexpectedly inhibited inducible NO synthase (iNOS), which is known to depress constitutive release of NO, thus increasing the effect of ferutinin on glutamate release ( Figure 2, Table 3).
- iNOS inducible NO synthase
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Abstract
Disclosed are compositions comprising Cimicifuga racemosa and Ferula extracts and optionally other phytotherapeutic extracts, vitamins and oligoelements. The compositions described are useful in the treatment of menopause symptoms..
Description
COMPOSITIONS FOR TREATMENT OF THE MENOPAUSE. OSTEOPENIA
AND OSTEOPOROSIS. AND MENOPAUSE-RELATED METABOLIC AND
VASCULAR DISORDERS
The present invention relates to compositions useful for treatment of the symptoms of the menopause, comprising extracts of plants with oestrogenic activity optionally combined with other medicinal plant extracts, vitamins and oligoelements.
State of the art
The symptoms associated with the menopause, which may be neurovegetative (hot flushes, sweating, headache) or psychiatric (irritability, depression, sleep disorders), and osteoporosis, which frequently arises during the menopause, are known to be attributable to oestrogen deficiency. Hormone replacement therapy is therefore an effective therapeutic remedy.
However, oestrogen administration is not risk-free, especially in the long term, due to the possible onset of oestrogen-dependent tumours; the administration of oestrogen-like substances of plant origin known as phytoestrogens, i.e. heterocyclic compounds contained in legumes and cereals which have a structure resembling that of oestradiol, is therefore preferable. Diet supplementation with soya derivatives or administration of phytoestrogens derived from soya consequently represents a promising alternative to oestrogen administration.
Soya is the main oestrogen source currently used; soya isoflavones have a well- established oestrogen-like activity, which is particularly effective against osteoporosis, due to its inhibiting action on tyrosine kinase which in turn inhibits osteoclastic activity, with a consequent increase in bone mineral density, and against post-menopausal symptoms, especially in reducing hot flushes, nervousness, headaches and palpitations.
Cimicifuga racemosa (black cohosh), a plant belonging to the Ranunculaceae family, is another source of phytoestrogens; the roots and rhizome of Cimicifuga contain formononetin, an oestrogen, in addition to triterpene glycosides. The extract, generally
titrated in triterpene glycosides with values ranging between 0.5 and 30%, has proved effective in the treatment of menopause-related neurovegetative disorders and dysmenorrhoea [E. Ducker et al, Planta Med., 57 (1991) 420] EP1200107 and EP0847755 disclose the use of Cimicifuga extracts as alternatives to hormone replacement therapy.
US6267994 discloses the use of the extract, combined with compounds having anti-oestrogen activity, especially tamoxifen, for the treatment of oestrogen-dependent tumours.
The association of formononetin with other phytoestrogens such as those derived from soya, namely genistein and daidzein, was described for the same use in US5830887, and for the treatment of premenstrual syndrome and menopausal syndrome. EP 1321149 discloses combinations of Cimicifuga racemosa extracts with adaptogenic plant extracts.
WO 201307807 describes the use of Cimicifuga racemosa extracts for the prevention and treatment of osteoporosis.
KR20020037292 discloses phytoestrogen compositions based on Ferula tenuisecta extract.
Although the formulations described to date provide safe, effective alternatives to hormone treatment, they do not control chronic disorders of multifactorial origin, such as the multiple degenerations associated with the menopause and aging. Metabolic syndrome, osteoporosis and neurological problems are normally present in many post menopausal patients, and therefore require therapeutic approaches based on different action mechanisms in order to slow the progress of the main pathological manifestations.
Description of the invention
It has now surprisingly been found that the combination of a Cimicifuga racemosa extract with a Ferula sp extract reduces the classic symptoms of the menopause, such as hot flushes, sweating, insomnia and anxiety, as from the first administrations. Said combination has surprisingly exhibited a synergic effect between the two ingredients, with a considerably greater activity than that obtained from the simple sum of the
individual ingredients.
In a first aspect thereof, the invention therefore provides compositions containing a Cimicifiiga racemosa extract and a Ferula sp extract. Water-alcohol extracts, available on the market from a number of sources, are preferred.
A further aspect of the invention also relates to the use of the compositions to treat pre-menopause, menopause and post-menopause symptoms.
The Ferula species which can be used according to the invention comprise Ferula sumbul (also known as Ferula moschata ), Ferula hermonis and Ferula communis. The Ferula sumbul extract is particularly preferred.
The weight ratio of Cimicifuga racemosa extract to Ferula sumbul extract can range from 1 :2 to 1 : 10, preferably from 1 :3 to 1 :7, and is more preferably 1 :5.
The unit doses in oral compositions typically range from 10 to 100 mg for the Cimicifuga extract and 20 to 1000 mg for the Ferula extract.
The compositions according to the invention can be administered orally in the form of tablets or cellulose or gelatin capsules, or topically, using suitable excipients. The compositions according to the invention are prepared by conventional techniques, such as those described in Remington’s Pharmaceutical Handbook, Mack Publishing Co., N.Y., USA.
The Ferula extracts contain substances which interact with the oestrogen receptors and inhibit the proliferation of ovarian and breast cancer cells, while the Cimicifuga racemosa extracts contain both bisdesmosidic saponins with oestrogenic activity (cimigenol glucosides) and other saponins which, after elimination of the glucoside residue from the C22 position, give rise to the formation of compounds with a spirostane structure having progestinic activity. The Cimicifuga racemosa extracts also contain vitamin K2, which plays an important part in osteogenesis, together with vitamin D (Abstracts of Papers, 253rd ACS National Meeting & Exposition, San Francisco, CA, USA, April 2-6, 2017 (2017), CHED-526). Vitamin K2 regulates the calcium metabolism responsible, and contributes to maintaining the bone mass.
In the compositions according to the invention, the Cimicifuga and Ferula extracts can be advantageously combined with oligoelements, vitamins, in particular vitamin D and vitamin B complex, lipoic acid and/or one or more phytotherapeutic extracts, as additional ingredients to supplement the beneficial properties of the compositions. For example, Vaccinium myrtillus or Vaccinium macrocarpon extracts, containing pentacyclic triterpenes and procyanidins A and B, improve the vascular function of menopausal women suffering from cardiovascular damage associated with excess weight, characteristic of the menopause, and from problems associated with the symptoms of metabolic syndrome and type 2 diabetes; the intake of antioxidants and alpha-glucosidase and alpha amylase enzyme inhibitors in the intestine gives rise, in addition to body weight modulation, to an improvement in endothelial function and normalisation of the lipid parameters, with a particular increase in HDL cholesterol and a reduction in blood glucose levels.
Alternatively or additionally, the compositions according to the invention may also contain Citrus bergamia and Cynara cardunculus var sylvestris extracts, described in IT RM2007A000515; EP 2364158; and WO 2010 554920.
Examples of other extracts useful for the purposes of the invention are Olea europaea, Ginkgo biloba, Citrus aurantium var. bergamia, Citrus reticulata var clementine, Salvia officinalis, Vitis vinifera (seed) and Berberis aristata extracts. Said extracts have a high content of polyphenols which perform a powerful action against free radicals, as well as inhibiting enzymes such as alpha-amylase, glucosidase and lipase in the intestine.
Extracts of Olea europaea leaves, Vaccinium myrtillus, Vaccinium macrocarpum and Salvia officinalis , as well as containing high percentages of chlorogenic acids and flavonoids, also contain ursane and oleanane triterpenic acids, which act as immune system modulators and enzymatic regulators of protein synthesis.
The lipophilic diterpenes present in Salvia officinalis extract, such as carnosol, carnosic acid and the like, cross the blood-brain barrier, wherein they exert an anti-
inflammatory and neuroprotective activity with favourable effects on the neurovegetative and vascular disorders frequent in the menopause.
Olea europaea leaf extracts contribute to the reduction of osteopenia and osteoporosis as a result of synergic effects between verbascoside, oleuropein and the pentacyclic triterpenes ursolic and oleanolic acid.
To counteract symptoms such as anxiety, depression, cognitive and memory impairment, adaptogenic plant extracts can be added. The preferred adaptogenic plant extract is Withania somnifera , which contains withanolides, active ingredients having a powerful inhibitory effect on acetyl and butyryl cholinesterase, enzymes involved in the brain function. Withania somnifera extracts having a withanolide content ranging between 4 and 12%, preferably about 8%, optionally combined with a phospholipid mixture containing 20% phosphatidylserine, are preferably used.
The amounts of said additional ingredients can vary within a wide range, determined by the skilled person on the basis of the common general knowledge available in the literature.
Pharmacological trial
The synergy of Cimicifuga racemosa and Ferula sumbul extracts has been demonstrated in clinical trials using the Greene parametric scale (Greene, JG. Measuring the symptom dimension of quality of life: General and menopause-specific scales and their subscale structure. In: Hormone replacement therapy and quality of life. The Parthenon Publishing Group. (Edited by: Schneider HPG) Boca Raton, London, New York, Washington. 2002: 35-43).
The products were administered to normal women and those at the start of surgical menopause after cessation of the menstrual cycle, the patients being monitored in a randomised trial according to the methods and criteria of conventional protocols such as the Greene scale. The patients were treated for 1 month with two capsules a day, morning and evening, containing 20 mg of Cimicifuga racemosa water-alcohol extract, 100 mg of Ferula sumbul , or a combination of the two in the same quantitative ratio.
Table 1 shows the data relating to the doses normally used for Cimicifuga racemosa and Ferula sumbul extracts, with the results expressed as the total scores obtained on the Greene scale.
Table 1
Table 2 shows the data produced with the Greene scale referring to the scores of
10 patients per group with analysis of the individual parameters examined.
Table 2
The data obtained demonstrate that the combination of the two extracts as a whole is markedly superior. Parameter-by-parameter analysis clearly demonstrates that
individual symptoms characteristic of the menopause are reduced by up to 90% after a few days’ treatment.
The examples below further illustrate the invention.
Example 1 - Soft gelatin capsules containing Cimicifuga racemosa and Ferula 1:5 extracts
Example 2 - Hard gelatin capsules containing Cimicifuga racemosa and
Ferula 1:5 extracts
Example 3 - Tablets containing Cimicifuga racemosa and Ferula 1:5 extracts for the treatment of osteoporosis
Example 4 - Tablets containing Cimicifuga racemosa and Ferula 1:5 extracts for the treatment of cognitive impairment
Example 5 - Tablets containing Cimicifuga racemosa and Ferula 1:5 extracts for the treatment of metabolic and cardiovascular disorders.
Example 6 - Tablets containing Salvia officinalis and Ferula extracts 1:1
650 mg soft gelatin capsules
Example 7- Synergic effect of Cimicifuga racemosa and Ferula sumbul extract on glutamate release from astrocyte and neurone co-cultures
The Ferula extract (0.1-10 uM; 20% ferutinin), incubated with neurones co-cultured with human astrocytes according to the scheme shown in Figure 1, stimulates
constitutive nitric oxide synthase (cNOS) in astroglial cells and increased expression of the enzyme glutamine synthase, and this effect is followed by glutamate release from the neurones and astrocytes (Table 1). Surprisingly, this effect was three times greater when the Ferula extract (10 uM) was added to the co-cultures (Figure 2, Table 3). In fact, Cimicifuga alone did not influence cNOS or glutamate release from the cell culture.
However, Cimicifuga unexpectedly inhibited inducible NO synthase (iNOS), which is known to depress constitutive release of NO, thus increasing the effect of ferutinin on glutamate release (Figure 2, Table 3). Table 3
The clear synergic effect between Cimicifuga and Ferula found for glutamate release is also correlatable with synergic effects in clinical practice, as known, for example, from Na-Ra Han et al, Nutrition Research 35(2015, 774-783; Xi-Dan et al, Phytomedicine, 63(2019) 153012.
Claims
1. Compositions comprising an extract of Cimicifuga racemosa and an extract of Ferula sp.
2. Compositions according to claim 1 wherein the extract of Ferula sp. is an extract of Ferula sumbul, Ferula hermonis or Ferula communis.
3. Compositions according to claim 1 wherein the extract of Ferula sp. is an extract of Ferula sumbul.
4. Compositions according to any one of claims 1 to 3 wherein the extracts of Cimicifuga and Ferula are water-alcohol extracts.
5. Compositions according to claims 3 and 4 wherein the weight ratio of extract of Cimicifuga racemosa to extract of Ferula sumbul is 1 :5.
6. Compositions according to any one of claims 1 to 5 further comprising at least one of the extracts of Olea europaea, Citrus bergamia, Vaccinium myrtillus, Vaccinium macrocarpum, Cynara cardunculus var sylvestris, Ginkgo biloba, Citrus aurantium var. bergamia, Citrus reticulata var clementine, Withania somnifera, Salvia officinalis, Vitis vinifera and Berberis aristata.
7. Compositions according to any one of claims 1 to 6 further comprising alpha-lipoic acid and/or vitamin D and/or vitamins of the B group and/or oligoelements.
8. Compositions according to claims 1 - 7 for use in the treatment of pre-menopause, menopause and post-menopause symptoms.
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