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  Pharmaceutical Patents  

 

Title:  Composition for treatment of menopause
United States Patent: 
8,110,228
Issued: 
February 7, 2012

Inventors:
 Cohen; Isaac (Piedmont, CA)
Assignee:
  Bionovo, Inc. (Emeryville, CA)
Appl. No.:
 12/259,991
Filed:
 October 28, 2008


 

George Washington University's Healthcare MBA


Abstract

A method of using an herbal extract of the a mixture of: Herba Scutellaria barbata, Radix Sophora subprostratae, Radix Anemarrhena, Semen Glycine sojae, Radix Glycyrrhiza, Rhizoma Rhei, Fructus Tritici levis, Radix Astragali, Radix Rehmania, Fructus Ligustri lucidi, Semen Zyziphi spinosa, Plumula Nelumbinis, Poria cocas, Rhizoma Alismatis, Cortex Moutan radicis, Fructus Corni, Radix Achyranthis, Concha Ostrea, Radix Aspargi, Radix Pueraria, Radix Atractylodis macrocephala and Herba Epimedium, for the treatment of hot flashes associated with menopause is disclosed herein.

Description of the Invention

BACKGROUND OF THE INVENTION

Menopause is that period after the cessation of normal ovulation cycles, during which normal menstruation ceases. A decrease in estradiol (E.sub.2) production accompanies menopause, as the ovaries cease manufacture of E.sub.2. This decrease in E.sub.2 production results in a shift in hormone balance in the body, which often gives rise to a variety of symptoms associated with menopause.

Peri-menopause, which is also known as pre-menopause or the climacteric, is that period prior to menopause during which normal ovulation cycles gradually give way to cessation of menses. As the ovulatory cycles lengthen and become more irregular, the level of E.sub.2 may initially increase, but will eventually drop with the onset of menopause. Menopausal symptoms often accompany the drop in E.sub.2 levels.

The symptoms of peri-menopause, menopause and post-menopause include physical symptoms such as hot flashes and sweating secondary to vasomotor instability. Additionally, psychological and emotional symptoms may accompany onset of climacteric, such as fatigue, irritability, insomnia, inability to concentrate, depression, memory loss, headache, anxiety and nervousness. Additional symptoms can include intermittent dizziness, paresthesias, palpitations and tachycardia as well as nausea, constipation, diarrhea, arthralgia, myalgia, cold hands and feet and weight gain. In addition, changes to the genitals, urinary incontinence, vaginal dryness, loss of pelvic muscle tone, increased risk of cardiovascular disease and osteoporosis increase with onset of menopause.

Hot flashes are prevalent in, and bothersome to, many peri-menopausal, menopausal and postmenopausal women. For decades hormone replacement therapy with estrogens has been the standard treatment for hot flashes, but many women have abandoned hormone therapy (HT) due to concerns about potential adverse effects, particularly breast cancer. Several recent studies, in particular the Women's Health Initiative (WHI), have found that HT increases the risk of breast cancer. The observation that the selective estrogen receptor modulators ("SERMs") raloxifene and tamoxifen prevent estrogen receptor (ER) positive breast cancer provides additional evidence that estrogens promote breast cancer.

There is thus a need for therapeutic compositions and methods for the treatment of menopause, especially menopausal symptoms such as hot flashes, which do not increase the risk of breast cancer. The present invention satisfies this need and provides related advantages as well.

SUMMARY

The present invention provides a composition for the treatment of menopause. The composition is a mixture of herbs, an extract of a mixture of herbs or a mixture of herbal extracts. The mixture of herbs comprises Herba Scutellaria Barbata, Radix Sophora Subprostratae, Radix Anamarrhena, Semen Glycine Sojae, Radix Glycyrrhiza, Rhizoma Rhei, Fructus Tritici Levis, Radix Astragali, Radix Rehmania, Fructus Ligustri Lucidi, Semen Zyziphi Spinozae, Plumula Nelumbinis, Poria Cocos, Rhizoma Alismatis, Cortex Moutan Radicis, Fructus Corni, Radix Achyranthis, Concha Ostrea, Radix Asparagi and Radix Pueraria. The composition activates the estrogen response element (ERE) through estrogen receptor beta (ER.beta.), but not estrogen receptor alpha (ER.alpha.) in an in vitro assay.

The invention also provides a method of treating menopause. The method comprises administering to a subject an amount of the above-mentioned composition sufficient to treat menopause. In some embodiments, treatment of menopause includes reducing the severity, frequency or severity and frequency of a menopausal symptom.

DETAILED DESCRIPTION OF THE INVENTION

Many women are eagerly awaiting safe and effective alternatives to estrogens used in HT for menopausal symptoms after the results of the Women's Health Initiative trial, which showed that the risks of HT exceed the benefits (Ettinger, B., Grady, D., Tosteson, A. N., Pressman, A. & Macer, J. L., "Effect of the Women's Health Initiative on women's decisions to discontinue postmenopausal hormone therapy," Obstet. Gynecol. 102, 1225-32 (2003)). In the meantime a recent survey reported that 79% of peri- and post-menopausal women are using botanical dietary supplements (BDS) (Mahady, G. B., Parrot, J., Lee, C., Yun, G. S. & Dan, A. Botanical dietary supplement use in peri- and postmenopausal women. Menopause 10, 65-72 (2003)). Despite the widespread use of BDSs, the mechanism of action, efficacy and safety of botanicals have not been rigorously examined. The present invention provides an herbal formula that contains Herba Scutellaria Barbata, Radix Sophora Subprostratae, Radix Anamarrhena, Semen Glycine Sojae, Radix Glycyrrhiza, Rhizoma Rhei, Fructus Tritici Levis, Radix Astragali, Radix Rehmania, Fructus Ligustri Lucidi, Semen Zyziphi Spinozae, Plumula Nelumbinis, Poria Cocos, Rhizoma Alismatis, Cortex Moutan Radicis, Fructus Corni, Radix Achyranthis, Concha Ostrea, Radix Asparagi and Radix Pueraria. In some embodiments, the extract is an extract of a significant amount of each of the herbs: Herba Scutellaria Barbata, Radix Sophora Subprostratae, Radix Anamarrhena, Semen Glycine Sojae, Radix Glycyrrhiza, Rhizoma Rhei, Fructus Tritici Levis, Radix Astragali, Radix Rehmania, Fructus Ligustri Lucidi, Semen Zyziphi Spinozae, Plumula Nelumbinis, Poria Cocos, Rhizoma Alismatis, Cortex Moutan Radicis, Fructus Corni, Radix Achyranthis, Concha Ostrea, Radix Asparagi and Radix Pueraria. An exemplary embodiment of the invention is MF101, which is described in more detail below. Although many of the herbs contained in MF101 have been used in traditional Chinese herbal concoctions for the treatment of climacteric symptoms, no previous study has every confirmed the efficacy of the mixture for treatment of menopause. A composition of the invention has ER.beta.-selective estrogen receptor activity, and thus is well-suited for the clinical treatment of menopause, especially to treat menopausal symptoms such as hot flashes.

The invention provides compositions and methods for the treatment of menopause, especially menopausal symptoms such as hot flashes. The compositions of the invention are herbal mixtures, extracts of herbal mixtures and mixtures of herbal extracts. The invention compositions additionally activate the estrogen response element (ERE) with estrogen receptor beta (ER.beta.) but not estrogen receptor alpha (ER.alpha.) in U2OS osteosarcoma cell assays. As the compositions activate the ERE through interaction with ER.beta. but not ER.alpha., only the latter of which is associated with adverse effects of estrogen HT, the invention compositions and methods represent an alternative to estrogen hormone therapy and are less likely to give rise to conditions identified in the WHI as being associated with estrogen supplementation, such as increased risk of breast cancer.

In the context of the present invention "menopause" includes peri-menopause, menopause and post-menopause, and in particular, symptoms that are caused or exacerbated by the decreased levels of estradiol (E.sub.2) that attend peri-menopause, menopause and post-menopause. Thus, in the context of the present invention, "treatment of menopause" means treatment of menopausal symptoms. Exemplary menopausal symptoms include hot flashes, sweating secondary to vasomotor instability, psychological and emotional symptoms such as fatigue, irritability, insomnia, inability to concentrate, depression, memory loss, headache, anxiety, nervousness, intermittent dizziness, paresthesias, palpitations, tachycardia, nausea, constipation, diarrhea, arthralgia, myalgia, cold hands and feet, weight gain, urinary incontinence, vaginal dryness, loss of pelvic muscle tone, increased risk of cardiovascular disease and osteoporosis.

Thus, "treatment of menopause" means the alleviation, palliation or prevention of one or more symptoms associated with peri-menopause, menopause or post-menopause, and includes reduction in the severity or frequency of at least one menopausal symptom. The use of "or" as used herein is intended to be conjunctive unless otherwise specified. Thus, treatment also includes reduction of both the severity and frequency of at least one menopausal symptom. In the sense that reduction of the frequency and severity of a symptom may be complete, treatment may also include prevention of the symptom. In this regard, it is noted that treatment of menopause does not include prevention of the natural cessation of menses in the adult female human, although it does include reduction to undetectable levels the frequency and severity of at least one symptom associated with menopause.

In the context of the present invention, "menopausal subject" and its verbal variants refers to an adult female, especially an adult female human, who has once attained menarche and who is experiencing peri-menopause, menopause or post-menopause. One of skill in the art of gynecology will be able to identify the diagnostic characteristics of the onset of menopause and identify a subject as being a "menopausal subject" by art-recognized clinical methods.

Compositions according to the present invention include herbal mixtures comprising each of the following herbs: Herba Scutellaria Barbata, Radix Sophora Subprostratae, Radix Anamarrhena, Semen Glycine Sojae, Radix Glycyrrhiza, Rhizoma Rhei, Fructus Tritici Levis, Radix Astragali, Radix Rehmania, Fructus Ligustri Lucidi, Semen Zyziphi Spinozae, Plumula Nelumbinis, Poria Cocos, Rhizoma Alismatis, Cortex Moutan Radicis, Fructus Corni, Radix Achyranthis, Concha Ostrea, Radix Asparagi and Radix Pueraria. In some embodiments, the herbal mixture comprises a significant amount of each of the foregoing herbs. In this context a significant amount means an amount greater than about 0.1% by weight, for example greater than about 0.5%, and more particularly greater than about 1% by weight of the mass of all herbal matter in the herbal mixture. Compositions according to the invention also include extracts of the foregoing herbal mixtures. The methods of making such extracts are described in detail below.

In some embodiments of the invention, the herbal mixtures comprise, consist essentially of, or consist of a mixture of the herbs in approximately or precisely the proportions listed in Table 2 (see Original Patent).

In some embodiments, the herbal mixtures of the invention comprise, consist essentially of or consist of the herbal ingredients in the approximate or precise proportions set forth in Table 3 (see Original Patent).

In particular embodiments, the invention provides herbal mixtures comprising, consisting essentially of or consisting of the herbal ingredients in approximately or precisely the proportions set forth in Table 4 (see Original Patent).

The terms comprising, consisting essentially of and consisting of have the meanings generally accepted in the art. The term approximate and its variants mean that the tolerance for a particular value in the respective table is in the range of +/-10% of the value given. Thus, for example, a value that is approximately 10% would be (10+/-1) %: that is in the range of 9-11%. The term precise and its variants mean that the tolerance for a particular value in the respective table is in the range of +/-1% of the value given. Thus, for example, a value that is precisely 10.0% would be (10+/-0.1) %: that is in the range of 9.9 to 10.1%. In some embodiments, the proportions given in Tables 1-3 are approximate, whereas in other embodiments the proportions are precise.

In some embodiments, the present invention provides a composition that is an extract of an herbal mixture as described above. In some embodiments, the extract of the invention is an extract of an herbal mixture comprising the herbs: Herba Scutellaria Barbata, Radix Sophora Subprostratae, Radix Anamarrhena, Semen Glycine Sojae, Radix Glycyrrhiza, Rhizoma Rhei, Fructus Tritici Levis, Radix Astragali, Radix Rehmania, Fructus Ligustri Lucidi, Semen Zyziphi Spinozae, Plumula Nelumbinis, Poria Cocos, Rhizoma Alismatis, Cortex Moutan Radicis, Fructus Corni, Radix Achyranthis, Concha Ostrea, Radix Asparagi and Radix Pueraria. In some embodiments, the extract is an extract of a significant amount of each of the herbs: Herba Scutellaria Barbata, Radix Sophora Subprostratae, Radix Anamarrhena, Semen Glycine Sojae, Radix Glycyrrhiza, Rhizoma Rhei, Fructus Tritici Levis, Radix Astragali, Radix Rehmania, Fructus Ligustri Lucidi, Semen Zyziphi Spinozae, Plumula Nelumbinis, Poria Cocos, Rhizoma Alismatis, Cortex Moutan Radicis, Fructus Corni, Radix Achyranthis, Concha Ostrea, Radix Asparagi and Radix Pueraria. In other embodiments, the extract is an extract of an herbal mixture set forth in Table 2. In further embodiments, the extract is an extract of an herbal mixture set forth in Table 3. In still further embodiments, the extract is an extract of an herbal mixture set forth in Table 4 (see Original Patent).

In some embodiments of the invention, the composition is a reduced or dehydrated extract of a herbal mixture. In some embodiments, the composition is a dehydrated or reduced extract of an herbal mixture comprising the herbs: Herba Scutellaria Barbata, Radix Sophora Subprostratae, Radix Anamarrhena, Semen Glycine Sojae, Radix Glycyrrhiza, Rhizoma Rhei, Fructus Tritici Levis, Radix Astragali, Radix Rehmania, Fructus Ligustri Lucidi, Semen Zyziphi Spinozae, Plumula Nelumbinis, Poria Cocos, Rhizoma Alismatis, Cortex Moutan Radicis, Fructus Corni, Radix Achyranthis, Concha Ostrea, Radix Asparagi and Radix Pueraria. In some embodiments, the composition is a reduced or dehydrated extract of a significant amount of each of the herbs: Herba Scutellaria Barbata, Radix Sophora Subprostratae, Radix Anamarrhena, Semen Glycine Sojae, Radix Glycyrrhiza, Rhizoma Rhei, Fructus Tritici Levis, Radix Astragali, Radix Rehmania, Fructus Ligustri Lucidi, Semen Zyziphi Spinozae, Plumula Nelumbinis, Poria Cocos, Rhizoma Alismatis, Cortex Moutan Radicis, Fructus Corni, Radix Achyranthis, Concha Ostrea, Radix Asparagi and Radix Pueraria. In other embodiments, the composition is a reduced or dehydrated extract of an herbal mixture set forth in Table 2 or Table 3 or Table 4 (see Original Patent).

In some embodiments, the present invention provides a composition that is a combination of one or more of the foregoing extracts or reduced or dehydrated extracts with one or more suitable diluents, flavoring agents, excipients or other additives. Suitable diluents include water, for example deionized water, water for injection (WFI), filtered water, etc. Other suitable diluents include fruit juices, teas, milk, milk of magnesia, etc. Suitable flavorings include fruit flavorings, wintergreen, peppermint, spearmint, cinnamon, etc. Other suitable additives including food colorings and ethanol. In some embodiments, the composition comprises a dehydrated extract combined with one or more diluents, flavoring agents or other additives. In other embodiments, the composition comprises a reduced extract in combination with one or more diluents, flavoring agents or other additives. In some particular embodiments, the dehydrated extract is a dehydrated extract of one of the mixtures set forth in Table 2, Table 3 or Table 4 (see Original Patent). In other particular embodiments, reduced extract is a reduced extract of one of the herbal mixtures set forth in Table 2, Table 3 or Table 4 (see Original Patent).

The compositions according to the invention include mixtures of the herbs: Herba Scutellaria Barbata, Radix Sophora Subprostratae, Radix Anamarrhena, Semen Glycine Sojae, Radix Glycyrrhiza, Rhizoma Rhei, Fructus Tritici Levis, Radix Astragali, Radix Rehmania, Fructus Ligustri Lucidi, Semen Zyziphi Spinozae, Plumula Nelumbinis, Poria Cocos, Rhizoma Alismatis, Cortex Moutan Radicis, Fructus Corni, Radix Achyranthis, Concha Ostrea, Radix Asparagi and Radix Pueraria, especially significant amounts of each of the herbs, and more particularly mixtures of each of the herbs approximately or precisely as set forth in one of Table 2, Table 3 or Table 4. Such mixtures of herbs may be made in a convention manner: that is by weighing out an appropriate amount of each herb and combining the various herbs to form the herbal mixture. This process may include additional steps, such as grinding or agitating the mixture. The mixture may be consumed as is, or it may be present in one or more capsules suitable for oral administration to a subject. In particular embodiments, the herbal mixture may be further processed, such as by preparing an extract of the mixture.

An extract of an herbal mixture according to the present invention may be prepared in a conventional manner, such as by combining the herbal mixture with one or more solvents for a time and under conditions suitable for preparing the extract. After the herbal mixture and solvent have been in contact for a period of time suitable to form the extract, the solvent and herbs are separated by a suitable method, such as filtering or centrifugation. The liquid comprising the solvent represents the extract. This extract can then be further processed, such as by reducing or dehydrating the extract, combining the extract with further ingredients, or both.

Suitable solvents for the extraction process (extraction solvents) include aqueous solvents, such as pure water and aqueous solutions of ethanol. Suitable conditions include applying heat to the mixture of extraction solvent and herbs. In certain embodiments, the solvent and herbal mixture are heated to boiling for a period of time. In particular embodiments, the herbal mixture is combined with water and the combination is boiled for a period exceeding about 1 minute, especially for a period exceeding 5 minutes.

In a particular embodiment of the invention, the herbal mixture set forth in Table 5 (see Original Patent), above, is combined with water and then heated to the boiling point for a period of time suitable to prepare an extract. After separating the water from the boiled herbs, water is removed by dehydration and the remaining residue is collected as a composition according to the invention (dehydrated extract). This dehydrated extract may then be diluted with hot water and drunk as a tea, or it may be combined with other flavorings or prepared in one or more gelatin capsules.

A method of the invention comprises consuming an amount of the invention compositions sufficient to treat a symptom of menopause. A "symptom of menopause" is a symptom associated with one or more of peri-menopause, menopause or post-menopause. Symptoms of menopause include hot flashes and sweating secondary to vasomotor instability, fatigue, irritability, insomnia, inability to concentrate, depression, memory loss, headache, anxiety, nervousness, intermittent dizziness, paresthesias, palpitations, tachycardia, nausea, constipation, diarrhea, arthralgia, myalgia, cold hands and feet, weight gain, urinary incontinence, vaginal dryness and loss of pelvic muscle tone. In particular embodiments, the method includes treatment of hot flashes.

The term treatment and its grammatical variants include reducing the frequency or severity of a particular symptom. The frequency of a symptom may be determined in an art-recognized manner, such as by one or more automated biometric methods (measurement of blood pressure, pulse rate, breathing rate, breathing volume, electrocardiogram, skin resistivity, electroencephalogram, etc.) or by requesting the subject to record the frequency of the symptom on a questionnaire. The severity of a symptom may also be determined by one or more of the aforementioned biometric methods or by questionnaire. Thus, measurement of frequency and severity of symptoms may be subjective, objective or both.

An amount of an invention composition sufficient to treat a symptom of menopause is thus an amount of the mixture of herbs, extract of the mixture of herbs, or mixture of extracts of herbs sufficient to reduce the frequency of the menopausal symptom, ameliorate the severity of the symptom, or both. In general, the amount needed to treat a symptom will depend upon the subject's age, weight, general health, genetic makeup, emotional condition, and other factors. The effective amount may be chosen to be more or less effective than estrogen hormone replacement therapy. Thus, an amount of an invention composition suitable for a daily dose will be equivalent to about 0.01 to 100 grams of an herbal mixture of the invention per kilogram body weight of the subject, and more particularly about 0.05 to about 50 grams per kilogram body weight of the subject. In terms of an extract according to the invention, the daily dose will be in the range of about 1 to 10,000 mg of dry extract per kg body weight, more particularly about 2 to about 5,000 mg/kg. The person skilled in the art will recognize that, although the invention compositions are believed to be safe, and in particular to present a reduced risk of causing estrogen replacement-related problems such as increased risk of breast cancer, nonetheless the lowest dose capable of reducing the menopausal symptom should be used. The person skilled in the art will likewise be able to titrate the dose necessary to achieve the desired symptom-relieving effect within the stipulated ranges, and will likewise recognize that upward or downward deviations from those ranges may be tolerated within the scope of the present invention.

Despite compelling evidence that estrogens cause breast cancer, observational studies paradoxically show that women in Asian countries have the lowest incidence of breast cancer even though they consume large quantities of plant estrogens (phytoestrogens). Likewise, Asian women report minimal symptoms during menopause and are far less prone to experience hot flashes at the time of cessation of ovarian function. These findings have encouraged many menopausal women in the United States to take phytoestrogens present in soybeans or herbal therapies as an alternative to estrogen, hoping to alleviate hot flashes without increasing their risk of developing breast cancer. Different estrogenic compounds may exert opposite effects on breast cells. Estrogens, such as estradiol (E.sub.2), promote breast cancer, whereas phytoestrogens may contribute to the low incidence of breast cancer that is observed in Asia. Although there are substantial laboratory and observational data to support this theory (Kurtzer M. Phytoestrogen supplement use by women. J. Nutr. 2003; 133: 1983S-1986S), to date no randomized controlled studies have documented that phytoestrogens reduce breast cancer risk.
 

Claim 1 of 9 Claims

1. A pharmaceutical composition comprising an extract of an herbal mixture comprising herbal ingredients of Herba Scutellaria barbara, Radix Sophora subprostrata, Radix Anamarrhena, Semen Glycine sojae, Radix Glycyrrhiza, Rhizoma Rhei, Fructus Tritici levis, Radix Astragali, Radix Rehmannia, Fructus Ligustri lucidi Semen Zyziphi spinosae, Plumula nelumbinis, Poria cocos, Rhizoma Alismatis, Cortex Moutan radicis, Fructus Corni, Radix Achyranthis, Concha Ostrea, Radix Aspargi, Radix Pueraria, Radix Atractylodis macrocephala and Herba Epimedium, wherein the herbal mixture contains the herbal ingredients in the proportions set forth in the following table (see Original Patent).

 

 

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If you want to learn more about this patent, please go directly to the U.S. Patent and Trademark Office Web site to access the full patent.
 

 

     
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