Designing Treatments for Chemotherapy-Induced and Age-Related Menopausal Symptoms Using Combinations of Natural Products and Prescription Medications

Abstract

The present invention provides methods for alleviating menopausal symptoms as a result of chemotherapy-induced or natural menopause in a subject, the method comprising administering an effective amount of a natural product or combination of natural products tailored to a subjects specific symptoms, with an effective amount of hormonal or non-hormonal synthetic prescription medication. In particular embodiments, the natural product or combination of natural products alleviate vasomotor menopausal symptoms in a subject, while the prescription medication alleviates symptoms associated with genitourinary syndrome of menopause. In some embodiments, the natural product or combination of natural products is prepared in formulations designed for administration at different times of day.

Claims

1. A method for alleviating chemotherapy induced or age related menopausal symptoms in a subject, the method comprising administering an effective amount of a natural product or combination of natural products, or pharmaceutically acceptable salts thereof, in combination with an effective amount of a hormonal or non-hormonal prescription medication to the subject.

2. The method of claim 1, wherein the prescription medication is ospemifene, represented by Formula I, bazedoxifene/conjugated estrogens, represented by Formula II, or paroxetine, represented by Formula III, ##STR00002##

3. The method of claim 1, wherein the prescription medication is a non-estrogen therapy prescribed for the treatment of menopausal symptoms in women.

4. The method of any one of claims 1 to 3, wherein the subject is experiencing menopausal symptoms as a result of chemotherapy-induced menopause.

5. The method of any one of claims 1 to 3, wherein the subject is experiencing menopausal symptoms as a result of natural menopause.

6. The method of claims 4 and 5, wherein the natural product or combination of natural products is selected from the group consisting of black cohosh, a phytoestrogen, a cannabinoid, a terpene, an herbal product, and combinations thereof.

7. The method of claims 4 and 5, wherein the phytoestrogen is selected from the group consisting of an isoflavone, a lignan, a coumestan, and combinations thereof.

8. The method of claims 4 and 5, wherein the cannabinoid is selected from the group consisting of Δ.sup.8-THC, Δ.sup.9-THC, Δ.sup.8-THCA, Δ.sup.9-THCA, CBD, CBDA, CBC, CBN, CBG, CBGA, Δ.sup.8-THCV, Δ.sup.9-THCV, or their synthetic equivalents, and combinations thereof.

9. The method of claims 4 and 5, wherein the terpene is selected from the group consisting of α-bisabolol, trans-caryophyllene, p-cymene, guaiol, α-humulene, limonene, linalool, myrcene, cis-nerolidol, trans-nerolidol, α-pinene, β-pinene, terpinolene, or their synthetic equivalents, and combinations thereof.

10. The method of claim 5, wherein the herbal product is selected from the group consisting of Panax ginseng C. A. Meyer, Panax quinquefolium, Ginkgo biloba, curcumin, and any other natural product that may have benefits in the management of menopausal symptoms but cannot be classified as a phytoestrogen.

11. The method of any one of claims 1 to 10, wherein the effective amount of hormonal or non-hormonal prescription medication is the amount prescribed by the subject's physician.

12. The method of any one of claims 1 to 11, wherein the effective amount of natural product or combination of natural products is the amount that effectively alleviates chemotherapy-induced menopausal symptoms in the subject.

13. The method of any one of claims 1 to 11, wherein the effective amount of natural product or combination of natural products is the amount that effectively alleviates natural menopausal symptoms in the subject.

14. The method of claims 12 and 13, wherein the subject individually tailors the dose of natural product or combination of natural products to achieve satisfactory treatment of the subject's specific menopausal symptoms.

15. A kit comprising one or more natural products or combinations of natural products.

16. The kit of claim 15, further comprising a label with instructions for administering the one or more natural products or combinations of natural products in combination with the subject's prescription medication.

17. The kit of claims 15 and 16, wherein the natural product or combinations of natural products are selected from the group consisting of black cohosh, a phytoestrogen, a cannabinoid, a terpene, an herbal product, and combinations thereof.

18. The kit of claim 17, wherein the phytoestrogen is selected from the group consisting of an isoflavone, a lignan, a coumestan, and combinations thereof.

19. The kit of claim 17, wherein the cannabinoid is selected from the group consisting of Δ.sup.8-THC, Δ.sup.9-THC, Δ.sup.8-THCA, Δ.sup.9-THCA, CBD, CBDA, CBC, CBN, CBG, CBGA, Δ.sup.8-THCV, Δ.sup.9-THCV, or their synthetic equivalents, and combinations thereof.

20. The kit of claim 17, wherein the terpene is selected from the group consisting of α-bisabolol, trans-caryophyllene, p-cymene, guaiol, α-humulene, limonene, linalool, myrcene, cis-nerolidol, trans-nerolidol, α-pinene, β-pinene, terpinolene, or their synthetic equivalents, and combinations thereof.

21. The kit of claim 17, wherein the herbal product is selected from the group consisting of Panax ginseng C. A. Meyer, Panax quinquefolium, Ginkgo biloba, curcumin, and any other natural product that may have benefits in the management of menopausal symptoms but cannot be classified as a phytoestrogen.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

[0036] FIG. 1. Chemical structures of ospemifene, BZA/CE, and paroxetine. Systematic (IUPAC) designation for ospemifene: Z-2-[4-(4-chloro-1,2-diphenyl-but-1-enyl)-phenoxy]ethanol. IUPAC designation for bazedoxifene: 1-[[4-[2-(azepan-1-yl)ethoxy]phenyl]methyl]-2-(4-hydroxyphenyl)-3-methylindol-5-ol. IUPAC designation for paroxetine: (3S,4R)-3-(1,3-benzodioxol-5-yloxymethyl)-4-(4-fluorophenyl)piperidine.

[0037] FIG. 2. Chemical structures of triterpene glycosides found in black cohosh. IUPAC designation for actein (CAS 18642-44-9): (1′R,2S,4'S,4aR,5'S,5aR,7R,7aR,7bR,8R,10R,11aS, 12aS,12bS,14aR)-4′-Hydroxy-1,1,5′,7a,8,12a-hexamethyl-2-(β-D-xylopyranosyloxy)hexa-deca-hydro-2H-spiro[cyclopropa[1′,8a′]naphtho[2′,1′:4,5]indeno[2,1-b]pyran-10,2′-[3,6]dioxabicyclo [3.1.0]hexan]-7-yl acetate. IUPAC designation for 23-epi-26-deoxyactein (CAS 264624-38-6): (1′R,2S,4aR,5′R,5aR,7R,7aR,7bR,8R,10R,11aS,12aS,12bS,14aR)-1,1,5′,7a,8,12a-hexamethyl-2-(β-D-xylopyranosyloxy)hexadecahydro-2H-spiro[cyclopropa[1′,8a′]naphtho[2′,1′:4,5]indeno [2,1-b]pyran-10,2′-[3,6]-dioxabicyclo[3.1.0]hexan]-7-yl acetate.

[0038] FIG. 3. Chemical structures of common cannabinoids. (1) Δ.sup.9-Tetrahydrocannabinol (Δ.sup.9-THC; CAS 1972-08-3): 6,6,9-trimethyl-3-pentyl-6a,7,8,10a-tetrahydrobenzo[c]chromen-1-ol. (2) Δ.sup.9-Tetrahydrocannabinolic acid (Δ.sup.9-THCA; CAS 23978-85-0): (6aR,10aR)-1-hydroxy-6,6,9-tri-methyl-3-pentyl-6a,7,8,10a-tetrahydro-benzo[c]chromene-2-carboxylic acid. (3) Cannabidiol (CBD; CAS 13956-29-1): 2-[(1R,6R)-3-methyl-6-prop-1-en-2-ylcyclohex-2-en-1-yl]-5-pentyl-benzene-1,3-diol. (4) Cannabidiolic acid (CBDA; CAS 1244-58-2): 2,4-dihydroxy-3-[(1R,6R)-3-methyl-6-prop-1-en-2-ylcyclohex-2-en-1-yl]-6-pentylbenzoic acid. (5) Cannabinol (CBN; CAS 521-35-7): 6,6,9-trimethyl-3-pentylbenzo[c]chromen-1-ol. (6) Cannabigerol (CBG; CAS 25654-31-3): 2-[(2E)-3,7-dimethylocta-2,6-dienyl]-5-pentylbenzene-1,3-diol. (7) Cannabigerolic acid (CBGA; CAS 25555-57-1): 3-[(2E)-3,7-dimethylocta-2,6-dienyl]-2,4-dihydroxy-6-pentylbenzoic acid. (8) Cannabichromene (CBC; CAS 20675-51-8): 2-methyl-2-(4-methyl-pent-3-enyl)-7-pentylchromen-5-ol. (9) Δ.sup.9-Tetrahydrocannabivarin (Δ.sup.9-THCV; CAS 31262 37-0): (6aR,10aR)-6,6,9-trimethyl-3-propyl-6a,7,8,10a-tetrahydrobenzo[c]chromen-1-ol.

[0039] FIG. 4. Chemical structures of common terpenes found in cannabis. (1) α-Bisabolol (CAS 515-69-5): (2R)-6-methyl-2-[(1R)-4-methylcyclohex-3-en-1-yl]hept-5-en-2-ol. (2) trans-Caryophyllene (CAS 87-44-5): (1R,9S,Z)-4,11,11-trimethyl-8-methylenebicyclo[7.2.0]undec-4-ene. (3) p-Cymene (CAS 99-87-6): 1-methyl-4-propan-2-ylbenzene. (4) Guaiol (CAS 489-86 1): 2-[(3S,5R,8S)-3,8-dimethyl-1,2,3,4,5,6,7,8-octahydroazulen-5-yl]propan-2-ol. (5) α-Humulene (CAS 6753-98-6): (1Z,4Z,8Z)-2,6,6,9-tetramethylcycloundeca-1,4,8-triene. (6) Limonene (CAS 138-86-3): 1-methyl-4-prop-1-en-2-ylcyclohexene. (7) Linalool (CAS 78-70-6): 3,7-di-methylocta-1,6-dien-3-ol. (8) Myrcene (CAS 123-35-3): 7-methyl-3-methylideneocta-1,6-diene. (9) cis-Nerolidol (CAS 3790-78-1): (6Z)-3,7,11-trimethyldodeca-1,6,10-trien-3-ol. (10) trans-Nerolidol (CAS 7212-44-4): (6E)-3,7,11-trimethyldodeca-1,6,10-trien-3-ol. (11) α-Pinene (CAS 80-56-8): 4,6,6-trimethylbicyclo[3.1.1]hept-3-ene. (12) β-Pinene (CAS 127-91-3): 6,6-di-methyl-4-methylidenebicyclo[3.1.1]heptane. (13) Terpinolene (CAS 586-62-9): 1-methyl-4-propan-2-ylidenecyclohexene.

DETAILED DESCRIPTION OF THE INVENTION

I. Introduction

[0040] This invention involves the development of tailored, hormonal and non-hormonal combinations of natural products, including but not limited to black cohosh, phytoestrogens, cannabinoids, herbal products, and terpenes, with synthetic prescription medications (e.g., ospemifene, BZA/CE, paroxetine) for the alleviation of menopausal symptoms, which include hot flashes, night sweats, insomnia, dyspareunia and vaginal dryness, in perimenopausal women, postmenopausal women who have become menopausal as a result of chemotherapy for breast, gynecologic and other cancers (i.e., chemotherapy-induced menopause), and postmenopausal women who have become menopausal naturally. These novel combinations are designed to provide the benefits of conjugated equine estrogens (CEE) (i.e., biosimilar) without the associated risks of estrogen, the use of which is contraindicated in women with a history of hormone-responsive cancer. The increased risks of breast cancer and coronary heart disease that have been associated with the use of hormone replacement therapy such as Premarin® have become a major concern among healthy postmenopausal women, and in cancer survivors in whom estrogen-based therapies are an option. The treatment combinations developed under this invention will be individually tailored such that cancer survivors suffering from chemotherapy-induced menopausal symptoms, as well as naturally postmenopausal women, would combine a dose of synthetic medication as prescribed by their physicians for a specific indication (e.g., a 60-mg dose for treatment of dyspareunia and/or vaginal dryness associated with GSM in the case of ospemifene), with an amount of black cohosh, phytoestrogens, terpenes, herbal products, or cannabinoids, or combinations thereof, that results in the satisfactory alleviation of their specific symptoms. Treatment combinations may also include other types of prescription medication (e.g., BZA/CE and paroxetine) used at the recommended dosages for treatment of the approved indications (e.g., vasomotor symptoms in the case of BZA/CE and paroxetine).

[0041] The dosing regimen will be individually tailored to the subject's specific symptoms by combining the prescription medication (e.g., ospemifene), with a low dose of black cohosh, phytoestrogens, herbal products, terpenes, or cannabinoids, or different combinations of these components. If the subject finds that symptom relief is unsatisfactory, the natural product dosing will be gradually increased until optimum benefits are achieved. Different combinations of natural products and doses may be required to achieve maximum efficacy. These combinations include, but are not limited to, black cohosh with one or more phytoestrogen(s), black cohosh with one more cannabinoids, black cohosh with one or more herbal products, and one or more cannabinoids with one or more phytoestrogens. Natural products may also be used as single agents in combination with a subject's hormonal or non-hormonal synthetic prescription medication. The cannabinoids component may consist of THC (Δ.sup.8 or Δ.sup.9), CBD, CBG, CBN, CBC or THCV (Δ.sup.8 or Δ.sup.9), or any combination of these, especially THC (Δ.sup.8 or Δ.sup.9) and CBD. The ratios between cannabinoid components can be equal (e.g., 1:1 Δ.sup.9-THC:CBD) or any other ratio designed to achieve a specific effect (e.g., 3:1 Δ.sup.9-THC:CBD for hot flashes and night sweats, or 3:1 CBD:Δ.sup.9-THC for symptoms of anxiety). Multiple dose levels of each natural product and various combinations are formulated to allow subjects to tailor their individual treatments to the fit their specific symptoms. The phytoestrogen component may consist of an isoflavone (e.g., genestein or daidzein), a lignan (e.g., enterodiol or enterolactone), or a coumestan (e.g., coumestrol). The herbal product component may consist of curcumin, ginseng (e.g., Panax ginseng C. A. Meyer; Panax quinquefolium, also known as American ginseng), Gingko, or other natural product with potentially beneficial effects against menopausal symptoms, or any combination of these agents. The terpenes component may consist of α-bisabolol, trans-caryophyllene, p-cymene, guaiol, α-humulene, limonene, linalool, myrcene, cis-nerolidol, trans-nerolidol, α-pinene, β-pinene, or terpinolene, or any combination of these.

[0042] The natural products and combinations are formulated as tinctures, gels, creams, lotions, patches for transdermal delivery, or other suitable formulation that most appeals to the individual subject. In addition to specific natural products or combinations used to treat a particular menopausal symptom or symptoms, formulations can be designed for use at a particular time of day such as morning or evening so that unwanted effects may be avoided. For example, a 3:1 Δ.sup.9-THC:CBD cannabinoid combination would be used in the evening when the sedative effects of Δ.sup.9-THC may be desired, whereas the 3:1 CBD:Δ.sup.9-THC cannabinoid combination would be used in the morning so that the subject can remain alert while still receiving the benefit of menopausal symptom relief.

II. Definitions

[0043] Unless specifically indicated otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by those of ordinary skill in the art to which this invention belongs. In addition, any method or material similar or equivalent to a method or material described herein can be used in the practice of the present invention. For purposes of the present invention, the following terms are defined.

[0044] The terms “a,” “an,” or “the” as used herein not only include aspects with one member, but also include aspects with more than one member. For instance, the singular forms “a,” “an,” and “the” include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to “a natural product” includes a plurality of such natural products, and reference to “a phytoestrogen,” “an herbal product,” “a cannabinoid,” or “a terpene” includes a plurality of such products or compounds known to those skilled in the art, and so forth.

[0045] The terms “subject,” “patient,” or “individual” are used herein interchangeably.

[0046] As used herein, the term “administering” includes oral administration, topical contact, administration as a suppository, intravenous, intraperitoneal, intramuscular, intralesional, intrathecal, intranasal, or subcutaneous administration to a subject. Administration is by any route, including parenteral and transmucosal (e.g., buccal, sublingual, palatal, gingival, nasal, vaginal, rectal, or transdermal). Parenteral administration includes, e.g., intravenous, intramuscular, intra-arteriole, intradermal, subcutaneous, intraperitoneal, intraventricular, and intracranial. Other modes of delivery include, but are not limited to, the use of liposomal formulations, intravenous infusion, transdermal patches, etc. One skilled in the art will know of additional methods for administering an effective amount of the compounds described herein for the alleviation of menopausal symptoms in an individual.

[0047] The term “effective amount” includes an amount or quantity effective, at dosages and for periods of time necessary, to produce a desired (e.g., therapeutic or prophylactic) result with respect to the indicated disease, disorder, or condition. The desired result may comprise a subjective or objective improvement in the recipient of the effective amount. In one non-limiting example, an effective amount of black cohosh extract used in combination with the prescription medication ospemifene includes an amount or dosage sufficient to relieve hot flashes and night sweats. Also, for example, an effective amount of natural product includes an amount or dosage sufficient to decrease symptoms of GSM in a subject taking prescription medication for the treatment of vasomotor symptoms. The effective amount will vary with the type of subject being treated and the compound or combination of compounds applied.

[0048] The term “cannabinoid” refers to any member of the broad class of phytocannabinoid compounds derived from the cannabis plant (Cannabis spp.), or their synthetic equivalents, including, but not limited to Δ.sup.8-THC, Δ.sup.9-THC, CBD, CBG, CBC, Δ.sup.8-THCV, Δ.sup.9-THCV, CBN and any of their associated carboxylic acid forms.

[0049] Δ.sup.8. THC and Δ.sup.9-THC refer to, respectively, Δ.sup.8-tetrahydrocannabinol and Δ.sup.9-tetrahydrocannabinol.

[0050] CBD refers to cannabidiol.

[0051] CBG refers to cannabigerol.

[0052] CBC refers to cannabichromene.

[0053] CBN refers to cannabinol.

[0054] Δ.sup.8-THCV and Δ.sup.9-THCV refer to, respectively, Δ.sup.8-tetrahydrocannabivarin and Δ.sup.9-tetrahydrocannabivarin.

[0055] The term “natural product” refers to black cohosh, phytoestrogens, terpenes, cannabinoids, and herbal products.

[0056] The term “phytoestrogen” refers to any plant-derived natural product that has non-steroidal, estrogen-like activity, including, but not limited to, isoflavones and lignans.

[0057] The term “isoflavone” refers to genistein, daidzein, and related compounds.

[0058] The term “lignan” refers to enterodiol, enterolactone, and related compounds.

[0059] The term “ginseng” refers to Panax ginseng C. A. Meyer, Panax quinquefolium, and related species.

[0060] The term “terpene” refers to any of a class of plant-derived monocyclic or bicyclic hydrocarbons, including, but not limited to, α-bisabolol, trans-caryophyllene, p-cymene, guaiol, α-humulene, limonene, linalool, myrcene, cis-nerolidol, trans-nerolidol, α-pinene, β-pinene, terpinolene and related compounds.

[0061] The term “herbal product” refers to ginseng, curcumin, Ginkgo biloba, and any other natural product that may have benefits in the management of menopausal symptoms but cannot be classified as a phytoestrogen.

[0062] The term “hormonal or non-hormonal prescription medication” refers to ospemifene, bazedoxifene/conjugated estrogens (BZA/CE), paroxetine, or any other non-estrogen therapy prescribed for the treatment of menopausal symptoms in women.

[0063] The term “menopausal symptoms” refers to any unpleasant symptoms experienced due to natural or chemotherapy-induced menopause, including, but not limited to, vaginal dryness, dyspareunia, hot flashes, insomnia, and night sweats.

[0064] The term “genitourinary syndrome of menopause” or GSM refers to the menopausal symptoms of vulvar and vaginal atrophy (VVA), vaginal dryness, itching, painful sexual intercourse (dyspareunia), and urinary symptoms such as urgency, incontinence, painful urination, and recurrent urinary tract infections.

III. Description of the Embodiments

[0065] A. Hormonal and Non-Hormonal Synthetic Prescription Medications

[0066] Hormonal and non-hormonal synthetic prescription medications can include any non-estrogen medications that are prescribed for the treatment of menopausal symptoms in post menopausal women. Examples include, but are not limited to, ospemifene (Formula I and FIG. 1), sold under the trade name Osphena® and indicated for the treatment of moderate to severe dyspareunia and vaginal dryness associated with GSM or VVA, BZA/CE (Formula II and FIG. 1), sold under the trade name Duavee® and indicated for the treatment of moderate to severe hot flashes and the prevention of postmenopausal bone loss, and paroxetine (Formula III and FIG. 1), sold under the trade name Brisdelle® and indicated for the treatment of moderate to severe vasomotor symptoms associated with menopause.

[0067] B. Natural Products

[0068] The natural products of the present invention are used in combination with a subject's hormonal or non-hormonal synthetic prescription medication for the alleviation of menopausal symptoms for which the subject's prescribed medication is not indicated. The natural product or combination of natural products used will depend on the nature of the menopausal symptoms afflicting the subject (e.g., vaginal dryness, dyspareunia, hot flashes, night sweats, insomnia), the prescription medication a subject is using, and whether the subject is menopausal as a result of chemotherapy for the treatment of a hormone-responsive cancer (i.e., chemotherapy-induced) or naturally menopausal.

[0069] Non-limiting examples of natural products include black cohosh, phytoestrogens, cannabinoids, herbal products, terpenes, and combinations thereof.

[0070] In some embodiments, the natural products of the present invention are agents that possess menopausal symptom alleviating effects that complement those of the subject's prescription medication when administered in combination. As a non-limiting example, a subject experiencing chemotherapy-induced menopausal symptoms being treated with ospemifene for vaginal dryness and/or dyspareunia can be administered a combination of black cohosh, cannabinoids, and terpenes to alleviate the subject's symptoms of hot flashes, night sweats, and insomnia, symptoms that are not addressed by the subject's prescription medication.

[0071] 1. Black Cohosh

[0072] Black cohosh (Cimicifuga racemosa) is an herbal remedy that is well known in the art for the treatment of menopausal symptoms, especially vasomotor symptoms. Extracts of black cohosh contain several pharmacologically active compounds, including triterpene gylcosides (e.g., actein and 23-epi-26-deoxyactein; FIG. 2), that have demonstrated utility in alleviating hot flashes in postmenopausal women.

[0073] In particular embodiments, extracts of black cohosh are useful when combined with hormonal and non-hormonal synthetic medications (e.g., ospemifene) that are prescribed for the treatment of menopausal symptoms related to GSM or VVA.

[0074] 2. Phytoestrogens

[0075] Phytoestrogens, which are estrogen-like, non-steroidal compounds derived from plants, include isoflavones from soy beans and red clover, lignans from flaxseed, and coumestans from peas, beans, and clover sprouts. These compounds are well known in the art and have been extensively evaluated clinically for their value in treating menopausal symptoms. Non-limiting examples of phytoestrogens include genistein, daidzein, enterodiol, enterolactone, and coumestrol.

[0076] In some embodiments, one or more phytoestrogens are combined with a synthetic prescription medication (e.g., ospemifene) to complement the therapeutic benefits of such medication in the treatment of menopausal symptoms.

[0077] 3. Cannabinoids

[0078] The medicinal qualities of cannabinoids, (e.g., Δ.sup.9-THC and CBD) are well known in the art, and have been studied for their potential utility in the management of menopausal symptoms. In the treatment of menopausal vasomotor symptoms, cannabinoids such as Δ.sup.9-THC and CBD have demonstrated some degree of efficacy. Non-limiting examples of cannabinoids include CBD, CBDA, CBG, CBGA, CBC, CBN, Δ.sup.9-THCV, Δ.sup.9-THC, and Δ.sup.9-THCA derived from Cannabis spp. and their synthetic equivalents.

[0079] In particular embodiments, a combination of CBD, CBDA, CBG, CBGA, Δ.sup.9-THC, and Δ.sup.9-THCA is combined with a synthetic prescription medication (e.g., ospemifene) indicated for the treatment of moderate to severe vaginal dryness and dyspareunia in order to provide additional relief from menopausal vasomotor symptoms in subjects with chemotherapy-induced menopause.

[0080] 4. Terpenes

[0081] Terpenes are ubiquitous among the various plant species that have been studied for their menopausal symptom alleviating effects and are well known in the art. In particular embodiments, the terpene component of cannabis extract, especially including a mixture of the compounds α-bisabolol, trans-caryophyllene, p-cymene, guaiol, α-humulene, limonene, linalool, myrcene, cis-nerolidol, trans-nerolidol, α-pinene, β-pinene, and terpinolene, is combined with a synthetic prescription medication (e.g., ospemifene) to augment and/or complement the efficacy of the prescribed medication in treating menopausal symptoms as a result of chemotherapy-induced menopause.

[0082] 5. Herbal Products

[0083] Other than black cohosh, phytoestrogens, cannabinoids, and terpenes, there are a number of other herbal products that have been studied for their potential efficacy in the treatment of menopausal symptoms. Non-limiting examples include ginseng (e.g., Panax ginseng C. A. Meyer and Panax quinquefolium), curcumin derived from turmeric, and Ginkgo (Ginkgo biloba). These compounds have demonstrated varying degrees of utility in the treatment of menopausal symptoms.

[0084] In some embodiments, one or more herbal products may be combined with synthetic prescription medication (e.g., ospemifene) to augment and/or complement the efficacy of the prescribed medication in treating menopausal symptoms.

[0085] C. Diseases and Conditions

[0086] 1. Chemotherapy-Induced Menopause

[0087] In certain other aspects, menopausal symptoms occurring as a result of chemotherapy-induced menopause, or simply induced menopause, can be effectively treated using a combination of one or more herbal products and a synthetic prescription medication indicated for such a subject's menopausal symptoms. Induced menopause occurs abruptly as a result of surgery, chemotherapy, and/or radiotherapy for cancer. Compared to women undergoing a natural transition into menopause, menopausal symptoms among cancer survivors can become more frequent and bothersome, particularly among breast cancer survivors, due to the effects of chemotherapy and adjuvant hormonal treatments such as aromatase inhibitors. Menopausal symptoms can be particularly distressing among younger, premenopausal women treated for breast cancer due to the harsh effects of chemotherapy and surgical removal of the ovaries. As the population of long-term cancer survivors continue to grow, so does the need for addressing the menopausal symptom treatment needs in these subjects.

[0088] In particular embodiments, a subject experiencing menopausal symptoms as a result of treatment for a hormone-responsive cancer (e.g., breast cancer), is treated with a combination of one or more natural products, especially a mixture of cannabinoids, black cohosh, and terpenes, in combination with a non-hormonal synthetic prescription medication (e.g., ospemifene).

[0089] 2. Menopausal Symptoms as a Result of Natural Menopause

[0090] In certain aspects, menopausal symptoms as a result of natural menopause can be effectively treated by administering one or more natural products in combination with a hormonal or non-hormonal synthetic prescription medication (e.g., ospemifene). Beginning during the menopausal transition (perimenopause) and continuing into postmenopause, women normally experience a number of different symptoms such as hot flashes, night sweats, insomnia, VVA, vaginal dryness, and painful sexual intercourse (dyspareunia), any or all of which can negatively affect their quality of life. Non-limiting examples of the most characteristic and problematic menopausal symptoms include hot flashes and night sweats, which are termed vasomotor symptoms and which are experienced by up to 80% of menopausal women at some point in their lives, insomnia, dyspareunia, and vaginal dryness. These symptoms are a natural result of the declining sex hormone levels that occur in women as they progress through the menopausal transition. Unlike vasomotor symptoms, which usually decrease in frequency and severity with time, symptoms such as vaginal dryness and dyspareunia are usually chronic and progressive without treatment.

[0091] In particular embodiments, a subject experiencing menopausal symptoms as a result of natural menopause is treated with a combination of one natural products, especially a mixture of black cohosh, cannabinoids, and terpenes, in combination with a hormonal or non-hormonal synthetic prescription medication (e.g., ospemifene).

[0092] D. Pharmaceutical Compositions

[0093] The natural products described herein are useful in the manufacture of a pharmaceutical composition or a medicament for alleviating menopausal symptoms in a subject experiencing such symptoms as a result of chemotherapy-induced menopause or natural menopause. In certain aspects, a pharmaceutical composition or medicament comprising one or more natural products can be administered to a subject for the treatment of menopausal symptoms in combination with synthetic hormonal or non-hormonal prescription medication to enhance the efficacy of the prescription medication.

[0094] Pharmaceutical compositions or medicaments for use in the present invention can be formulated by standard techniques or methods well-known in the art of pharmacy using one more physiologically acceptable carriers or excipients. Suitable pharmaceutical carriers are described herein and in, e.g., Remington's Pharmaceutical Sciences by E. W. Martin. Compounds and agents of the present invention and their physiologically acceptable salts and solvates can be formulated for administration by any suitable route, including, but not limited to, orally, topically, nasally, rectally, pulmonary, parenterally (e.g., intravenously, subcutaneously, intramuscularly, etc.), and combinations thereof. In some embodiments, the natural products are dissolved in a liquid, for example, water. The most suitable route of administration for a natural product or combination of natural products in any given case will depend, in part, on the type of natural product or products being used as well as the nature and severity of the subject's menopausal symptoms. In embodiments where the natural product or products are administered in combination with a synthetic prescription medication, the natural product or products and prescription medication may be administered by the same or different route of administration. For example, the prescription medication may be administered orally, while the natural product or products may be administered transdermally or topically.

[0095] The pharmaceutical compositions or medicaments of the present invention can include one or more natural products or any pharmaceutically acceptable salts thereof, as an active ingredient and a pharmaceutically acceptable carrier and/or excipient or diluent. In some embodiments, the pharmaceutical compositions comprising different natural products are prepared as separate medicaments. In some embodiments, the pharmaceutical compositions comprising different natural products are prepared as a single medicament.

[0096] In embodiments where more than one natural product is used, the natural products can be combined as an active ingredient in intimate admixture with a suitable pharmaceutical carrier and/or excipient according to conventional pharmaceutical compounding techniques. Any carrier and/or excipient suitable for the form or preparation desired for administration in contemplated for use with the compounds disclosed herein.

[0097] In certain embodiments, the pharmaceutical compositions or medicaments described herein are suitable for systemic administration. Systemic administration includes enteral administration (e.g., absorption of the compound through the gastrointestinal tract) or parenteral administration (e.g., injection, infusion, or implantation). In some embodiments, the pharmaceutical compositions or medicaments may be administered via a syringe or intravenously. In preferred embodiments, the pharmaceutical compositions or medicaments are injected subcutaneously.

[0098] In some embodiments, the present invention provides a pharmaceutical composition including black cohosh extract, phytoestrogens, cannabinoids, herbal products, terpenes, and a synthetic prescription medication. In some embodiments, the black cohosh extract, phytoestrogens, cannabinoids, herbal products, terpenes, and synthetic prescription medication are separately prepared pharmaceutical compositions. In some embodiments, the pharmaceutically acceptable excipient includes a salt or a diluent.

[0099] In some embodiments, the present invention provides a pharmaceutical composition including a phytoestrogen and a synthetic prescription medication. In some embodiments, the phytoestrogen and the synthetic prescription medication are separately prepared pharmaceutical compositions. In some embodiments, the pharmaceutically acceptable excipient includes a salt or a diluent.

[0100] In some embodiments, the present invention provides a pharmaceutical composition including an herbal product and a synthetic prescription medication. In some embodiments, the herbal product and the synthetic prescription medication are separately prepared pharmaceutical compositions. In some embodiments, the pharmaceutically acceptable excipient includes a salt or a diluent.

[0101] In some embodiments, the present invention provides a pharmaceutical composition including a combination of one or more natural products and a synthetic prescription medication. In some embodiments, the natural product or combination of natural products and the synthetic prescription medication are separately prepared pharmaceutical compositions. In some embodiments, the pharmaceutically acceptable excipient includes a salt or a diluent.

[0102] For oral administration, a pharmaceutical composition or a medicament can take the form of, e.g., a tablet or a capsule prepared by conventional means with a pharmaceutically acceptable excipient. Preferred are tablets and gelatin capsules comprising the active ingredient(s), together with (a) diluents or fillers, e.g., lactose, dextrose, sucrose, mannitol, sorbitol, cellulose (e.g., ethyl cellulose, microcrystalline cellulose), glycine, pectin, polyacrylates and/or calcium hydrogen phosphate, calcium sulfate, (b) lubricants, e.g., silica, anhydrous colloidal silica, talcum, stearic acid, its magnesium or calcium salt (e.g., magnesium stearate or calcium stearate), metallic stearates, colloidal silicon dioxide, hydrogenated vegetable oil, corn starch, sodium benzoate, sodium acetate and/or polyethylene glycol; for tablets also (c) binders, e.g., magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, polyvinylpyrrolidone and/or hydroxypropyl methylcellulose; if desired, (d) disintegrants, e.g., starches such as potato starch or sodium starch, glycolate, agar, alginic acid or its sodium salt, or effervescent mixtures; (e) wetting agents, e.g., sodium lauryl, sulfate, and/or (f) absorbents, colorants, flavors and sweeteners. In some embodiments, the tablet contains a mixture of hydroxypropyl methyl cellulose, polyethylene glycol 6000 and titanium dioxide. Tablets may be either film coated or enteric coated according to methods known in the art.

[0103] Liquid preparations for oral administration can take the form of, e.g., solutions, syrups, suspensions, and tinctures, or they can be presented as a dry product for constitution with water or other suitable vehicle before use. Such liquid preparations can be prepared by conventional means with pharmaceutically acceptable additives, e.g., suspending agents such as sorbitol syrup, cellulose derivatives, or hydrogenated edible fats; emulsifying agents such as lecithin or acacia; non-aqueous vehicles, e.g., almond oil, oily esters, ethyl alcohol, or fractionated vegetable oils; and preservatives, e.g., methyl- or propyl-p-hydroxybenzenes or sorbic acid. The preparations can also contain buffer salts, flavoring, coloring, and/or sweetening agents as appropriate. If desired, preparations for oral administration can be suitably formulated for any type of administration, e.g., intradermal, subdermal, intravenous, intramuscular, or intranasal, with a syringe or other devices. Formulation for administration by inhalation (e.g., aerosol), or for oral, rectal, or vaginal administration is also contemplated.

[0104] Pharmaceutical compositions for pulmonary administration include, but are not limited to, dry powder compositions consisting of the powder of a compound described herein, or a salt thereof, and the powder of a suitable carrier and/or lubricant. The compositions for pulmonary administration can be inhaled from any suitable dry powder inhaler device known to a person skilled in the art. In certain instances, the compositions may be conveniently delivered in the form of an aerosol spray from pressurized packs or a nebulizer, with the use of a suitable propellant, e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide, or other suitable gas. In the case of a pressurized aerosol, the dosage unit can be determined by providing a valve to deliver a metered amount. Capsules and cartridges of, e.g., gelatin for use in an inhaler or insufflator can be formulated containing a powder mix of the compound(s) and a suitable powder base such as lactose or starch.

[0105] The natural products of the present invention can also be formulated in rectal compositions such as suppositories or retention enemas, e.g., containing conventional suppository bases such as cocoa butter or other glycerides.

[0106] The compositions set forth herein can be formulated for parenteral administration by injection, e.g., by bolus injection. Formulations for injection can be presented in unit dosage form, e.g., in ampoules or in multi-dose containers, with an added preservative. Injectable compositions are preferably aqueous isotonic solutions or suspensions, and suppositories are preferably prepared from fatty emulsions or suspensions. The compositions may be sterilized and/or contain adjuvants, such as preserving, stabilizing, wetting or emulsifying agents, solution promoters, salts for regulating the osmotic pressure and/or buffers. Alternatively, the compound(s) can be in powder form for reconstitution with a suitable vehicle such as sterile pyrogen-free water, before use. In addition, they may also contain other therapeutically valuable substances. The compositions are prepared according to conventional mixing, granulating or coating methods, respectively, and contain approximately 0.1 to 75%, preferably about 1 to 50%, of the compound(s).

[0107] In some embodiments, the compounds are prepared with polysaccharide such as chitosan or derivatives thereof (e.g., chitosan succinate, chitosan phthalate, etc.), pectin and derivatives thereof (e.g., amidated pectin, calcium pectinate, etc.), chondroitin and derivatives thereof (e.g., chondroitin sulfate), and alginates.

[0108] In some embodiments, the compositions further include a pharmaceutical surfactant. In other embodiments, the compositions further include a cryoprotectant. Non-limiting examples of cryoprotectants include glucose, sucrose, trehalose, lactose, sodium glutamate, PVP, cyclodextrin, 2-hydroxypropyl-13-cyclodextrin (HP13CD) glycerol, maltose, mannitol, saccharose, and mixtures thereof.

[0109] E. Methods of Administration

[0110] Pharmaceutical compositions or medicaments comprising a natural product or products can be administered to a subject at a therapeutically effective dose in combination with an effective amount of synthetic hormonal or non-hormonal prescription medication, taken as prescribed by the subject's physician, to more effectively alleviate the subject's menopausal symptoms, as described herein. In some embodiments, the pharmaceutical composition or medicament comprising a natural product or product is administered to a subject in an amount sufficient in combination with an effective amount of synthetic prescription medication to elicit an effective therapeutic response in the subject. In some embodiments, the pharmaceutical composition or medicament comprising a natural product or products can be administered to a subject at a therapeutically effective dose in combination with an effective amount of a synthetic prescription medication (e.g., ospemifene) to effectively alleviate menopausal vasomotor symptoms as a result of chemotherapy-induced menopause. In some embodiments, the pharmaceutical composition or medicament comprising a natural product or products can be administered in combination with an effective amount of synthetic prescription medication to effectively alleviate vaginal dryness and dyspareunia in a subject experiencing chemotherapy-induced menopausal symptoms.

[0111] The combination therapy described herein includes simultaneous administration as well as sequential administration. In some embodiments, the pharmaceutical composition or medicament comprising a natural product or products is administered on a different time schedule than the synthetic prescription medication. As a non-limiting example, the pharmaceutical composition or medicament may be administered weekly, while the synthetic prescription medication (e.g., ospemifene) may be administered daily, or the pharmaceutical composition or medicament may be administered daily, while the synthetic prescription medication is administered weekly. The administration schedule of the prescription medication is dependent on the type of medication and the symptoms for which it is prescribed by the subject's physician.

[0112] In some embodiments, one or more natural products are administered to a subject in combination with synthetic prescription medication to alleviate vasomotor symptoms as a result of chemotherapy-induced menopause.

[0113] In particular embodiments, one or more natural products are administered to a subject in combination with ospemifene (Formula I) to alleviate vasomotor symptoms as a result of chemotherapy-induced menopause.

[0114] In some embodiments, one or more natural products are administered to a subject in combination with synthetic prescription medication (e.g., ospemifene) to alleviate vasomotor symptoms as a result of natural menopause.

[0115] In particular embodiments, one or more natural products are administered to a subject in combination with ospemifene (Formula I) to alleviate vasomotor symptoms as a result of natural menopause.

[0116] In some embodiments, one or more natural products are administered to a subject in combination with synthetic prescription medication (e.g., paroxetine, Formula III) to alleviate symptoms of vaginal dryness and dyspareunia as a result of chemotherapy-induced menopause.

[0117] In some embodiments, one or more natural products are administered to a subject in combination with synthetic prescription medication (e.g., paroxetine, Formula III) to alleviate symptoms of vaginal dryness and dyspareunia as a result of natural menopause.

[0118] In some embodiments, one or more natural products are administered to a subject without a synthetic prescription medication to alleviate vasomotor symptoms as a result of chemotherapy-induced menopause.

[0119] In some embodiments, one or more natural products are administered to a subject without a synthetic prescription medication to alleviate symptoms of vaginal dryness and dyspareunia as a result of chemotherapy-induced menopause.

[0120] In some embodiments, one or more natural products are administered to a subject without a synthetic prescription medication to alleviate vasomotor symptoms as a result of natural menopause.

[0121] In some embodiments, one or more natural products are administered to a subject without a synthetic prescription medication to alleviate symptoms of vaginal dryness and dyspareunia as a result of natural menopause.

[0122] In some embodiments, the methods of alleviating menopausal symptoms described herein are administered to a subject with chemotherapy-induced or natural menopause. In certain embodiments, the therapeutic agent is a natural product or combination of natural products combined with a hormonal or non-hormonal synthetic prescription medication.

[0123] The formulations of the present invention are useful in the manufacture of a pharmaceutical composition or a medicament. A pharmaceutical composition or medicament can be administered to a subject in need thereof, e.g., a subject experiencing menopausal symptoms as a result of chemotherapy-induced or natural menopause.

[0124] In certain methods of alleviating menopausal symptoms, set forth herein, the methods comprise administering a natural product or combination of natural products together with a hormonal or non-hormonal synthetic prescription medication. The natural products may be administered simultaneously with the prescription medication, or they may be administered according to a dosing schedule that best fits the subject's symptoms.

[0125] F. Dosage

[0126] Pharmaceutical compositions or medicaments comprising a natural product or products in combination with a hormonal or non-hormonal synthetic prescription medication can be administered to a subject at a therapeutically effective dose to alleviate menopausal symptoms as a result of chemotherapy-induced or natural menopause as described herein. The pharmaceutical compositions or medicaments are administered to a subject in an amount sufficient to elicit an effective therapeutic response in the subject.

[0127] The dosage of compounds administered is dependent on the subject's body weight, age, individual condition, and/or on the form of administration. The size of the dose will also be determined by the existence, nature, and extent of any adverse effects that accompany the administration of a particular compound in a particular subject. Typically, a dosage of the active compounds is a dosage that is sufficient to achieve the desired effect. Optimal doses and dosing schedules of natural product compositions can be determined on an individualized basis based on the needs of a particular subject. In general, dosage may be given once or more daily, weekly, or monthly. Persons of ordinary skill in the art can easily determine optimum dosages, dosing methodologies, and repetition rates.

[0128] The effective amount of a hormonal or non-hormonal synthetic prescription medication administered in combination with a natural product or combination of natural products may be provided at the dosages generally recommended for each prescription medication used.

[0129] In some embodiments, a unit dosage for oral administration of a natural product or combination of natural products to a subject (e.g., a human) of about 50 to about 70 kg may contain about 1 and about 500 mg, about 5 and about 500 mg, about 5 and about 250 mg, about 25 to about 250 mg, about 100 and about 1000 mg, about 200 and about 2000 mg, about 500 and about 5000 mg, or about 1000 and about 2000 mg of the compound(s). In particular embodiments, a unit dosage for oral administration of natural product or combination of natural products to a subject (e.g., a human) of about 50 to about 70 kg may contain about 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 75 mg, 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 700 mg, 800 mg, 900 mg, 1000 mg, 1250 mg, 1500 mg, 2000 mg, 2500 mg, 3000 mg, or more of the compound(s).

[0130] In some embodiments, a unit dosage for topical administration of natural product or combination of natural products to a subject (e.g., a human) of about 50 to about 70 kg may contain between 1 and about 100 mg, about 5 and about 100 mg, about 5 and about 50 mg, about 5 and about 25 mg, about 5 and about 10 mg, about 2.5 to about 50 mg, about 2.5 to about 25 mg, about 1 to about 50 mg, about 1 to about 25 mg, or about 1 to about 10 mg of the compound(s). In particular embodiments, a unit dosage for topical administration of a natural product or combination of natural products, to a subject (e.g., a human) of about 50 to about 70 kg may contain about 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 75 mg, 100 mg, or more of the compound(s).

[0131] When or more of the natural product compositions of the invention is administered to a subject, a relatively low dose is recommended at first, with the subject subsequently increasing the dose until an appropriate response is achieved (i.e., satisfactory alleviation of the subject's menopausal symptoms). In addition, it is understood that the specific dose level for any particular subject will depend upon a variety of factors including the activity of the specific composition employed, the age, body weight, general health, and diet of the subject, the time of administration, the route of administration, the rate of excretion, any drug combination, and the nature and degree of severity of the menopausal symptoms to be treated.

[0132] In some embodiments, a pharmaceutical composition or medicament of the present invention is administered orally once per day or divided into sub-doses and administered in multiple doses, e.g., twice, three times, or four times per day. In particular embodiments, a pharmaceutical composition comprised of a natural product or combination of natural products is administered twice per day, with or without a synthetic prescription medication (e.g., ospemifene), with each dose formulated specifically for the time of day (e.g., a morning dose and an evening dose). As a non-limiting example, the morning dose is formulated to include a 3:1 CBD:Δ.sup.9-THC cannabinoid ratio, and the evening dose is formulated to include a 3:1 Δ.sup.9-THC:CBD cannabinoid ratio. However, as will be appreciated by a skilled artisan, oral compositions described herein may be administered in different amounts and at different times.

[0133] In some embodiments, a pharmaceutical composition or medicament of the present invention is administered topically once per day or divided into sub-doses and administered in multiple doses, e.g., twice, three times, or four times per day. In particular embodiments, a pharmaceutical composition comprised of a natural product or combination of natural products is administered twice per day, with or without a synthetic prescription medication (e.g., ospemifene), with each dose formulated specifically for the time of day (e.g., a morning dose and an evening dose). As a non-limiting example, the morning dose is formulated to include a 3:1 CBD:Δ.sup.9-THC cannabinoid ratio, and the evening dose is formulated to include a 3:1 Δ.sup.9-THC:CBD cannabinoid ratio. However, as will be appreciated by a skilled artisan, topical compositions described herein may be administered in different amounts and at different times.

[0134] In some embodiments, the natural product or products are administered for about 1 to about 31 days, e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, or 31 days. In some embodiments, the natural product or products are administered for at least 1 day. In other embodiments, the natural product or products are administered for one or more weeks, e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or more weeks. In yet other embodiments, the natural product or products are administered for one or more months, e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or more months.

[0135] To achieve the desired therapeutic effect, the natural product or combination of natural products may be administered in combination with synthetic prescription medication for multiple days, weeks, months, or years at the therapeutically effective daily dose. Thus, therapeutically effective administration of the natural product or natural product combinations to alleviate pertinent menopausal symptoms described herein in a subject requires periodic (e.g., daily or twice daily) administration that continues for a period ranging from a few days, to a few weeks, to few months or longer. While consecutive daily doses are a preferred route to achieve a therapeutically effective dose, a therapeutically beneficial effect can be achieved even if the agents are not administered daily, so long as the administration is repeated frequently enough to maintain a therapeutically effective concentration of the agents in a subject. For example, one can administer the agent every day, every other day, or if higher dose ranges are employed and tolerated by the subject, twice a week.

[0136] The dosage of a pharmaceutical composition or medicament of the present invention can be monitored and adjusted throughout treatment, depending on the severity of symptoms, frequency of recurrence, and/or the physiological response to the therapeutic regimen. Those of skill in the art commonly engage in such adjustments in therapeutic regimens. Single or multiple administrations of the pharmaceutical compositions or medicaments can be administered depending on the dosage and frequency as required and tolerated by the subject. In any event, the composition or medicament should provide a sufficient quantity of the compounds of the invention to effectively treat a subject. Generally, the dose is sufficient to alleviate menopausal symptoms without producing unacceptable toxicity or side effects in a subject.

[0137] G. Kits, Container, Devices, and Systems

[0138] A wide variety of kits and systems can be prepared according to the present invention, depending on the intended user of the kit and system and the particular needs of the user. In some aspects, the present invention provides a kit that includes one or more natural products selected from a phytoestrogen, black cohosh, a cannabinoid, an herbal product, a terpene, and combinations thereof. In certain embodiments, the kit includes black cohosh, cannabinoids, and terpenes.

[0139] Some of the kits described herein include a label describing a method of administering one or more natural products to be used in combination with a subject's prescription medication for menopausal symptoms.

[0140] The compositions of the present invention, including but not limited to compositions comprising one or more natural products described herein, may, if desired, be presented in a bottle, inhaler, jar, vial, ampoule, tube, or other container closure system, which may provide one or more dosages containing the compounds. In certain aspects, the kit may include a formulation or composition as described herein, a container closure system including the formulation or a dosage unit form including the formulation, and a notice or instructions describing a method of use as described herein.

[0141] In some embodiments, the kit includes a container which is compartmentalized for holding the various elements of a formulation (e.g., the dry ingredients and the liquid ingredients) or composition, instructions for making the formulation or composition, and instructions for administering the formulation or composition for alleviating menopausal symptoms in a subject who is experiencing chemotherapy-induced or natural menopause.

[0142] In some embodiments, the instructions include timing information on when to administer one or more natural product or natural product combinations. In some embodiments, different formulations of natural products are included for use at particular times of day (e.g., morning or evening). A non-limiting example is a kit that includes instructions for administering formulations containing different ratios of the cannabinoids CBD and Δ.sup.9-THC. In particular embodiments, the cannabinoid ratios are 3:1 CBD: Δ.sup.9-THC and 3:1 Δ.sup.9-THC:CBD.

[0143] In certain embodiments, the kit may include the pharmaceutical preparation in dehydrated or dry form, with instructions for its rehydration (or reconstitution) and administration.

[0144] Kits with unit doses of the compounds described herein, e.g., in oral, inhalant, topical, or transdermal doses, are provided. In such kits, an information package insert describing the use and attendant benefits of the composition for alleviating menopausal symptoms in a subject experiencing chemotherapy-induced or natural menopause may be included in addition to the containers containing the unit doses.

[0145] Some embodiments of the present invention include packages that include one or more natural products or one or more natural product combinations as described herein.

IV. Examples

[0146] The following examples are offered to illustrate, but not to limit, the claimed invention.

[0147] In particular, Examples 1 and 2 illustrate the formulation of natural product tinctures for oral administration in accordance with embodiments of the invention.

Example 1: Formulation of IMT-121 (Morning “AM” Dose)

[0148] A tincture for oral administration for the alleviation of menopausal symptoms was formulated use in the morning (“AM Dose”) in combination with the non-hormonal synthetic prescription medication ospemifene. This tincture was formulated to contain cannabinoids, terpenes, and black cohosh extract. The cannabinoids and terpenes were obtained by ethanol extraction of different strains of commercially available cannabis containing varying amounts of CBD and Δ.sup.9-THC. These extracts are prepared in both activated form, whereby the extract is heated for a sufficient amount of time at sufficient temperature known in the art to convert the carboxylic acid forms of the cannabinoids to their active forms, and in inactivated form, which retains the natural content of the active and inactive forms of the major cannabinoids. The cannabinoid and terpene profiles of the IMT-121 AM Dose tincture are shown in the tables below. Concentrations of cannabinoids and terpenes were determined using validated HPLC and GC-FID analytical methodologies, respectively.

TABLE-US-00001 TABLE 1 IMT-121 AM Dose Cannabinoid Profile Cannabinoid Concentration (mg/mL) Cannabidiolic Acid (CBDA) 3.397 Cannabidiol (CBD) 3.172 Cannabigerol (CBG) 0.301 Cannabigerolic Acid (CBGA) 0.267 Δ.sup.9-Tetrahydrocannabinol (Δ.sup.9-THC) 1.475 Δ.sup.9-Tetrahydrocannabinolic Acid (Δ.sup.9-THCA) 1.312 Total Cannabinoids 9.924

TABLE-US-00002 TABLE 2 IMT-121 AM Dose Terpene Profile Terpene Concentration (mg/mL) α-Pinene 0.031 β-Pinene 0.014 Myrcene 0.043 p-Cymene 0.001 Limonene 0.012 Terpinolene 0.004 Linalool 0.008 trans-Caryophyllene 0.156 α-Humulene 0.051 cis-Nerolidol 0.032 trans-Nerolidol 0.115 Guaiol 0.007 α-Bisabolol 0.020 Total Terpenes* 0.494 *Includes unidentified terpenes.
Black cohosh was obtained from an extract containing 333 mg/mL herb weight equivalence. The triterpene glycoside content profile, determined by LC-MS/MS analytical methodology, is as follows:

TABLE-US-00003 TABLE 3 IMT-121 AM Dose Triterpene Glycoside Profile Triterpene Glycoside Concentration (mg/mL) Actein 22.2 23-epi-26-deoxyactein 22.2 Total Triterpene Glycosides 44.4

[0149] The IMT-121 AM Dose tincture for oral administration was prepared by combining the following materials in a 30-mL amber glass bottle fitted with glass dropper: (1) 7.5 mL of a 50%/50% (v/v) activated/inactivated extract of a high-CBD cannabis strain; (2) 1.0 mL of black cohosh extract (333 mg/mL); (3) 1.5 mL of 95% ethanol; (4) 5.0 mL of deionized water. The subject being treated for menopausal symptoms will take their prescribed daily dose of ospemifene, as directed by their physician, in combination with the described tincture designed to alleviate those menopausal symptoms for which ospemifene is not indicated (e.g., hot flashes, night sweats, insomnia).

Example 2: Formulation of IMT-121 (Evening “PM” Dose)

[0150] A tincture for oral administration for the alleviation of menopausal symptoms was formulated use in the evening (“PM Dose”) in combination with the non-hormonal synthetic prescription medication ospemifene. This tincture was formulated to contain cannabinoids, terpenes, and black cohosh extract. The cannabinoids and terpenes were obtained by ethanol extraction of different strains of commercially available cannabis containing varying amounts of CBD and Δ.sup.9-THC. These extracts were prepared in both activated form, whereby the extract was heated for a sufficient amount of time at a sufficient temperature known in the art to convert the carboxylic acid forms of the cannabinoids to their active forms, and in inactivated form, which retains the natural content of the active and inactive forms of the major cannabinoids. The cannabinoid and terpene profiles of the IMT-121 PM Dose tincture are shown in the tables below. Concentrations of cannabinoids and terpenes were determined using validated HPLC and GC-FID analytical methodologies, respectively.

TABLE-US-00004 TABLE 4 IMT-121 PM Dose Cannabinoid Profile Cannabinoid Concentration (mg/mL) Cannabidiolic Acid (CBDA) 3.397 Cannabidiol (CBD) 3.172 Cannabigerol (CBG) 0.238 Cannabigerolic Acid (CBGA) 0.133 Δ.sup.9-Tetrahydrocannabinol (Δ.sup.9-THC) 4.049 Δ.sup.9-Tetrahydrocannabinolic Acid (Δ.sup.9-THCA) 1.312 Total Cannabinoids 12.301

TABLE-US-00005 TABLE 5 IMT-121 PM Dose Terpene Profile Terpene Concentration (mg/mL) α-Pinene 0.031 β-Pinene 0.014 Myrcene 0.044 p-Cymene 0.001 Limonene 0.013 Terpinolene 0.004 Linalool 0.007 trans-Caryophyllene 0.162 α-Humulene 0.053 cis-Nerolidol 0.070 trans-Nerolidol 0.125 Guaiol 0.007 α-Bisabolol 0.046 Total Terpenes 0.577 *Includes unidentified terpenes.
Black cohosh was obtained from an extract containing 333 mg/mL herb weight equivalence. The triterpene glycoside content profile, determined by LC-MS/MS analytical methodology, is as follows:

TABLE-US-00006 TABLE 6 IMT-121 PM Dose Triterpene Glycoside Profile Triterpene Glycoside Concentration (mg/mL) Actein 22.2 23-epi-26-deoxyactein 22.2 Total Triterpene Glycosides 44.4

[0151] The IMT-121 PM Dose tincture for oral administration was prepared by combining the following materials in a 30-mL amber glass bottle fitted with glass dropper: (1) 7.5 mL of a 50%/50% (v/v) activated/inactivated extract of a high-CBD cannabis strain; (2) 1.0 mL of black cohosh extract (333 mg/mL); (3) 1.5 mL of an activated extract of a high-Δ.sup.9-THC cannabis strain; (4) 5.0 mL of deionized water. The subject being treated for chemotherapy-induced or natural menopausal symptoms will take their prescribed daily dose of ospemifene, as directed by their physician, in combination with the described tincture designed to alleviate those menopausal symptoms for which ospemifene is not indicated (e.g., hot flashes, night sweats, insomnia).

[0152] Although the foregoing invention has been described in some detail by way of illustration and example for purposes of clarity of understanding, one of skill in the art will appreciate that certain changes and modifications may be practiced within the scope of the appended claims. In addition, each reference provided herein is incorporated by reference in its entirety to the same extent as if each reference was individually incorporated by reference.