Methods of treating endometriosis and other non-cancer gynecological conditions with hemp extracts

Abstract

A method for treating a non-cancerous gynecological condition, the method comprising administering to a patient an effective amount of a composition comprising a cannabis extract comprising cannabidiol (CBD) wherein the composition is preferably administered in mucosal form, such as intravaginal.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims the benefit of the following U.S. provisional patent applications filed with the U.S. Patent and Trademark Office: No. 63 / 263,026 filed on October 26, 2021, No. 63 / 263,020 filed on October 26, 2021, and No. 63 / 263,022 filed on October 26, 2021, the contents of which are incorporated herein by reference in their entirety. Technical Field

[0003] The invention disclosed herein relates to compositions and therapeutic treatments for treating endometriosis and other non-cancerous gynecological conditions by administering an effective amount of a cannabis extract alone or in combination with a second therapeutic agent. The cannabis extract comprises one or more cannabinoids, particularly cannabidiol (CBD) in a therapeutic amount, and often comprises one or more additional cannabinoids, terpenes or other molecules within the cannabis extract. Background Art

[0004] Women face many non-cancerous gynecological conditions for which there are currently no adequate treatments. These conditions include non-life-threatening painful conditions such as fibroids, polycystic ovary syndrome, ovarian cysts, adhesions, pelvic masses, pelvic infections, endometriosis, dysmenorrhea, and other conditions (collectively referred to as "non-cancerous gynecological cancers"). Many of these conditions are not only annoying, but often cause significant pain and suffering.

[0005] Various forms of pelvic pain, including dysmenorrhea and endometriosis, affect more than 80% of women. Global studies report that more than 30% of women experience pelvic pain severe enough to miss school or work, and up to 80% report lost productivity due to associated symptoms. This disruption is not limited to menstrual days, as chronic pelvic pain, characterized by a duration of three to six months, has a high prevalence, affecting 24% of women. The negative consequences of pelvic pain are significant and include socioeconomic impacts from absenteeism, decreased quality of life, and increased reports of anxiety, sleep disturbances, and other mood disorders. Between 80% and 93% of women with pelvic pain report using analgesics at varying frequencies. Overall, 47% reported using analgesics “always” or “often.” Studies report that misuse or inappropriate use of both NSAIDs and narcotic analgesics, such as opioids, further increases the health risks of pelvic pain.

[0006] Endometriosis, a condition in which tissue that normally lines the uterus grows outside of it, is a common gynecological disease that affects an estimated 6 to 10 percent of women of childbearing age in the United States. Current treatment options for endometriosis include: monitoring the progression of the disease if women show no signs of relief; prescribing painkillers and anti-inflammatory medications that relieve symptoms associated with endometriosis but do not treat the underlying cause of the disease; hormone therapy, which can have adverse side effects for women; non-invasive surgery, such as laparoscopy or laparotomy, but the relief provided by these procedures is not permanent and symptoms may return after surgery; or hysterectomy, which is highly avoidant and will prevent women from having children in the future. Even in the best of circumstances, many treatment options are completely inadequate. Clearly, none of the treatment options currently available to women diagnosed with endometriosis can provide lasting relief from the condition without taking drastic action that could render the woman infertile.

[0007] Women diagnosed with severe dysmenorrhea (pain during menstruation caused by uterine contractions) may be unable to carry out normal daily activities for several days each month. For some women, the severe pain is accompanied by other symptoms, including diarrhea, nausea, vomiting, headaches, and dizziness. There are currently a variety of options for managing dysmenorrhea symptoms, such as taking pain relief medications or nonsteroidal anti-inflammatory drugs, resting, changing diet, or increasing exercise. There are also invasive procedures, such as endometrial ablation (a procedure that destroys the lining of the uterus), endometrial resection (a procedure that removes the lining of the uterus), and hysterectomy (surgical removal of the uterus). Non-invasive measures to manage dysmenorrhea symptoms do not treat the condition itself, and surgical procedures are highly invasive and may cause fertility problems for women of childbearing age.

[0008] Fibroids are a common condition diagnosed in more than 200,000 women each year and are noncancerous growths of the uterus. Fibroids can cause discomfort and may lead to complications such as a drop in red blood cells (anemia) due to severe blood loss, which can cause fatigue. Current treatment options for fibroids are similar to those discussed above—watchful waiting, nonsteroidal anti-inflammatory drugs, hormone therapy, surgical removal or hysterectomy.

[0009] Treatment options for non-cancerous gynecological conditions remain inadequate. Applicants have confirmed that therapeutic levels of cannabis extracts containing CBD are effective in treating endometriosis and other non-cancerous gynecological conditions. In certain embodiments, these cannabis extracts are provided in administration forms, such as oral administration forms, oral mucosal administration forms, intravaginal administration forms, and combinations of these administration forms. These and other embodiments are described in more detail herein. Summary of the invention

[0010] Certain embodiments disclosed herein relate to methods of treating endometriosis and other non-cancerous gynecological conditions by intravaginal application of a BSHE or FSHE formulation containing CBD. Specifically, the formulation enables intravaginal delivery of CBD and other cannabinoids and other terpenes and molecules within the FSHE or BSHE and can alleviate the symptoms of endometriosis, including the destruction of endometrial cells that are displaced and inappropriately present outside the uterus.

[0011] In another embodiment, a method for treating endometriosis comprises administering to a patient an effective amount of an intravaginal composition comprising a full spectrum hemp extract (FSHE) or a broad spectrum hemp extract (BSHE) comprising cannabidiol (CBD).

[0012] In another preferred embodiment, in the method, the endometriosis is ovarian endometrioma or deep endometriosis.

[0013] In another embodiment, a method of treating dysmenorrhea or fibroids comprises administering to a patient an effective amount of an intravaginal composition comprising a full spectrum hemp extract (FSHE) or a broad spectrum hemp extract (BSHE) comprising cannabidiol (CBD).

[0014] In another preferred embodiment of the aforementioned method, use or therapeutic agent, it further comprises hormone therapy, Gn-RH therapy, progesterone therapy, aromatase inhibitor or a combination thereof.

[0015] In one embodiment, the present invention provides a cannabis extract for use in a method of treating a non-cancerous gynecological disorder (NCGD) in a patient, wherein the cannabis extract comprises cannabidiol (CBD), and wherein the method is a method for treating endometrial cancer and endometriosis simultaneously, and the method comprises administering the cannabis extract to the patient concomitantly via an oral formulation and via an intravaginal formulation. As defined herein, the term "concomitantly" means that the oral formulation and the intravaginal formulation are administered to the patient no more than 72 hours apart, preferably no more than 48 hours apart, and more preferably no more than 24 hours apart, for example no more than 12 hours apart, no more than 6 hours apart, no more than 4 hours apart, no more than 3 hours apart, no more than 2 hours apart, no more than 1 hour apart, no more than 30 minutes apart, or simultaneously. Therefore, in one embodiment, the present invention provides an oral formulation for use in a method for the simultaneous treatment of endometrial cancer and endometriosis, wherein the oral formulation comprises a cannabis extract containing cannabidiol (CBD) and a pharmaceutically acceptable excipient, and the method comprises administering the oral formulation concomitantly with an intravaginal formulation comprising a cannabis extract containing cannabidiol (CBD) and a pharmaceutically acceptable excipient. In another embodiment, the present invention provides an intravaginal formulation for use in a method for the treatment of NCGD, wherein the intravaginal formulation comprises a cannabis extract containing cannabidiol (CBD) and a pharmaceutically acceptable excipient, and the method comprises administering the intravaginal formulation concomitantly with an oral mucosal formulation comprising a cannabis extract containing cannabidiol (CBD) and a pharmaceutically acceptable excipient.

[0016] In one embodiment, the present invention provides a pharmaceutical composition for use in a method of treating NCGD, wherein the pharmaceutical composition comprises a cannabis extract having an effective amount of CBD.

[0017] In one embodiment, the present invention provides the use of a cannabis extract comprising cannabidiol (CBD) in the manufacture of a medicament for use in a method of treating NCGD.

[0018] In one embodiment, the present invention provides the use of an intravaginal composition comprising a cannabis extract comprising cannabidiol and a pharmaceutically acceptable excipient for the manufacture of a medicament for use in a method of treating NCGD.

[0019] In one embodiment, the present invention provides the use of a cannabis extract comprising cannabidiol (CBD) in the manufacture of a medicament for use in a method of treating NCGD.

[0020] In a preferred embodiment, the method of treating NCGD comprises administering to a patient via intravaginal application an effective amount of a pharmaceutical composition comprising a cannabis extract comprising between 1% and 99.9% CBD.

[0021] In another embodiment, in the method, the effective dose is sufficient to produce a concentration of CBD of at least 10 μg / mL at the target tissue.

[0022] Therefore, mucosal administration, especially intravaginal administration, has therapeutic efficacy that may allow targeted treatment of EC cells, which would treat local lesions and internalized tissues. These data were confirmed by further testing in human patients, showing that treatment with CBD is effective in treating NCGDs such as endometriosis, ovarian endometriomas, deep endometriosis, dysmenorrhea or fibroids.

[0023] In a preferred embodiment, a cannabis extract for use in a method of treating a non-cancerous gynecological disorder (NCGD) in a patient, wherein the cannabis extract comprises cannabidiol (CBD).

[0024] In another embodiment, a cannabis extract for use is provided, wherein the cannabis extract is selected from the group consisting of full spectrum hemp extract (FSHE), broad spectrum hemp extract (BSHE), CBD isolate, and cannabidiolic acid (CBDA), optionally wherein the BSHE or FSHE comprises (i) 50% to 99% by weight CBD and (ii) at least one other cannabinoid selected from the group consisting of: delta-9-tetrahydrocannabinol (Δ-9-THC), Δ-9-THC and Δ-9-THC. 9 -THC), tetrahydrocannabinolic acid (THCA), tetrahydrocannabidiol (THCV), Δ-8-tetrahydrocannabinol (Δ 8 -THC), cannabichromene (CBC), cannabichromene acid (CBCA), cannabigerol (CBG), cannabigerolic acid (CBGA), cannabidiolic acid (CBDA), cannabidiol (CBDV), cannabinol (CBN), cannabichromene (CBL), and combinations thereof.

[0025] In another embodiment, a cannabis extract for use is provided, wherein the cannabis extract comprises between 10 mg and 4,250 mg of CBD per dose.

[0026] In another embodiment, a cannabis extract for use is provided, wherein: (a) the method comprises administering the cannabis extract to the patient via an oral dose, an oromucosal dose, an intravaginal dose, or a combination thereof; and / or (b) the method comprises administering a dose of the cannabis extract to the patient at least once every three days, preferably at least once a day, at least twice a day, or at least three times a day; and / or (c) the method comprises administering an amount of the cannabis extract sufficient to produce a concentration of at least 10 μg / mL of the cannabis extract at a target tissue of the patient, preferably wherein the target tissue is non-cancerous tissue of the female reproductive tract; and / or (d) the method comprises administering an amount of the cannabis extract sufficient to achieve an effective therapeutic level as measured by systemic plasma levels of CBD; and / or (e) the method comprises administering between 20 mg and 4,250 mg of CBD to the patient per day; and / or (f) the cannabis extract is formulated at an acidic pH, preferably at a pH between 3.5 and 6.

[0027] In another embodiment, a cannabis extract for use is provided, wherein: (a) the NCGD is endometriosis; and / or (b) the NCGD is dysmenorrhea, and / or (c) the NCGD is fibroids.

[0028] In another embodiment, a cannabis extract for use is provided, wherein the cannabis extract comprises between 1% and 99.9% CBD, and wherein the method comprises administering the cannabis extract to a patient via intravaginal administration, preferably wherein: (a) the cannabis extract comprises between 60% and 99.9% CBD; and / or (b) the cannabis extract is selected from a full spectrum hemp extract (FSHE), a broad spectrum hemp extract (BSHE) and a CBD isolate; and / or (c) the cannabis extract comprises CBDA.

[0029] In a preferred embodiment, a mucosal composition for use in a method of treating a non-cancerous gynecological disorder (NCGD), wherein the mucosal composition comprises a cannabis extract and a pharmaceutically acceptable excipient.

[0030] In another embodiment, a mucosal composition for use is provided, wherein the composition comprises (i) an oil or fat as a carrier and / or (ii) at least one terpene, at least one polyphenol, at least one essential fatty acid, at least one phytonutrient or a combination thereof, optionally wherein the at least one terpene, at least one polyphenol, at least one essential fatty acid, at least one phytonutrient or a combination thereof is present in an amount between 1 wt % and 50 wt % of the total weight of the composition, further optionally wherein: the terpene is selected from β-myrcene, β-caryophyllene, linalool, α-pinene, citral, D-limonene, eucalyptol and a combination thereof; and / or the polyphenol is selected from catechins, quercetin, geranylflavonoids A / B / C, rutin, chlorogenic acid and a combination thereof; and / or the essential fatty acid is selected from ω3 acids, ω6 acids, ω9 acids and a combination thereof; and / or the phytonutrient is selected from tocopherols, sterols, carotenes, fatty alcohols, minerals and a combination thereof.

[0031] In another embodiment, a mucosal composition for use is provided, wherein: (a) the mucosal composition comprises between 25 mg and 4,250 mg of CBD in a dosage, and the method comprises administering the composition to the patient via insertion into a mucosal surface selected from the oral mucosa, rectum, vagina, or nasal passage; and / or (b) the method comprises administering at least two doses of the mucosal composition to the patient per day, wherein each dose of the mucosal composition comprises between 10 mg and 2,125 mg of cannabis extract; and / or (c) the mucosal composition has an acidic pH, preferably a pH between 3.5 and 6.

[0032] In another embodiment, a cannabis extract for use is provided, wherein the method is a method for treating NCGD and the method comprises concomitantly administering the cannabis extract to a patient via a mucosal preparation, preferably wherein the cannabis extract is a full spectrum hemp extract (FSHE) or a broad spectrum hemp extract (BSHE).

[0033] In another embodiment, a cannabis extract for use is provided, wherein the method comprises co-administering to a patient an effective amount of the cannabis extract and an effective amount of a second therapeutic agent.

[0034] In a preferred embodiment, a pharmaceutical composition for use in a method of treating non-cancerous gynecological disorders (NCGD), wherein the pharmaceutical composition comprises a cannabis extract comprising an effective amount of CBD.

[0035] In another embodiment, the pharmaceutical composition for use, wherein the composition further comprises: (a) a carrier; and / or (b) at least one selected from Δ 9 -THC, THCA, THCV, Δ 8-THC, CBC, CBCA, CBG, CBGA, CBDA, CBDV, CBN, CBL and combinations thereof; and / or (c) at least one terpene, preferably wherein the terpene is selected from β-myrcene, β-caryophyllene, linalool, α-pinene, citral, D-limonene, eucalyptol and combinations thereof; and / or (d) at least one polyphenol, preferably wherein the polyphenol is selected from catechins, quercetin, geranylflavonoids A / B / C, rutin, chlorogenic acid and combinations thereof; and / or (e) essential fatty acids, preferably wherein the essential fatty acids are selected from ω3 acids, ω6 acids, ω9 acids and combinations thereof; and / or (f) phytonutrients, preferably wherein the phytonutrients are selected from tocopherols, sterols, carotenes, fatty alcohols, minerals and combinations thereof.

[0036] In a preferred embodiment, a method for treating a non-cancerous gynecological disorder (NCGD) comprises administering to a patient an effective amount of a composition comprising a cannabis extract (CE).

[0037] In another embodiment, in the method, the CE comprises between 50% and 99.9% cannabidiol (CBD).

[0038] In another embodiment, in the method, the CE is selected from the group consisting of: full spectrum hemp extract (FSHE), broad spectrum hemp extract (BSHE), CBD isolate, and cannabidiolic acid (CBDA) isolate.

[0039] In another embodiment, in the method, the CE is administered via an oral form, an oromucosal form, an intravaginal form, a nasomucosal form, a rectal form, an injectable form, and combinations thereof.

[0040] In another embodiment, in the method, the effective amount of cannabis extract comprising CBD comprises between 10 mg and 4,250 mg CBD per day. In another embodiment, in the method, administering the CE is a dose given at least once a day, at least twice a day, or at least three times a day.

[0041] In another embodiment, in the method, the NCGD is ovarian endometrioma, deep endometriosis, dysmenorrhea, or fibroids.

[0042] In another embodiment, in the method, the CE comprises CBDA at a concentration between 0.1% and 10%.

[0043] In another embodiment, in the method, the CE is a BSHE or a FSHE, and wherein each of the BSHE or the FSHE comprises 50% to 99% by weight of CBD and at least one other cannabinoid in a concentration of 0.1% to 10%, the at least one other cannabinoid being selected from the group consisting of: Δ 9 -THC, THCA, THCV, Δ 8 -THC, CBC, CBCA, CBG, CBGA, CBDA, CBDV, CBN, CBL and combinations thereof.

[0044] In another embodiment, in the method, the CE comprises CBD at a concentration between 60% and 99% and at least one other cannabinoid at a concentration between 0.1% and 10%, wherein the at least one other cannabinoid is selected from the group consisting of: 9 -THC, THCA, THCV, Δ 8 -THC, CBC, CBCA, CBG, CBGA, CBDA, CBDV, CBN, CBL and combinations thereof; and wherein the CE comprises a total cannabinoid concentration between 65% and 99%.

[0045] In another embodiment, in the method, the composition comprises at least one additional compound selected from the group consisting of terpenes, polyphenols, essential fatty acids, phytonutrients, and combinations thereof; wherein the at least one additional compound is present in an amount between 0.1% and 50% by weight of the total weight of the composition.

[0046] In another embodiment, in the method, the composition comprises an oil or fat as a carrier.

[0047] In another embodiment, in this method, the effective amount of the composition is an amount sufficient to achieve effective therapeutic levels of CBD as measured by systemic plasma levels.

[0048] In another embodiment, in the method, the composition is applied at an acidic pH. In another embodiment, in the method, the acidic pH is between 3.5 and 6.

[0049] In another embodiment, in this method, the effective amount of the composition is sufficient to achieve effective therapeutic levels as measured by systemic plasma levels of CBD.

[0050] In another embodiment, in the method, the composition further comprises at least one terpene. In another embodiment, in the method, the terpene is selected from the group consisting of β-myrcene, β-caryophyllene, linalool, α-pinene, citral, D-limonene, eucalyptol, and combinations thereof.

[0051] In another embodiment, in the method, the composition further comprises at least one polyphenol. In another embodiment, in the method, the polyphenol is selected from the group consisting of catechins, quercetin, geranylflavonoids A / B / C, rutin, chlorogenic acid, and combinations thereof.

[0052] In another embodiment, in the method, the composition further comprises essential fatty acids selected from the group consisting of ω3, ω6, ω9, and combinations thereof.

[0053] In another embodiment, in the method, the composition further comprises a phytonutrient. In another embodiment, in the method, the phytonutrient is selected from the group consisting of tocopherols, sterols, carotenes, fatty alcohols, minerals, and combinations thereof.

[0054] In another embodiment, in the method, the CBD is a phytocannabinoid derived from a cannabis extract.

[0055] In a preferred embodiment, a method for treating a non-cancerous gynecological disorder (NCGD) comprises: (a) obtaining gynecological cells from a patient and forming at least one organoid from the gynecological cells; (b) screening the at least one organoid to identify a cannabis extract (CE) to which the patient's organoid is responsive; and (c) administering the CE to the patient together with an effective amount of a composition comprising a CE having between 50% and 99.9% CBD.

[0056] In another embodiment, in the method, the CE is administered to the patient in oral form, oromucosal form, nasal form, rectal form, intravaginal form, injectable form, and combinations thereof. In another embodiment, in the method, the CE is administered oromucosally and intravaginally.

[0057] In a preferred embodiment, a method for treating endometriosis comprises administering to a patient an effective amount of an intravaginal composition comprising a cannabis extract (CE) comprising cannabidiol (CBD).

[0058] In another embodiment, in the method, the endometriosis is ovarian endometrioma or deep endometriosis.

[0059] A method of treating dysmenorrhea or fibroids comprises administering to a patient an effective amount of an intravaginal composition comprising a cannabis extract (CE) containing cannabidiol (CBD).

[0060] In another embodiment, in the method, the CE comprises between 50 wt.% and 99.9 wt.% CBD.

[0061] In a preferred embodiment, the therapeutic agent comprising cannabis extract (CE) is used for the treatment of a gynecological condition selected from the group consisting of endometriosis, dysmenorrhea, fibroids, and combinations thereof.

[0062] In a preferred embodiment, a therapeutic agent for treating endometriosis comprises a cannabis extract (CE) having an effective amount of CBD.

[0063] In another embodiment, the therapeutic agent further comprises a carrier.

[0064] In another embodiment, the therapeutic agent further comprises at least one additional cannabinoid selected from the group consisting of: 9 -THC, THCA, THCV, Δ 8 -THC, CBC, CBCA, CBG, CBGA, CBDA, CBDV, CBN, CBL and combinations thereof.

[0065] In another embodiment, the therapeutic agent further comprises at least one terpene. In another embodiment, in the therapeutic agent, the terpene is selected from the group consisting of β-myrcene, β-caryophyllene, linalool, α-pinene, citral, D-limonene, eucalyptol, and combinations thereof.

[0066] In another embodiment, the therapeutic agent further comprises at least one polyphenol. In another embodiment, in the therapeutic agent, the polyphenol is selected from the group consisting of catechins, quercetin, geranylflavone A / B / C, rutin, chlorogenic acid, and combinations thereof.

[0067] In another embodiment, the therapeutic agent further comprises an essential fatty acid selected from the group consisting of ω3, ω6, ω9, and combinations thereof.

[0068] In another embodiment, the therapeutic agent further comprises a phytonutrient. In another embodiment, in the therapeutic agent, the phytonutrient is selected from the group consisting of tocopherols, sterols, carotenes, fatty alcohols, minerals, and combinations thereof.

[0069] In another embodiment, the method or therapeutic agent further comprises hormone therapy, GnRH therapy, progestin therapy, aromatase inhibitors, or a combination thereof.

[0070] In a preferred embodiment, a composition for use in a method of treating a non-cancerous gynecological disorder, wherein the composition comprises between 1 wt% and 99 wt% CE.

[0071] In a preferred embodiment, a composition is provided, wherein the CE of the composition comprises (a) FSHE, BSHE, CBD isolate and / or CBDA isolate; and / or (b) wherein the composition comprises between 1 wt % and 99 wt % of a carrier of the composition; and / or (c) wherein the composition further comprises between 1 wt % and 50 wt % of one or more excipients of the composition.

[0072] In a preferred embodiment, a composition for treating non-cancerous gynecological conditions, wherein the composition comprises a cannabis extract (CE), wherein the CE is present in the composition at a ratio between 1% and 100% by weight, and may be any percentage within this range. In a preferred embodiment, the CE is present in the composition at a ratio between 10% and 90% by weight, or between 20% and 90% by weight, and preferably between 40% and 80% by weight. As described in detail herein, the CE is preferably BSHE, FSHE, CBD isolate or CBDA isolate. In each of these different CEs, i.e., BSHE, FSHE, CBD isolate or CBDA isolate, the ratio they are present in the CE is between 50% and 99.9% by weight, and the remainder is wax, fat, fatty acid, etc. However, a preferred embodiment utilizes a carrier present in the composition at a ratio between 1% and 99% by weight, and preferably, one or more additional excipients are utilized depending on the use of the composition. The composition is then typically administered based on a dose in mg of the CBD administered. The amount of composition required to meet this mg CBD content depends on the amount of CBD in each CE.

[0073] In another preferred embodiment, a method for treating NCGD comprises administering to a patient in need thereof an effective amount of a composition according to any one of the preceding embodiments. In a preferred embodiment, in the method, the effective amount is cannabidiol (CBD) between 20 mg and 4,250 mg.

[0074] In a preferred embodiment, a composition for use in a method of treating a non-cancerous gynecological disorder (NCGD), wherein the composition comprises between 1 wt% and 99 wt% cannabis extract (CE).

[0075] In another embodiment, wherein the CE of the composition comprises: (a) full spectrum hemp extract (FSHE), broad spectrum hemp extract (BSHE), CBD isolate, CBDA isolate, or a combination thereof; and / or (b) wherein the composition comprises between 1 wt % and 99 wt % of a carrier of the composition; and / or (c) wherein the composition further comprises between 1 wt % and 50 wt % of one or more excipients of the composition.

[0076] In a preferred embodiment, a composition for treating non-cancerous gynecological disorders (NCGD), wherein the composition comprises cannabis extract (CE), wherein the ratio of CE in the composition is between 1 wt % and 100 wt %, and can be all percentages within this range.

[0077] In another embodiment, in the composition, the ratio of the CE in the composition is between 10 wt % and 90 wt %, or between 20 wt % and 90 wt %, and preferably between 40 wt % and 80 wt %.

[0078] In another embodiment, in the composition, the CE is preferably full spectrum hemp extract (FSHE), broad spectrum hemp extract (BSHE), CBD isolate or CBDA isolate. In another embodiment, in the composition, the ratio of BSHE and / or FSHE and / or CBD isolate and / or CBDA isolate in CE is between 50 wt % and 99.9 wt %.

[0079] In another embodiment, the composition comprises between 1% and 99% by weight of the composition of the carrier.

[0080] In another embodiment, the composition further comprises at least one or more additional excipients.

[0081] In another embodiment, wherein the composition is a mucosal composition.

[0082] In another embodiment, the composition comprises between 20 mg and 4,250 mg of CBD.

[0083] In a preferred embodiment, the method for treating non-cancerous gynecological disorders (NCGD) comprises administering an effective amount of a composition to a patient. In another embodiment, in the method, the effective amount is cannabidiol (CBD) between 20 mg and 4,250 mg. BRIEF DESCRIPTION OF THE DRAWINGS

[0084] Figure 1A , Figure 1B , Figure 1C , Figure 1D , Figure 1E , Figure 1F and Figure 1G Depicts endometrial cancer cells treated with a cannabis extract containing CBD, wherein Figure 1A A schematic diagram showing the process of capturing data on protein expression, Figure 1B Protein differentiation numbers are depicted; Figure 1C Depicted are cells that were upregulated and downregulated in vehicle, upon treatment with cannabis extracts containing CBD; Figure 1D The top 20 up- and down-regulated proteins in treated ECC cells are depicted; Figure 1E The effects of cannabis extracts on signaling and trafficking of various physiological and pathophysiological pathways are depicted. Figure 1F Delineated the expression of cannabinoid receptor 1 protein in endometrial cancer cells; Figure 1G Depicted is the expression of cannabinoid receptor 2 protein in endometrial cancer cells.

[0085] Figure 2A and Figure 2B depicts endometriosis-based organoids treated with cannabis extract, Figure 2A Depicted are cells with cannabis extracts containing different amounts of CBD delivered via BSHE. Of note, Figure 2B Results showing minimal inhibitory concentrations (in the absence of organoids), but as low as 50 μg, and all values ​​above, are pooled.

[0086] Figure 3A and Figure 3B Depicted is the reduction in organoid number compared to vehicle for endometrial cancer organoids treated with different concentrations of hemp extract including 2 μg / mL, 3 μg / mL, 4 μg / mL, and 5 μg / mL.

[0087] Figure 4A and Figure 4B Depicted are the reduction in organoid number in endometrial cancer organoids treated with different concentrations of hemp extract, including 3 μg / mL, 5 μg / mL, 7 μg / mL, and 10 μg / mL, compared to vehicle for different grades of endometrial cancer organoids.

[0088] Figure 5A and Figure 5B Depicted are grade 3 endometrial cancer organoids tested in two experiments at concentrations of 2 μg / mL, 3 μg / mL, 4 μg / mL, 5 μg / mL, 7 μg / mL, and 10 μg / mL.

[0089] Fig. 6A and Figure 6BAdditional graphs depicting the effects of BSHE, FSHE, and CBD isolates at concentrations of 1 μg / mL, 2 μg / mL, 3 μg / mL, 4 μg / mL, 5 μg / mL, 7 μg / mL, and 10 μg / mL on endometrial organoids, Figure 6B Graphical depiction of the response of endometrial organoids to CBDA is depicted.

[0090] Figure 7 A graph depicting endometrial cancer tumor volume in mice injected with patient-derived endometrial cancer cells. The data shows the change in tumor volume from day 7 to day 21 and depicts the therapeutic efficacy of various cannabis extracts on tumor volume.

[0091] Fig. 8A and Figure 8B Depicted are images of histopathological examination of mouse tissues treated with cannabis extract and depict that therapeutic treatment with cannabis extract does not damage normal reproductive tract cells.

[0092] Fig. 9 Depicted is a graph showing the effect of pH on the therapeutic efficacy of cannabis extracts. DETAILED DESCRIPTION

[0093] Various embodiments are described more fully below with reference to the accompanying drawings, which form a part of the embodiments. However, these embodiments can be embodied in many different forms and should not be construed as limited to the embodiments set forth herein; on the contrary, these embodiments are provided so that the disclosure will be thorough and complete, and will fully convey the scope of the embodiments to those skilled in the art. Among them, various embodiments can be therapeutic products, methods of treatment, and the use of therapeutic agents in treating one or more afflictions of non-cancerous gynecological conditions. Therefore, the following detailed description should not be made in a limiting sense.

[0094] As used herein, the term "about" means plus or minus 5% of the numerical value of the number used. Thus, about 50% means a range of 45%-55%, about 20 mg means a range of 19 mg to 21 mg, etc.

[0095] When used together with a therapeutic agent, "administering" means that the therapeutic agent is directly administered to the subject, whereby the agent has a positive effect on the target. "Administering" a therapeutic drug or compound can be achieved by, for example, injection, oral administration, topical administration, mucosal administration and / or in combination with other known techniques. Administration techniques may also include heating, radiation, chemotherapy, ultrasound and the use of delivery agents. Preferably, in the present disclosure, administration is by oral, oral mucosal / sublingual and / or intravaginal dosage forms. Such intravaginal forms are intended to be typically inserted into the vagina together with a carrier, wherein the active ingredient passes through the vaginal mucosa. The active ingredient can also be provided in an oral form for swallowing. Another oral form is oral mucosal application, which is often provided as a sublingual application, and when it is finally swallowed into the stomach, it is intended to be kept in the mouth, for example, kept under the tongue, and the active ingredient passes through the oral mucosa and is swallowed afterwards, or enters the stomach by saliva action or active swallowing of the material or both.

[0096] As used herein, "broad spectrum hemp extract" (BSHE) is a composition derived from a Cannabis plant that has undergone at least some purification to refine the extract. Typically, a BSHE contains between 60% and 99.9% CBD and between 0.1% and 40% of at least one additional cannabinoid selected from the group consisting of: 9 -THC, THCA, THCV, Δ 8 -THC, CBC, CBCA, CBG, CBGA, CBDA, CBDV, CBN, CBL and combinations thereof.

[0097] As used herein, "cannabis extract" (CE) and "cannabis extract containing CBD" means a composition derived from the plant of the genus Cannabis (including hemp). Typically, the cannabis extract contains cannabidiol (CBD), and more typically contains CBD and between 0.1% and 40% of at least one additional cannabinoid selected from the group consisting of: Δ 9 -THC, THCA, THCV, Δ 8-THC, CBC, CBCA, CBG, CBGA, CBDA, CBDV, CBN, CBL and combinations thereof. The hemp extract according to the present invention is generally rich in cannabidiol and may contain between 1% and 99.9% CBD, preferably between 20% and 99.9% CBD, more preferably between 50% and 99.9% CBD, even more preferably between 70% and 99.9% CBD, and most preferably between 90% and 99.9% CBD. When described herein, the percentage of hemp extract means, as in the preceding sentence, that the ratio of total cannabinoids in the hemp extract is between 50% and 99.9% by weight, or between 70% and 99% by weight, or between 90% and 99% by weight. Full-spectrum hemp extract, broad-spectrum hemp extract, CBD isolate and CBDA isolate are forms of hemp extracts utilized herein as non-limiting examples of CE. Throughout the application, the term CBD is often used interchangeably with CE to refer to a CE product containing a specific amount of CBD. In other cases, which will be apparent to the reader, CBD refers to CBD isolate, which means that CE has been processed to remove and isolate CBD, thereby removing substantially all other components of CE.

[0098] As used herein, "co-administration" means administration of the cannabis extract and the second therapeutic agent no more than 72 hours apart, preferably no more than 48 hours apart, and more preferably no more than 24 hours apart, for example no more than 12 hours apart, no more than 6 hours apart, no more than 4 hours apart, no more than 3 hours apart, no more than 2 hours apart, no more than 1 hour apart, no more than 30 minutes apart, or simultaneously.

[0099] As used herein, "concomitantly" means that the first formulation and the second formulation are administered to the patient no more than 72 hours apart, preferably no more than 48 hours apart, and more preferably no more than 24 hours apart, for example no more than 12 hours apart, no more than 6 hours apart, no more than 4 hours apart, no more than 3 hours apart, no more than 2 hours apart, no more than 1 hour apart, no more than 30 minutes apart, or simultaneously.

[0100] As used herein, "full spectrum hemp extract" (FSHE) is a composition derived from the cannabis plant that contains CBD and an amount of THC greater than 0, preferably between 0.01% and 5%, and most preferably between 0.01% and 0.3%. FSHE may contain additional cannabinoids to produce an extract containing at least 50% to 99% CBD, at least 0.01% to 10% total THC (Δ 9 -THC, THCA, THCV, Δ 8-THC), and products in which the ratio of total cannabinoids in CE is between 50% and 99% by weight.

[0101] For the purposes of this application, "hemp" is measured on a dry weight basis. 9 -Cannabis plants with a THC content of 0.3% or less.

[0102] "Pharmaceutically acceptable" means components including, but not limited to, carriers, diluents, adjuvants or excipients must be compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.

[0103] As used herein, the term "composition" is intended to encompass a product comprising specified ingredients in specified amounts, as well as any product resulting directly or indirectly from the combination of specified ingredients in specified amounts. Such terms related to "pharmaceutical composition" are intended to encompass a product comprising active ingredients and inert ingredients constituting a carrier, as well as any product resulting directly or indirectly from the combination, complexation or aggregation of any two or more ingredients, or from the dissociation of one or more ingredients, or from other types of reactions or interactions of one or more ingredients. Thus, the pharmaceutical compositions of the present invention encompass any composition made by mixing one or more compounds of the present invention with a pharmaceutically acceptable carrier.

[0104] As used herein, the term "agent," "active agent," "therapeutic agent," or "treatment" means a compound or composition used to treat, counter, alleviate, prevent, or improve an undesirable condition or disease in a patient. In addition, the term "agent," "active agent," "therapeutic agent," or "treatment" encompasses cannabis extracts and / or additional agents as described in the present disclosure.

[0105] The "therapeutically effective amount" or "effective amount" of a composition is a predetermined amount calculated to achieve the desired effect (i.e., inhibit, block or reverse activation, migration, proliferation, changes in cell function) and maintain the normal function of the cell. The activity contemplated by the methods described herein includes medical therapeutic and / or preventive treatments as appropriate, and the compositions of the present invention can be used to provide improvements in any condition described. It is also contemplated that the compositions described herein can be administered to healthy subjects or individuals who do not show symptoms but may be at risk of developing a particular condition. Of course, the specific dose of the compound administered according to the present invention to obtain a therapeutic and / or preventive effect will be determined by the specific circumstances surrounding the case, including, for example, the compound administered, the route of administration, and the condition treated. However, it should be understood that the selected dosage range is not intended to limit the scope of the present invention in any way. The therapeutically effective amount of the compound of the present invention is generally such an amount that, when it is administered in a physiologically tolerable excipient composition, it is sufficient to achieve an effective systemic concentration or local concentration in the tissue to achieve a therapeutic response. Specifically, the therapeutic agent is effective in treating non-cancerous gynecological conditions.

[0106] As used herein, the term "treatment" refers to therapeutic treatment and preventive measures, wherein the purpose is to prevent or slow down (mitigate) an undesirable physiological condition, disorder or disease, or to obtain a beneficial or desired clinical result. For the purposes of this disclosure, beneficial or desired results include, but are not limited to, alleviation of symptoms; reduction in the extent of a condition, disorder or disease, such as a reduction in tumor size; stabilization of the state of a condition, disorder or disease (i.e., not worsening); delay in the onset or slowing of the progression of a condition, disorder or disease; alleviation of a condition, disorder or disease state; and alleviation (partial or complete) (detectable or undetectable) or enhancement or improvement of a condition, disorder or disease.

[0107] The association between endometriosis and endometrial cancer (EC) has been indirectly suggested by epidemiological, biological and molecular studies, and recent studies suggest an overlapping genetic basis. Studies have demonstrated that the heritability of endometriosis is approximately 50% and that of EC is 27%. A review of published SNP evidence identified genetic overlap between endometriosis and endometrial cancer in genetic association analyses, with more SNPs in the same direction of effect than expected by chance. In a cross-disease meta-analysis, 13 SNPs appeared to be involved in replication after adjustment. SNPrs2475335, located on chromosome 9p23, was most significantly associated with both diseases (P=4.9×10-8). This SNP is housed within the protein tyrosine phosphatase receptor type D (PTPRD) gene. PTPRD deletions and mutations have been found in endometrial tumors. In addition, PTPRD exerts its effects on the STAT3 pathway, which has been identified as being associated with both endometriosis and endometrial cancer. Furthermore, endometriosis and EC are associated with higher levels of estrogen exposure, and a reduced risk is associated with the use of oral contraceptives and progestin-containing hormone therapy.

[0108] Endometriosis is a painful condition in which tissue similar to the lining of the uterus grows outside the uterus. Endometriosis affects 6% to 10% of women of childbearing age and 35% to 50% of women with infertility. Endometriosis and endometrial cancer are associated with higher levels of estrogen exposure, with reduced risk associated with the use of oral contraceptives and progestin-containing hormone therapy. Endometriosis most commonly involves the ovaries, fallopian tubes, and tissue lining the pelvic cavity, including the vagina. In the case of endometriosis, the endometrial tissue acts as normal uterine cells as they thicken and break down, thus causing bleeding during each menstrual cycle. However, in many cases, when the tissue cannot leave the body, it becomes trapped. When endometriosis involves the ovaries, cysts called endometriomas can form. The key problem is the formation of irritation and the development of scar tissue as well as adhesions, which are bands of fibrous tissue that can cause pelvic tissue and organs to stick together. This leads to a very common side effect of pain, which is sometimes severe, especially during menstruation. Furthermore, in some cases the shocks caused fertility problems.

[0109] The cause of endometriosis is uncertain, however some possible explanations include: retrograde menstruation, in which endometrial cells flow back through the fallopian tubes instead of out of the body; peritoneal cell transformation, known as the induction theory, in which hormones or immune factors promote peritoneal cell transformation; blastogenic transformation, in which hormones during puberty convert certain embryonic cells into endometrial-like cells; surgical scar implantation, which occurs after surgical procedures; transport of endometrial cells through the blood vessels of the lymphatic system; or caused by an immune system disorder.

[0110] Treatments for endometriosis are limited, with the most common treatments including pain medications, hormone therapy, and surgical procedures. Hormonal therapy treatments include various forms of hormonal contraceptives, gonadotropin-releasing hormone (Gn-RH) agonists and antagonists, progestin therapy, and aromatase inhibitors. Hormonal therapy with contraceptives attempts to shorten menstrual flow and have infrequent cycles, which reduces some of the side effects of endometriosis. Gn-RH therapy attempts to lower estrogen levels and cause endometrial cells to contract, essentially causing artificial menopause. Progestin therapy attempts to stop menstruation and can be achieved through intrauterine devices, implantable contraceptives, or injections. Finally, aromatase inhibitors reduce estrogen in the body, similar to some of the above treatments. These can be used alone or in combination with each other or with additional therapeutic treatments.

[0111] Surgical options include removal of endometriotic implants as the most conservative option, while more invasive surgical procedures include removal of the uterus and / or ovaries. Therefore, treatment options remain limited. Furthermore, even with the most invasive surgical options, endometrial tissue often remains and continues to cause pain and discomfort. Based on the parallel with EC, the incidence of EC and endometriosis correlates with the need for treatment.

[0112] EC is one of the most frequently diagnosed gynecological cancers worldwide, and its prevalence has increased by more than 50% in the past two decades. Endometrial cancer (also called endometrial carcinoma) begins in the cells of the inner lining of the uterus (endometrium). It is the most common type of cancer in the uterus. Endometrial carcinomas can be divided into different types based on the appearance of the cells under a microscope. (These are called histological types.) They include: adenocarcinoma (most endometrial cancers are a type of adenocarcinoma called endometrioid carcinoma [see below]); uterine carcinosarcoma, or CS; squamous cell carcinoma; small cell carcinoma; transitional carcinoma; and serous carcinoma. Clear cell carcinoma, mucinous adenocarcinoma, undifferentiated carcinoma, dedifferentiated carcinoma, and serous adenocarcinoma are less common types of endometrial adenocarcinoma. They tend to grow and spread faster than most types of endometrial cancer. They often have spread outside the uterus by the time they are diagnosed.

[0113] By far, most endometrial cancers are adenocarcinomas, and endometrioid carcinoma is the most common type of adenocarcinoma. Endometrioid carcinomas begin in glandular cells and look a lot like the normal lining of the uterus (endometrium). Some of these cancers have squamous cells (squamous cells are flat, thin cells) as well as glandular cells. There are many variants (or subtypes) of endometrioid carcinoma, including: adenocarcinoma (with squamous differentiation); adenoacanthoma; adenosquamous carcinoma (or mixed cell); secretory carcinoma; ciliated carcinoma; and chorioglandular adenocarcinoma of the cervix.

[0114] The grade of endometrial cancer is based on how many cancer cells are organized into glands that look like the glands found in the normal, healthy endometrium. In lower grade cancers (grades 1 and 2), more cancer cells form glands. In higher grade cancers (grade 3), more cancer cells are disorganized and do not form glands. Grade 1 tumors have 95% or more of the cancer tissue forming glands. Grade 2 tumors have between 50% and 94% of the cancer tissue forming glands. Grade 3 tumors have less than half of the cancer tissue forming glands. Grade 3 cancers tend to be invasive (they grow and spread quickly) and have a worse appearance than lower grade cancers.

[0115] Grade 1 and grade 2 endometrioid cancers are type 1 endometrial cancers. Type 1 cancers are usually not very aggressive, and they do not spread quickly to other tissues. Type 1 endometrial cancers are thought to be caused by too much estrogen. They sometimes develop from atypical hyperplasia, an abnormal overgrowth of cells in the endometrium. A small amount of endometrial cancer is type 2 endometrial cancer. Type 2 cancers are more likely to grow and spread outside the uterus, and they have a poorer appearance (compared to type 1 cancers). Doctors tend to treat these cancers more aggressively. They do not seem to be caused by too much estrogen. Type 2 cancers include all endometrial cancers that are not type 1, such as papillary serous carcinomas, clear cell carcinomas, undifferentiated carcinomas, and grade 3 endometrioid cancers. These cancers are not at all like normal endometrium, and are therefore referred to as poorly differentiated or high-grade. Uterine carcinosarcoma (CS) begins in the endometrium and has the characteristics of both endometrial cancer and sarcoma. (A sarcoma is a cancer that starts in the muscle cells of the uterus.) In the past, CS was considered a different type of uterine cancer, called a uterine sarcoma (see below), but doctors now consider CS to be a type of endometrial cancer that is no longer as abnormal as the cells from which it originated (it is poorly differentiated). Uterine CS is a type 2 endometrial cancer. CS tumors are also called malignant mixed mesodermal tumors or malignant mixed Müllerian tumors (MMMTs). They account for about 3% of uterine cancers.

[0116] Despite the understanding of the main signaling pathways that drive the growth and metastasis of endometrial cancer, clinical trials targeting these signals have reported poor outcomes. The heterogeneous nature of endometrial cancer is suspected to be one of the key reasons for the failure of targeted therapies. EC is generally understood to be divided into four molecular subtypes, including hypermutated cases with POLE mutations and 25%-30% with mismatch repair deficiency (dMMR) with microsatellite instability (MSI) phenotypes. Some of these subtypes are therefore treated with PD-1 / PD-L1 inhibitors or with immune checkpoint inhibitors and other molecules such as pembrolizumab or Lenvatinib. However, these molecules, like first-line chemotherapeutic agents, have high toxicity characteristics and therefore have significant comorbidities associated with their use. In addition, being targeted, they sometimes miss the heterogeneous nature of cancer.

[0117] In some cases, EC has few, if any, symptoms, and is one of the key reasons why many EC patients only discover the disease in its late stages. However, for others, some of the symptoms of EC are masked by normal reproductive cycle symptoms, non-cancerous endometriosis, and those that occur during menopause. Therefore, some women miss early signs of EC due to confounding factors. However, for others, EC presents with abnormal uterine bleeding, which allows a portion of patients to detect the disease at an early stage. Once detected, treatment for EC is almost always surgical removal of tissue and organs, combined with chemotherapy and / or radiation therapy. In some cases, early detection of EC can prevent the need for chemotherapy or radiation therapy because the cancer is only contained in the uterus. However, EC is quite vicious, and even a few missed cells that have migrated from the uterus then allow the proliferation of diseased tissue, providing evidence that chemotherapy is needed even after organ removal when diagnosed in the early stages.

[0118] For early stage (stage I and II EC) and stage III and IV EC, first-line treatment for EC almost always includes hysterectomy and bilateral salpingo-oophorectomy. In most cases, this is followed by chemotherapy. In view of the significant side effects of chemotherapy, a small number of stage I and II patients can omit or reduce the use of chemotherapy compared with stage III and IV patients. Chemotherapy is actually always given to patients with stage III or IV EC, and is often accompanied by several rounds of therapy, with the aim of optimizing risk and return. Therefore, for stage III and IV EC, chemotherapy treatment is usually performed after organ and tumor removal to capture metastatic disease, because endometrial cancer cells have often migrated from the uterus. However, it is well known that chemotherapeutic agents are somewhat indiscriminate in their killing, so significant secondary effects occur on patients, resulting in an impact on quality of life. In fact, even in cases where chemotherapy is effective in treating cancer, the toxic effects of chemotherapy over time often prove to be fatal. In almost all cases, chemotherapy is given in a cycle, which means that a drug or a combination of drugs is given for a period of usually 2-6 weeks, followed by a rest period, followed by a second or more treatment periods. Currently, drugs used to treat endometrial cancer include paclitaxel, carboplatin, doxorubicin, cisplatin, docetaxel, and combination therapy of carboplatin or cisplatin with paclitaxel.

[0119] However, endometriosis, while related to endometrial cancer, does not metastasize throughout the body and does not undergo the unregulated growth hallmarks of cancer. Therefore, no chemotherapeutic agents are indicated for endometriosis and other noncancerous conditions of the female reproductive system.

[0120] Given the widespread presence of ECS in mammals, particularly in the reproductive system, the effects of cannabis extracts (CE), including CBD, on protein expression in endometrial cancer cells were examined. Proteomics is the large-scale study of proteins, where the proteome is the entire set of proteins produced by the sample being studied. The proteome will differ from cell to cell and over time. Therefore, comparison of protein expression in untreated cells to treated cells provides insights into which proteins change expression in endometrial cancer cells and which proteins remain the same. Using this knowledge, additional, targeted studies can ensue. Reference Figure 1A , endometrial cancer cells (ECC) were treated with CE containing CBD (1 μg / mL) or left untreated as a control (vehicle). After treatment, proteins were extracted from test and control cells and digested for analysis by liquid chromatography (LC) tandem mass spectrometry (MS / MS). Figure 1B , Venn diagram shows the results of LC-MS / MS analysis, treated cells expressed 2,842 proteins that were different from untreated cells, untreated cells expressed 2,681 proteins that were different from treated cells, and 3,747 common proteins were expressed by both treated and untreated cells. Clearly, based on the differences in protein expression, treatment with as little as 1 μg / mL of CE containing CBD had a clear effect on proteins that were exclusively expressed and proteins that were no longer expressed. Figure 1C The extent to which certain proteins are expressed (or not expressed) in untreated cells and treated cells is compared.

[0121] refer to Figure 1D , among the thousands of proteins differentially expressed between treated and untreated cells, the top 20 upregulated proteins (e.g., only in treated cells) and downregulated proteins (e.g., only in untreated cells) were identified and counted. Figure 1E , showed the effects of treatment with CBD-containing CE on signaling and trafficking of various physiological and pathophysiological pathways. As an example, it was shown that proteins associated with endocannabinoid neuronal synapses were upregulated in untreated cells and downregulated in treated cells. Finally, reference Figure 1F , tissue samples from patients with endometrial cancer were selectively stained for CB1 receptor expression. Figure 1G are similar tissue samples selectively stained to show CB2 receptor expression.

[0122] Almost at the same time as the above experiments, the response of organoids derived from endometrial cancer to CE containing CBD was also studied. Typically, patients with EC are identified and tumor cells are collected. Patient-derived organoids are produced using EC tumor cells, and the method is described in the method section below. As the name implies, organoids are miniature structures that simulate organs with all their complexity. They are derived from stem cells collected via biopsy and / or resected healthy tissue or tumor. In culture, they self-organize into three-dimensional tissues that simulate the tissues of individual patients from which they are derived. That is, organoids have the same genetic instructions as the individuals from which they are derived, and therefore demonstrate the same mutations, proliferation, and disease progression as their human counterparts. Organoids can be prepared to replicate selected aspects of organs with differentiated cell types or expression-identified target cells. Unlike traditional cell line models associated with high failure rates in clinical trials, the response of organoids is accurately and directly translated into human responses. Organoids have been established and have transformed medical research in providing breakthroughs in the treatment of cystic fibrosis, pancreatic cancer, diabetes, and other diseases. In a simplified example, imagine organoids as clones of individual organs. Essentially, it is a living, growing avatar of a different patient that exists outside the body. The avatar will mimic tumor growth and respond to treatment for cancer just as it would inside the body. This personalized replica identification allows for the identification of individualized targeted therapies within days. This allows patients to avoid wasting time and risking the toxicity of ineffective therapies.

[0123] Initial experiments with endometriosis-based organoids derived from endometrial cells used 250μg / mL of BSHE containing CBD as the lowest treatment dose. This dose was 100% effective in killing endometriosis organoids, which was certainly unexpected. Subsequent experiments used 150μg / mL of BSHE as the lowest treatment dose. Again, 100μg / mL was 100% effective in killing endometrial cancer organoids. Thereafter, endometriosis organoids were treated with lower doses of BSHE, with 50μg / mL being the lowest dose tested. Figure 2A As can be seen in the figure, organoids generated from endometrial cells were treated with medium only (the growth medium in which the organoids were grown), vehicle (the only solution used to deliver BSHE to other organoids), and then the test doses of 50 μg / mL, 100 μg / mL, 150 μg / mL, and 250 μg / mL. Figure 2B (and Figure 2A), the vehicle and culture medium showed only almost the same number of organoids. However, at concentrations as low as 50pg / mL, BSHE was able to completely kill EC organoids. Higher doses of BSHE (100μg / mL and 150μg / mL) also showed 100% killing of EC organoids. Each test of Figure 2 was run at least in triplicate, including the vehicle alone, which was dimethyl sulfoxide (DMSO).

[0124] For comparison, the doses of the treated organoids were converted to human equivalent doses of 500 mg / day and 1000 mg / day, respectively, for the lowest dose. The current prescription doses of CBD isolate (in the United States) are between 5 mg CBD / kg and 50 mg CBD / kg. An average weight between 65 kg and 85 kg (about 143 pounds to about 187 pounds) produces a CBD dose between 325 mg / day and 4250 mg / day. Therefore, our actual testing is well within these guidelines. We believe that in this case (endometriosis), the upper limit of the human dosing range is also completely appropriate, which will repeat the experiments conducted at 100 μg / mL and higher doses. In particular, as an alternative to such CBD doses are NSAIDs or other painkillers, surgical removal or other hormonal therapies, none of which have shown long-term success. Finally, some new so-called treatments have low success rates and significant side effects, limiting their use.

[0125] Shortly after the experiment detailed above, a 31-year-old Caucasian woman came to us. She was initially diagnosed with endometriosis and later diagnosed with endometrial cancer after presenting with significant pain and discomfort. She had undergone total hysterectomy and bilateral salpingo-oophorectomy, followed by five rounds of chemotherapy. Each of the first five rounds of chemotherapy was a combination chemotherapy with paclitaxel / carboplatin. The treatment was ultimately ineffective, and due to the ineffectiveness of the first few rounds, she did not continue with these agents for the sixth round of chemotherapy. Thereafter, she was treated with Abemaciclib, followed by Atezolizumab, which also failed and caused severe side effects. Because she did not respond to chemotherapy, it was believed that she had chemoresistant endometrial cancer.

[0126] When she came to us, her endometrial cancer was stage IV, and due to the chemo-resistance and invasive nature of the cancer, she also had extensive metastatic disease throughout her body. The affected areas included her brain, breast, heart, stomach, lungs, peritoneum, and lymphatic system. The size of the metastatic nodules was determined using PET scanning and other techniques, ranging from 11×7mm to 29×10mm. See, Tables 1 and 2 below. In view of the experiments detailed above, organoids were made from the patient's endometrial cancer to evaluate her response to alternative chemotherapy (after seven rounds of chemotherapy failure) based on her chemo-resistance to the tested BSHE. Her organoids showed a partial response to gemcitabine / capecitabine (GemCap), a combination chemotherapy that she had not yet provided, and a significant response to BSHE. Therefore, she started standard regimen GemCap treatment, combined with a regimen of 30mg BSHE delivered twice a day via oral mucosal delivery and 75mg FSHE delivered once a day via intravaginal delivery. Therefore, her total daily dose of cannabis extract including CBD is 135mg. After 12 weeks of treatment, a follow-up PET scan reported alarming results, which are detailed in Tables 1 and 2 .

[0127] Table 1 : Comparison of metabolic responses in lymph nodes of patients before and after treatment

[0128]

[0129] Table 2: Comparison of metabolic responses in lung metastases and peritoneum of patients before and after treatment.

[0130]

[0131] Surprisingly, radiologically inferred a complete metabolic response to treatment.

[0132] It is noteworthy that a significant reduction in the size of metastases has been recorded. In addition, there are no new enlarged or high metabolic nodules in the neck, chest, abdomen, pelvic or inguinal regions indicating new sites of metastatic adenopathy. And there are no new high metabolic pulmonary metastases, no lymphangitis, no pleural or pericardial effusions, no abnormal metabolism in solid abdominal organs and no evidence of solid abdominal viscera or metastatic disease on diagnostic CT. The malignant ascites in the pelvic region previously confirmed is almost completely resolved, and there is a complete metabolic reaction in peritoneal deposits. For example, the peritoneum has one of the largest deposits of 22x10mm before treatment, and SUV max is 7.2, and after treatment, it can no longer be measured via PET, without new high metabolic peritoneal deposits. In addition, there is no abnormal metabolism in the brain, no suspicious lesions on low dose, non-contrast CT, and no abnormal metabolism in the bone indicates bone metastasis. In addition, when she scans CT subsequently, her endometriosis is also resolved and controlled.

[0133] Additional results for testing agents on organoids derived from the above patents are shown in Table 3. IC50 values ​​were calculated from such tests. This value indicates the dose at which 50% of the organoids are killed by the treatment. max As can be seen in the table, only a few IC50 values ​​could be calculated because the remaining agents did not have sufficient inhibitory effect to determine an IC50 value. In other words, they were ineffective in killing the patient's organoids.

[0134] Table 3: Effects of various agents on patient-derived organoids.

[0135]

[0136]

[0137] Some of the tested agents were slightly effective against the organoid samples, but the IC50 values ​​were still below the Cmax, identifying them as poor choices for therapeutic use.

[0138] It is noteworthy that none of the agents listed in Table 3 were as effective as the cannabis extract used to treat the patients.

[0139] In addition to the agents listed above, several other drugs were tested to see if they affected organoid growth. The results are shown in Table 4. In this case, the results are shown as % of cells that died compared to the control. Notably, paclitaxel was shown to be completely ineffective, so 39% cell death indicated that a greatly increased dose would be needed for successful treatment. This is consistent with the patient's actual lack of response to paclitaxel treatment.

[0140] Table 4: Effects of various agents on the death of patient-derived organoids.

[0141]

[0142]

[0143] Although the patient achieved remission of cancer after treatment with a combination of GemCap and BSHE at 130 mg / day, she had extensive organ damage due to many rounds of chemotherapy. Due to organ damage, she eventually died of complications, but it is estimated that her life span was extended by about 1 year. At the time of her death, she had no cancerous growth. Therefore, even if chemotherapy and a combination therapy of a cannabis extract containing CBD proved to be highly effective in reducing tumor growth, pre-existing chemotherapy damage also proved to be fatal. It is impossible to determine whether she could achieve early remission during the early rounds of chemotherapy if she had been treated with a cannabis extract containing CBD. If so, she would not have endured several rounds of unsuccessful chemotherapy. However, we can confirm that her last treatment was proven to be effective with a combination therapy of chemotherapy and a cannabis extract containing CBD.

[0144] Due to the success of our initial experiments and the results achieved when treating live patients with cannabis extracts containing CBD, we are continuing additional studies with great vigor. Since our initial experiments showed a complete decline in organoid numbers using BSHE with a CBD dose of about 50 μg / mL, we were interested in observing the response of the organoids to lower concentrations of CE. Due to the similarities and genetic features of endometriosis and endometrial cancer, as well as similar responses in protein signaling and the response of CB1 and CB2 receptors, both endometrial cancer-based organoids and endometriosis-based organoids were used to show the efficacy of CE treatment containing CBD.

[0145] We were able to obtain tissue samples from many patients with different grades of endometrial cancer. Grade 1 tumors are described as having less than 5% solid non-glandular, non-squamous growth. In other words, most grade 1 tumors appear to have glandular and / or squamous cell similarities. In contrast, grade 2 tumors show solid non-glandular, non-squamous growth between 6% and 50%, while grade 3 tumors show greater than 50% solid non-glandular, non-squamous growth. With the number of participants and the different grades of tumors, we were able to test the growth of many organoids under different doses of BSHE. The methods and experimental protocols for generating organoids are described in the methods section below.

[0146] For this set of experiments, 6 different sets of level 1 and 3 patient-derived samples each and at least 9 different sets of level 2 patient-derived samples were prepared for testing at 2 μg / mL, 3 μg / mL, 4 μg / mL, and 5 μg / mL of BSHE. Representative results were selected for Figure 3A , Figure 3B and Figure 5A Reference Figure 3A , experimental results for grade 1 endometrial cancer samples are shown as a percentage reduction in the mean number of organoids compared to the mean number of organoids observed in vehicle. Data are shown for patient 1A, patient 4A, patient 5A, and patient 6A. In each case, organoid growth was inhibited at doses as low as 2 μg / mL, with cells from patient 1 being most sensitive at this low dose, resulting in a reduction in organoid number greater than 50%. For the remaining patients, a 50% reduction occurred at about 3 μg / mL to about 4 μg / mL. At 5 μg / mL, organoid formation was inhibited by at least about 80%. Reference Figure 3B , the number of grade 2 organoids followed a similar pattern, except that most grade 2 tissues showed a 50% decrease in mean organoid number at approximately 3 μg / mL to 4 μg / mL. All samples showed an approximately 80% decrease in mean organoid number at 5 μg / mL. Figure 5ASurprisingly, all six groups of samples derived from grade 3 endometrial cancer tumors showed a greater than 50% reduction in mean organoid number at as low as 3 μg / mL, and close to a 100% reduction at 5 μg / mL. Within each grade of tumor sample, individual responses to BSHE treatment varied. However, they all responded at the lower end of the dose spectrum, and in most cases very well.

[0147] Patient-derived samples were also tested for their responses to 3 μg / mL, 5 μg / mL, 7 μg / mL, and 10 μg / mL BSHE. Figure 4A , except for cells from 2B, representative samples of level 1 tissues also mostly showed a reduction in the average number of organoids by about 50% between 3 μg / mL and 5 μg / mL. However, with 7 μg / mL BSHE, all level 1 patient-derived samples showed complete inhibition of organoid number, even patient 2B. Figure 4B Surprisingly, the level 2 samples in this group were affected by 3 μg / mL BSHE such that in the representative sample shown, all four samples had a reduction of about 50% or greater in mean organoid number. Likewise, at 5 μg / mL, the response was a reduction of greater than 80%, and at 7 μg / mL BSHE there was 100% inhibition of organoid formation. Figure 5B , Grade 3 patient-derived samples in this group were also surprisingly sensitive to low doses of BSHE, with a 50% reduction in mean organoid number for all patient samples less than 3 μg / mL. A 5 μg / mL dose of BSHE again showed a greater than 80% reduction in mean organoid number, and no organoids at 7 μg / mL.

[0148] Therefore, based on Figure 3A , Figure 3B , Figure 4A , Figure 4B , Figure 5A and Figure 5B , at concentrations as low as 2 μg / mL, and in each case at concentrations as low as 7 μg / mL, organoids from grade 1, 2, and 3 EC were able to show a significant reduction in the mean number of organoids compared to vehicle. Thus, application of a cannabis extract comprising CBD at a defined CBD concentration effectively reduced the number of viable patient-derived organoids from EC. The data clearly demonstrate that a given dose of a cannabis extract containing a known amount of CBD effectively reduces endometrial cancer organoid growth.

[0149] After narrowing down the range in which 50% of endometrial cancer organoids were inhibited from forming in the presence of BSHE, we then turned to other cannabis extracts containing CBE to determine their efficacy in inhibiting cancer organoid formation. Therefore, in addition to retesting the broad-spectrum hemp extract (BSHE) that served as the basis for all previous studies, we also tested full-spectrum hemp extract (FSHE), which typically contains less than 0.3% of Δ 9 -THC, isolated CBD (which is a natural source and isolated CBD) and finally isolated CBDA (which is a precursor to CBD). These cannabis extracts were then tested on endometrial-based organoids, confirming their efficacy across different cells in endometrial cancer-based organoids and in endometriosis-based organoids.

[0150] Fig. 6A Depicted is a test of the % viability of endometriosis-based organoids after treatment with BSHE, FSHE, and CBD isolate at 0 μg / mL, 1 μg / mL, 2 μg / mL, 3 μg / mL, 4 μg / mL, 5 μg / mL, 7 μg / mL, and 10 μg / mL. The data here surprisingly showed that each organoid was significantly more viable with doses as low as 5 μg / mL (for CBD isolate) as well as 7 μg / mL (for both BSHE and CBD isolate) and finally 10 μg / mL (for Fig. 6A This data is consistent with results seen in all previous studies testing endometrial cancer organoids.

[0151] Figure 6B The same endometrial-based organoids were then tested with CBDA isolate. Here, slightly higher concentrations were required to achieve viability below 10%. In these experiments, viability below 10% is considered 95%-100% cell death due to residual signaling from dead cells and Matrigel. We see that viability starts just below 50% at 15μg / mL, then rapidly decreases to below 10% at 25μg / mL, and completely resolves at 50μg / mL. However, these studies confirm that the efficacy of CBD-containing CE is conserved across different grades of endometrial cancer as well as endometriosis-based organoids.

[0152] To further investigate the effects of cannabis extracts containing CBD, we looked at endometrial cancer tumor volume in mice. Mouse studies can be used to conduct cell-based applications and confirm their efficacy in whole animal systems. In addition, mice allow for systemic delivery of testing drugs. Figure 7Depicted are the results of administration of 30 mg / kg of four different CBD types over a 21 day test period. Mouse experiments were performed according to the protocol in the Methods section below.

[0153] Typically, EC stem cells from the same patients involved in the endometrial cancer organoid study were injected into mice and allowed to grow. After the tumors reached a certain size, the mice were injected (3 times / week) with either an extract delivery vehicle or a specific cannabis extract. After a certain amount of time had passed, the tumor size was measured. Details on the patient-derived xenograft methodology and experimental protocol are provided in the Methods section.

[0154] refer to Figure 7 , for each of vehicle, BSHE, FSHE, CBD isolate, and CBDA, the treatment days were plotted against the % change in tumor volume. The % change is the average of the tumor volumes taken from three mice compared to the starting average tumor volume on treatment day 0. The change can be positive (increase in tumor size) or negative (decrease in tumor size). As expected, the vehicle (no treatment control) continued to increase in size over 21 days, increasing by almost 150% from the day treatment began. In contrast, tumor size decreased in mice treated with cannabis extracts containing CBD. Therefore, at least we have confirmed that systemic delivery of cannabis extracts containing CBD can be used to treat endometrial cancer. This is an important validation because it confirms the bioavailability of various cannabis extracts containing CBD.

[0155] However, the successful delivery of various cannabis extracts containing CBD was confirmed by the changes observed in tumor volume. For example, after one week of treatment (i.e., 3 doses of approximately 30 mg / kg extract), all tumor averages indicated an initial increase in size. However, by day 10, most mean tumor volumes began to decrease, with tumors in mice treated with CBDA showing the greatest decrease in three days, from an increase of slightly more than 30% to a decrease of more than 30%; the total decrease was greater than 60% in just three days. Mice treated with BSHE and FSHE showed a similar transition from an increase in mean tumor volume to a decrease in mean tumor volume, but not as significant as that observed with CBDA. Interestingly, tumors in mice treated with CBD isolate did not respond as well as tumors in mice treated with other cannabis extracts, which was particularly surprising because CBDA is a precursor to CBD. Within 2 weeks (14 days total - 6 doses), most tumors were reduced in volume by at least 50% compared to their starting size, with the exception of those in mice treated with CBD, which were less than 50%, but the mean tumor volume was still reduced. In contrast, mice treated with CBDA showed an average 70% reduction in tumor volume compared to the starting tumor volume mean. By day 21, with only three weeks of treatment and a total of nine doses, the average tumor volume in each treatment group was reduced by at least 50%, with those treated with CBDA achieving 100% regression. Even more surprising was that when no treatment was given, the increase in average tumor volume was slightly less than 150%. Therefore, cannabis extracts containing CBD not only prevented the increase in endometrial tumor volume, but they also reversed tumor volume, in some cases almost completely. These results confirm the observations in the organoid experiments as well as those in human patients treated with CE.

[0156] It is worth noting that the concentration of the cannabis extract containing CBD used in the mouse model experiment is considered to be the lower limit of the therapeutic dose administered to human patients or mice. For example, 30mg / kg given to mice translates to about 170mg for the average woman. It should be noted that the concentration of CBD isolate in the current US prescription is 5mg / kg-50mg / kg per day. We intentionally used low doses to treat mice to show the effects of these low doses of various cannabis extracts containing CBD on tumor volume over time, rather than forcing the data to 0 by using two times, three times or higher doses to be applied to mice, and each of the two times, three times or higher doses would be the appropriate human equivalent dose. In addition, even at lower doses, within 3 weeks of treatment, the tumor volume of almost all samples progressed to 0, especially those treated with CBDA. Therefore, when the doses used in mice were compared with the doses applied to organoids, we saw that each sample in mice retained the efficacy of the organoid data. In other words, endometrial cancer cells obtained from the same patient responded to cannabis extracts containing CBD in both organoid form and patient-derived xenograft form. Therefore, administering a higher dose of a cannabis extract containing CBD will produce a greater reduction in tumor volume in the mouse model. From all of these experiments conducted in total, it is very clear that administering a cannabis extract containing CBD is effective in greatly reducing the volume of endometrial cancer tumors, which not only slows the growth of endometrial cancer tumors, but can eradicate tumor cells all together, as demonstrated in our mouse model. Similarly, these studies confirm efficacy in endometriosis and NCGD. Therefore, a new method for treating NCGDs such as endometriosis is provided.

[0157] Furthermore, we have demonstrated that gynecological tissues can be targeted by certain applications of cannabis extracts containing CBD, whether orally, oral mucosa, vaginal mucosa, or by other administration to treat EC and reduce tumor size. Due to the targeted approach to gynecological tissues, one of ordinary skill in the art will recognize that certain therapeutic agents are able to cross the vaginal mucosa and contact tissue on the vaginal wall and tissue adjacent to the vaginal wall, including the entire gynecological duct, including the uterus, cervix, ovaries, etc. as non-restrictive tissue. In fact, while these tissues are generally connected, application into the vagina does not always ensure that the therapeutic agent will also travel to and affect the uterus or ovaries. However, as Figure 1E and Figure 1F As depicted, there are a large number of endocannabinoid receptors in the female reproductive tract to allow for the possible therapeutic effects of administered cannabinoids on such tissues. In addition, intravaginal delivery of cannabinoids may result in uptake via the inguinal lymph nodes, leading to additional systemic uptake from the reproductive tract.

[0158] It is also critical that the CE composition is able to treat the patient without significant damage to surrounding and other healthy cells. This is equally true when chemotherapy is administered in cancer patients as when the non-cancerous conditions detailed herein are treated with CE comprising CBD as detailed herein.

[0159] Cannabis extracts, such as those used in our study, had no damage or adverse effects on tissues of mice used in patient-derived xenograft experiments. For example, FIG8 compares histological tissue samples taken from mice treated with cannabis extracts containing CBD with healthy mouse tissues. Fig. 8A Untreated and treated samples from ovaries and fallopian tubes are shown. Chemotherapy is known to adversely affect oocytes and follicles. Here, the treated mice have mature oocytes and follicles that are both healthy. Likewise, it is also known that healthy epithelial tissue is damaged by chemotherapy, often leading to severe organ / organ system damage that can be fatal. When comparing untreated and treated epithelial tissue in mouse fallopian tubes, both appear healthy. Similarly, in Figure 8B The study compared tissue from the uterus, vagina, and liver of treated and untreated mice. The liver was particularly damaged by chemotherapy. Figure 8B As can be seen in the results, liver samples are virtually identical. This is crucial because treatment with high-dose chemotherapy is indiscriminate and can damage these cells when given over time. Therefore, reducing the amount of chemotherapy drugs combined with cannabis extracts (whether at lower doses or without) can improve the patient's outcome by reducing tumor volume at a higher rate, reducing tumor volume to a higher total percentage than chemotherapy alone, and will not cause damage to the corresponding healthy tissues of the reproductive tract and liver as occurs with chemotherapy. CBD is non-toxic in non-transformed cells and does not affect physiological parameters (heart rate, blood pressure and body temperature), gastrointestinal transit or psychomotor or psychological function. Long-term use of CBD and doses up to 1,500mg / day have been determined to be well tolerated in humans.

[0160] Furthermore, CBD-dominant cannabis extracts have no potential for abuse or dependence. This was best emphasized during the 41st World Health Organization Expert Committee on Drug Dependence held in Geneva, Switzerland in November 2018. Annex 1 from the report of that meeting stated “cannabidiol should not be scheduled within the International Drug Control Conventions. Cannabidiol is found in cannabis and cannabis resin but does not have psychoactive properties and has no potential for abuse and no potential to produce dependence. It does not have significant ill-effects.”

[0161] A further interesting observation was made by looking at the effect of pH on the efficacy of cannabis extracts containing CBD on organoid viability. Fig. 9, showing the % of live organoids according to pH and BSHE and CBD isolate treatment (each 10 μg / mL). In this set of experiments, organoids were derived from ovarian cancer tissue. Interestingly, the carrier alone does not destroy the organoids, so no data is depicted. At the natural pH of the extract, organoid production was limited to about 2% in the presence of 10 μg / mL BSHE, and in the presence of the same amount of CBD isolate, organoid production was about 12%. However, increasing pH caused a significant improvement in efficacy, as shown at pH 12 and 14. At this end of pH, scale substances tend to be corrosive, and are highly corrosive at pH 14, and alkaline concentrations are not suitable for therapeutic use. In fact, such pH will not be isotonic and is not suitable for intravaginal application. The vagina has an acidic pH, which is necessary to maintain bacterial balance. However, a strong change in pH may cause protein denaturation or other problems. It is obvious that the first attempt to buffer (even if slightly buffered) pH to more acidic produces worse results. In fact, each of the two cannabis extracts examined in this trial had lower efficacy by lowering the pH from 10.5 to about 10. Furthermore, lowering the pH again to 8 made BSHE almost twice as weak at killing organoids as the native pH, while CBD isolate showed almost no change. Even at a pH of 7 (neutral pH), the changes were minimal at best.

[0162] In such cases, further lowering the pH will not likely result in any further increase in therapeutic efficacy, as the change will generally be worse or almost no change compared to the native pH. In contrast, by further lowering the pH to 4, a significant improvement in % viability was seen for each of the BSHE and CBD isolates, bringing each below 1% viability, which was unexpected based on previous data that trended toward a worse response or a substantially unchanged response. Thus, when providing a cannabis extract, particularly in the case of providing the cannabis extract intravaginally or to the oral mucosa, adjusting the pH to between 2 and 6 with a buffer results in a superior response compared to administering the cannabis extract at its native pH. Preferably, the cannabis extract is provided in a carrier at a pH between 3.5 and 5.5, more preferably at a pH between 4 and 5.

[0163] Patient Sample Overview

[0164] Using organoids to test therapies is exciting because we can use representative cells to determine responses to different therapies, rather than relying on similar models in other species. So, the results showed that the organoids were destroyed at a variety of different concentrations when exposed to BSHE or FSHE containing CBD, but often at concentrations as low as 5μg / mL, 7μg / mL, 10μg / mL, or 20μg / mL. This was shown in several different patients with organoids based on different stages and grades of endometrial cancer and endometriosis, all with the same success rate. These numbers were translated into a mouse model, confirming the same efficacy, where tumor growth was blocked and tumor size was reduced across the board.

[0165] Intravaginal delivery is well studied and considered safe, effective and well tolerated. Intravaginal delivery avoids gastrointestinal absorption and bypasses first-pass metabolism, while promoting local action and a stable, sustained therapeutic response. With similar lipophilic compounds, absorption and systemic delivery via the vaginal epithelium occur rapidly. Changes in vaginal epithelial thickness and vaginal fluid characteristics (including pH, presence of cervical mucus and microbiota) can affect absorption rate and bioavailability.

[0166] Compared with the oral route of CBD, rectal suppository delivery leads to increased bioavailability (51% to 60%). Data on oral mucosal or sublingual delivery prove that the maximum plasma concentration of CBD is 1.6 hours, but this may be extended in some individuals. The maximum plasma concentration of oral CBD is about 2.5 hours to 5 hours, but it may be extended to 6 hours for some individuals. It has been confirmed that co-administration with high-fat food will increase Cmax, up to 5 times the concentration. Delivery of CBD via highly vascularized nasal mucosa causes rapid uptake and Tmax of about 10 minutes. However, vaginal mucosa has not yet been used for therapeutic treatment. Therefore, the CBD uptake achieved by intravaginal absorption remains an opportunistic administration route as described in detail herein.

[0167] Therefore, mucosal administration, particularly intravaginal administration, has therapeutic efficacy that may allow targeted treatment of EC cells, which would treat both localized tumors as well as metastatic tumors. These data were confirmed by further testing in human patients, showing that treatment with CBD was effective in reducing chemoresistant EC that had metastasized within the body.

[0168] Methods and calculations

[0169] Patient-derived organoids

[0170] Patient-derived organoids were generated by collecting endometrial cancer tissue samples after surgery. The collected tissue was immersed in Hank's balanced salt solution (HBSS) (Hyclone, SH30031.02) containing 1% penicillin / streptomycin (P / S) (Life Technologies, 15070-063) on ice. The tissue sample was placed on an oscillator (70rpm) and washed three times with Dulbecco's phosphate-buffered saline (DPBS) and 1% P / S, each wash for 15 minutes. The tissue sample was then placed in a pre-sterilized cell culture hood, where it was finely minced with a sterile blade. All minced parts were enzymatically digested at room temperature (Accumax TM —Innovative Cell Technologies Inc., AM105-500) for about 2.5 hours. After 2.5 hours, the completely digested tissue was transferred and lysed in a 37°C water bath with TrypLE TM express (Gibco, 12604-021) is further enzymatically digested for 45 minutes. During this period, the solution is continuously stirred at intervals of 5 minutes. Then, the digested tissue solution is passed through a 70 μm filter on a 50 mL falcon tube. Remove the filter and collect the flow-through containing cells in 5% FBS AD+++ culture medium (comprising 1% ITS, 2% B27, 1% N2, 25% WRN, hegf-50ng / mL, hfgf-10-100ng / mL, nicotinamide-1mM, N-acetylcysteine-1.25mM, Primocin-0.2%, estrogen-2nm, A8301-0.5μM and Y27632). The cell suspension is centrifuged at 1000rpm for 5 minutes at room temperature to obtain a cell pellet for counting. When checked under a hemocytometer, the number of cells is calculated and processed for organoid culture. The final cell suspension was checked under a microscope for RBC contamination and if found, RBCs were lysed using red blood cell lysis buffer (Roche Diagnostics, 11814389001). The resulting endometrial cancer cells from human patients were cultured and maintained in a humidified chamber at 37°C with 5% CO2.

[0171] Organoids derived from ascites samples were treated somewhat differently; the ascites was centrifuged at 1000 rpm for 10 minutes at room temperature to obtain a cell suspension. The cell suspension was then treated with red blood cell lysis buffer (Roche Diagnostics, 11814389001) to remove RBCs from the final cell suspension.

[0172] In order to culture patient-derived organoids, 2 to 3 × 10^3 cells were plated in 10 μL of Matrigel (5% FBS AD+++ culture medium) per well in a pre-warmed (37 ° C) 96-well plate. Individual patient cell organoids were cultured separately in different plates. Individual patient cells were processed separately to reduce the chance of cross-contamination. After the cells were mixed with Matrigel, 10 μL droplets were placed in the wells and then placed in a 37 ° C incubator containing 5% CO2 for 30 minutes. After the Matrigel droplets with cells inside solidified, the plate was placed in a sterile hood and the Matrigel droplets were immersed in 200 μL of organoid growth medium. The cells were grown for 14 days to become mature organoids. Treatment with a single CBD agent (broad spectrum, full spectrum, CBD isolate and CBDA) or in combination with a chemotherapeutic agent (paclitaxel or carboplatin) usually starts on the 5th day, where a single drug or drug combination is added to the growth medium. All treatments were performed in triplicate, including a vehicle-only control (the highest concentration of DMSO in the culture medium used for drug treatment).

[0173] Some human equivalent doses were calculated using the standard formula: (M = m / MW*1 / V, where m = mass (grams), MW = molecular weight of the substance, and V = volume of diluent (liters). For example, if the organoid is dosed with 54.35 μM drug X, 0.0032 mg of drug X is required in 100 μL or 0.0001 L (V) of solute. This is equivalent to a concentration of 0.00005435 M or 54.35 μM, where the MW of drug X = 588.72 g / mol, and m = 0.0000032 g.

[0174] When using a 96-well plate, the following formula is used to convert a given dose into a human dose. The surface area of ​​a single well in a 96-well plate is 0.32 cm 2 Therefore, according to the following formula, the clinical dose equivalent (mg / m 2 ) is 100 mg / m 2 :Clinical dose (mg / m 2 ) = (mg / culture plate surface area cm 2 PDO dose)×100 2 When two different methods of converting organoid doses to human doses were compared, both calculations showed similar human equivalent doses, e.g., approximately 200 mg / day for an organoid equivalent of 10 μg / mL.

[0175] IC50 is a 50% inhibitory concentration routinely used to determine drug efficacy using a cell-based cytotoxicity test. In order to determine the IC50 of a specific patient-derived organoid, each of BSHE, FSHE, CBD isolate and CBDA was used to treat individual patient organoids as described above. By using the least squares regression (in Graphpad Prism9) to the inhibitor (i.e., a specific cannabis extract) to compare the normalized response-variable slope, the individual IC50 was found using the results of such treatment. Therefore, the IC50 of each cannabinoid extract and the selected patient-derived organoid was determined. Thereafter, for each patient-derived organoid selected for testing a combination of a cannabis extract containing CBD and a chemotherapeutic agent, the organoid was treated with a combination of a single chemotherapeutic agent or a chemotherapeutic agent and a cannabinoid extract equivalent to the calculated IC50 of a specific extract / organoid combination. The same IC50 dose was given with each increasing dose of the chemotherapeutic agent. It is worth noting that the dose of each chemotherapeutic agent given in the organoid was lower than the equivalent of the maximum dose suitable for human administration. In this way, we can determine whether the specific IC50 of a given cannabis extract containing CBD and a reduced amount of a chemotherapeutic (paclitaxel, doxorubicin, or carboplatin) can be used to achieve the same amount of cancer cell death as a standard human dose of the chemotherapeutic.

[0176] Cell viability assay

[0177] To assess cell viability in treated organoids, use CellTiter- Luminescence assay (Promega #G7572). Briefly, on day 14 of organoid culture, the Matrigel droplets with organoids inside each well were immersed in 100 μL of fresh growth medium and 100 μL of CellTiter- Each plate also contained only culture medium and CellTiter The plate was then placed on a shaker at 110 rpm for 5 minutes at room temperature to induce cell lysis and then kept at room temperature for 25 minutes to stabilize the luminescent signal. Each step after the reagent was carried out in the dark. Luminescence was measured on a FLUOstar OPTIMA plate reader (BMG Labtechnologies, Offenburg, Germany). The treatment values ​​were normalized to the vehicle control and plotted as a percentage of the vehicle control for analysis. The drug IC50 values ​​were determined by comparing the inhibitor to the normalized response-variable slope using the least squares regression in Graphpad Prism 9.

[0178] Generation of Patient-Derived Xenograft (PDX) Mice

[0179] Human patient cells from endometrial cancer were resuspended in 100 μL of solution and injected subcutaneously into female NOD / SCIDγ mice. Once tumors grew to a visible size, all mice were injected intraperitoneally with a single cannabis extract containing a CBD agent, either alone at 10 mg / kg to 30 mg / kg body weight, or with a cannabis extract containing a CBD agent together with a given chemotherapeutic agent, where the given cannabis extract was given at 10 mg / kg to 30 mg / kg body weight, paclitaxel was given at up to 20 mg / kg body weight, or vehicle was given three times a week for up to 5 weeks. Tumor size was measured before treatment and then twice a week. All treated group mice remained alive for up to 10 weeks after drug injection, or until the tumor volume grew to greater than 2500 mm 3 .

[0180] Tumor size and body weight were measured at the time of tissue collection. All tumor tissues were carefully removed from euthanized mice. Tumor tissue samples were saved for histology, proteomics, genomics, and other downstream processing. All downstream processing was completed following the NCI Patient-Derived Model Repository SOP.

[0181] Mouse PDX to human dose conversion

[0182] The U.S. Food and Drug Administration (FDA) has proposed that the extrapolation of animal doses to humans can be performed correctly only by normalizing to body surface area (BSA), which is often expressed in mg / m 2 The human equivalent dose (HED) can be more appropriately calculated by using the following formula: Human equivalent dose (mg / kg) = mouse dose (mg / kg) × (mouse K m / personK m ). The average body weight (kg) of a species is divided by its body surface area (m 2 ) to estimate the correction factor (K m For example, the average human body weight is 60 kg and the body surface area is 1.62 m 2 Therefore, the K of a person is calculated by dividing 60 by 1.62 m factor, which is 37, and the K for mice was calculated in the same way m factor, which is 3. Now use K m Factors are converted to animal or human dosage units (mg / kg to mg / m 2 ): mg / m 2 Dose = K m × Dose in mg / kg.

[0183] Implementation

[0184] In a preferred embodiment, CE comprises CBD between 50% and 95%. Therefore, a 10 mg dose of CE comprises CBD between 5 mg and 9 mg. The remaining components of CE include additional cannabinoids, terpenes, polyphenols, essential fatty acids and phytonutrients. The pharmaceutical composition herein comprises CE, and the ratio of CE in the composition is between 1% by weight and 99% by weight. When provided in a pharmaceutical composition, the concentration of CBD is generally given at a dose between 50 mg / mL pharmaceutical composition and 50 mg / mL pharmaceutical composition. Certain compositions comprise additional excipients and ingredients, including but not limited to fats, oils, MCT oils, long-chain triglyceride oils, and very long-chain triglyceride oils. Terpene components include but are not limited to β-myrcene, β-caryophyllene, linalool, α-pinene, citral, D-limonene, eucalyptol. Polyphenols may include but are not limited to catechins, quercetin, geranylflavonoids A / B / C, rutin and chlorogenic acid. Omega 3, omega 6 and omega 9 fatty acids may be present, as well as additional phytonutrients such as tocopherols, sterols, carotenes, fatty alcohols and certain minerals. These components (including carriers) may be present in the pharmaceutical composition in an amount of up to 99.9% by weight, however, more preferably, the CE containing CBD is present in an amount of between 1% and 99% by weight, and preferably in an amount of between 40% and 99% by weight in the composition.

[0185] Thus, a preferred embodiment relates to a method for treating endometriosis, the method comprising administering to a patient an effective amount of a pharmaceutically acceptable composition comprising CBD, wherein the composition comprises a CE, such as a BSHE or FSHE. In a preferred embodiment, the effective amount is an amount effective to produce a concentration of at least 10 μg / mL of BSHE or FSHE at the target tissue, and more preferably a target concentration of at least 20 μg / mL. In another preferred embodiment, the effective dose is between 10 mg and 4250 mg of CBD per day, wherein the CBD is provided in the CE by mucosal application, such as intravaginal, oral mucosal / sublingual, nasal or rectal. The treatment methods herein effectively eliminate inappropriate lesions, i.e., cells that have migrated from their intended location in the body. In addition, these methods terminate or hinder the growth of endometrial cells outside the endometrium without harming the endometrium. In addition, the methods herein limit or eliminate the migration of endometrial cells outside the endometrium, and are ultimately used to control symptoms, including reducing pain, bleeding, and the formation of endometriomas and fibrous tissue that lead to scar tissue development and adhesions.

[0186] In another embodiment, the method of treatment can be used to alleviate and treat ovarian endometrioma or deep endometriosis. In a further embodiment, the method of treatment comprises applying a pharmaceutically acceptable composition by intravaginal administration to treat dysmenorrhea or fibroids, wherein the pharmaceutically acceptable composition comprises a CE containing CBD, wherein the ratio of CBD to the total weight of CE is between 75% and 99%. In a preferred embodiment, the effective amount is an amount effective to produce a concentration of at least 10 μg / mL of BSHE or FSHE at the target tissue. In another preferred embodiment, the effective dose is between 10 mg and 250 mg of CBD per day, wherein the CBD is provided in a pharmaceutically acceptable carrier in BSHE or FSHE by intravaginal application.

[0187] In certain embodiments, the CE may be administered without the need for an additional carrier. Thus, a composition suitable for administration to a patient may be a CE that does not contain any other carriers or excipients.

[0188] However, preferred embodiments include compositions for treating NCGD, wherein the composition comprises a cannabis extract (CE), wherein the CE is present in the composition at a ratio between 1% and 100% by weight, and may be any percentage within this range. In preferred embodiments, the CE is present in the composition at a ratio between 10% and 90% by weight, or between 20% and 90% by weight, and preferably between 40% and 80% by weight. As described in detail herein, the CE is preferably BSHE, FSHE, CBD isolate or CBDA isolate. In each of these different CEs, i.e., BSHE, FSHE, CBD isolate or CBDA isolate, the ratio they present in the CE is between 50% and 99.9% by weight, and the remainder is wax, fat, fatty acid, etc. However, preferred embodiments utilize a carrier present in the composition at a ratio between 1% and 99% by weight, and preferably, one or more additional excipients are utilized depending on the use of the composition. The composition is then typically administered based on a dose in mg of the CBD administered. The amount of composition required to meet this mg CBD content depends on the amount of CBD in each CE.

[0189] It should be understood that the embodiments and illustrations described herein are provided by way of example, and the present invention is not limited to what has been specifically disclosed. On the contrary, the scope of the present invention includes combinations and sub-combinations of the various features described above, as well as variations and modifications thereof that will occur to those skilled in the art after reading the foregoing description and that are not disclosed in the prior art. Therefore, as understood by those who implement the various methods and systems detailed herein, various compositions and methods may include one or all of the limitations of an embodiment, in any order, or may combine limitations from different embodiments.

Claims

1. A cannabis extract for use in a method of treating a non-cancerous gynecological disorder (NCGD) in a patient, wherein the cannabis extract comprises cannabidiol (CBD).

2. A cannabis extract for use according to claim 1, wherein the cannabis extract is selected from the group consisting of full spectrum hemp extract (FSHE), broad spectrum hemp extract (BSHE), CBD isolate and cannabidiolic acid (CBDA), optionally wherein the BSHE or FSHE comprises (i) 50% to 99% by weight CBD and (ii) at least one other cannabinoid selected from the group consisting of: delta-9-tetrahydrocannabinol (Δ-9-THC) 9 -THC), tetrahydrocannabinolic acid (THCA), tetrahydrocannabidiol (THCV), Δ-8-tetrahydrocannabinol (Δ 8 -THC), cannabichromene (CBC), cannabichromene acid (CBCA), cannabigerol (CBG), cannabigerolic acid (CBGA), cannabidiolic acid (CBDA), cannabidiol (CBDV), cannabinol (CBN), cannabichromene (CBL), and combinations thereof.

3. A cannabis extract for use according to claim 1 or 2, wherein the cannabis extract comprises between 10 mg and 4,250 mg of CBD per dose.

4. A cannabis extract for use according to any one of claims 1 to 3, wherein: a. The method comprises administering the cannabis extract to the patient via an oral dose, an oromucosal dose, an intravaginal dose, or a combination thereof; and / or b. The method comprises administering to the patient a dose of the cannabis extract at least once every three days, preferably at least once a day, at least twice a day or at least three times a day; and / or c. the method comprising administering an amount of the cannabis extract sufficient to produce a concentration of at least 10 μg / mL of the cannabis extract at a target tissue of the patient, Preferably, wherein the target tissue is non-cancerous tissue of the female reproductive tract; and / or d. the method comprises administering an amount of the cannabis extract sufficient to achieve a therapeutically effective level as measured by systemic plasma levels of CBD; and / or e. The method comprises administering to the patient between 20 mg and 4,250 mg of CBD per day; and / or f. formulating the cannabis extract at an acidic pH, preferably at a pH between 3.5 and 6.

5. A cannabis extract for use according to any one of claims 1 to 4, wherein: a. the NCGD is endometriosis; and / or b. The NCGD is dysmenorrhea and / or c. The NCGD is a fibroid.

6. A cannabis extract for use according to any one of claims 1 to 5, wherein the cannabis extract comprises between 1% and 99.9% CBD, and wherein the method comprises administering the cannabis extract to the patient via intravaginal administration, preferably wherein: a. the cannabis extract contains between 60% and 99.9% CBD; and / or b. The cannabis extract is selected from full spectrum hemp extract (FSHE), broad spectrum hemp extract (BSHE) and CBD isolate; and / or c. The cannabis extract contains CBDA.

7. A mucosal composition for use in a method of treating a non-cancerous gynecological disorder (NCGD) in a patient, wherein the mucosal composition comprises a cannabis extract as defined in any one of claims 1 to 3 and 6, and a pharmaceutically acceptable excipient.

8. A mucosal composition for use according to claim 7, wherein the composition comprises (i) an oil or fat as a carrier and / or (ii) at least one terpene, at least one polyphenol, at least one essential fatty acid, at least one phytonutrient or a combination thereof, Optionally, the at least one terpene, at least one polyphenol, at least one essential fatty acid, at least one phytonutrient or a combination thereof is present in a ratio between 1% and 50% by weight of the total weight of the composition, Further optionally wherein: The terpene is selected from β-myrcene, β-caryophyllene, linalool, α-pinene, citral, D-limonene, eucalyptol and combinations thereof; and / or The polyphenol is selected from catechin, quercetin, geranylflavonoids A / B / C, rutin, chlorogenic acid and combinations thereof; and / or The essential fatty acids are selected from ω3 acids, ω6 acids, ω9 acids and combinations thereof; and / or The phytonutrients are selected from tocopherols, sterols, carotenes, fatty alcohols, minerals and combinations thereof.

9. The mucosal composition for use according to claim 7 or 8, wherein: a. the mucosal composition comprises between 25 mg and 4,250 mg of CBD in a dose, and the method comprises administering the composition to the patient via insertion into a mucosal surface selected from the oral mucosa, rectum, vagina, or nasal passages; and / or b. The method comprises administering to the patient at least two doses of the mucosal composition per day, wherein each dose of the mucosal composition comprises between 10 mg and 2,125 mg of cannabis extract; and / or c. The mucosal composition has an acidic pH, preferably a pH between 3.5 and 6.

10. A cannabis extract for use according to any one of claims 1 to 6, wherein the method is a method for treating NCGD and the method comprises concomitantly administering the cannabis extract to the patient via a mucosal preparation, preferably wherein the cannabis extract is a full spectrum hemp extract (FSHE) or a broad spectrum hemp extract (BSHE).

11. A cannabis extract for use according to any one of claims 1 to 6, wherein the method comprises co-administering to a patient an effective amount of the cannabis extract and an effective amount of a second therapeutic agent.

12. A pharmaceutical composition for use in a method of treating a non-cancerous gynecological disorder (NCGD), wherein the pharmaceutical composition comprises a cannabis extract containing an effective amount of CBD.

13. The pharmaceutical composition for use according to claim 12, wherein the composition further comprises: a. carrier; and / or b. At least one selected from Δ 9 -THC, THCA, THCV, Δ 8 - Additional cannabinoids of THC, CBC, CBCA, CBG, CBGA, CBDA, CBDV, CBN, CBL and combinations thereof; and / or c. at least one terpene, preferably wherein the terpene is selected from β-myrcene, β-caryophyllene, linalool, α-pinene, citral, D-limonene, eucalyptol and combinations thereof; and / or d. at least one polyphenol, preferably wherein the polyphenol is selected from catechins, quercetin, geranylflavonoids A / B / C, rutin, chlorogenic acid and combinations thereof; and / or e. essential fatty acids, preferably wherein the essential fatty acids are selected from ω3 acids, ω6 acids, ω9 acids and combinations thereof; and / or f. Phytonutrients, preferably wherein the phytonutrients are selected from tocopherols, sterols, carotenes, fatty alcohols, minerals and combinations thereof.

14. A method for treating non-cancerous gynecological disorders (NCGDs) comprising administering to a patient an effective amount of a composition comprising a cannabis extract (CE).

15. The method of claim 14, wherein the CE comprises between 50% and 99.9% cannabidiol (CBD).

16. The method of claim 14 or 15, wherein the CE is selected from the group consisting of full spectrum hemp extract (FSHE), broad spectrum hemp extract (BSHE), CBD isolate, and cannabidiolic acid (CBDA) isolate.

17. The method according to any one of claims 14 to 16, wherein the CE is administered via an oral form, an oromucosal form, an intravaginal form, a nasomucosal form, a rectal form, an injectable form, and combinations thereof.

18. The method of any one of claims 14 to 17, wherein the effective amount of the cannabis extract comprising CBD comprises between 10 mg and 4,250 mg CBD per day.

19. The method of any one of claims 14 to 18, wherein administering the CE is in a dosage given at least once a day, at least twice a day, or at least three times a day.

20. The method of any one of claims 14 to 19, wherein the NCGD is ovarian endometrioma, deep endometriosis, dysmenorrhea, or fibroids.

21. The method of any one of claims 14 to 20, wherein the CE comprises CBDA at a concentration between 0.1% and 10%.

22. The method of any one of claims 14 to 21, wherein the CE is a BSHE or a FSHE, and wherein each of the BSHE or FSHE comprises 50% to 99% by weight of CBD and at least one other cannabinoid in a concentration of 0.1% to 10%, the at least one other cannabinoid being selected from the group consisting of: Δ 9 -THC, THCA, THCV, Δ 8 -THC, CBC, CBCA, CBG, CBGA, CBDA, CBDV, CBN, CBL and combinations thereof.

23. The method according to any one of claims 14 to 22, wherein the CE comprises CBD at a concentration between 60% and 99% and at least one other cannabinoid at a concentration between 0.1% and 10%, wherein the at least one other cannabinoid is selected from the group consisting of: Δ 9 -THC, THCA, THCV, Δ 8 -THC, CBC, CBCA, CBG, CBGA, CBDA, CBDV, CBN, CBL and combinations thereof; and wherein the CE comprises a total cannabinoid concentration between 65% and 99%.

24. The method of any one of claims 14 to 23, wherein the composition comprises at least one additional compound selected from the group consisting of terpenes, polyphenols, essential fatty acids, phytonutrients, and combinations thereof; wherein the at least one additional compound is present in an amount between 0.1% and 50% of the total weight of the composition.

25. The method according to any one of claims 14 to 24, wherein the composition comprises an oil or fat as a carrier.

26. The method of any one of claims 14 to 25, wherein the effective amount of the composition is an amount sufficient to achieve effective therapeutic levels of CBD as measured by systemic plasma levels.

27. The method of any one of claims 14 to 26, wherein the composition is administered at an acidic pH.

28. The method of claim 27, wherein the acidic pH is between 3.5 and 6.

29. The method of any one of claims 14 to 28, wherein the effective amount of the composition is sufficient to achieve effective therapeutic levels as measured by systemic plasma levels of CBD.

30. The method of any one of claims 14 to 29, wherein the composition further comprises at least one terpene.

31. The method of claim 30, wherein the terpene is selected from the group consisting of β-myrcene, β-caryophyllene, linalool, α-pinene, citral, D-limonene, eucalyptol, and combinations thereof.

32. The method of any one of claims 14 to 31, wherein the composition further comprises at least one polyphenol.

33. The method of claim 32, wherein the polyphenol is selected from the group consisting of catechin, quercetin, geranylflavone A / B / C, rutin, chlorogenic acid, and combinations thereof.

34. The method of any one of claims 14 to 33, wherein the composition further comprises an essential fatty acid selected from the group consisting of ω3, ω6, ω9, and combinations thereof.

35. The method of any one of claims 14 to 34, wherein the composition further comprises a phytonutrient.

36. The method of claim 35, wherein the phytonutrient is selected from the group consisting of tocopherols, sterols, carotenes, fatty alcohols, minerals, and combinations thereof.

37. The method of any one of claims 14 to 36, wherein the CBD is a phytocannabinoid derived from a cannabis extract.

38. A method of treating a non-cancerous gynecological disorder (NCGD), comprising: a. Obtaining gynecological cells from a patient, and forming at least one organoid from the gynecological cells; b. screening the at least one organoid to identify a cannabis extract (CE) to which the patient's organoid is responsive; and c. administering said CE to said patient together with an effective amount of a composition comprising said CE having between 50% and 99.9% CBD.

39. The method of claim 38, wherein the CE is administered to the patient in an oral form, an oromucosal form, a nasal form, a rectal form, an intravaginal form, an injectable form, and combinations thereof.

40. The method of claim 39, wherein the CE is administered oromucosally and intravaginally.

41. A method for treating endometriosis comprising administering to a patient an effective amount of an intravaginal composition comprising a cannabis extract (CE) comprising cannabidiol (CBD).

42. The method of claim 41, wherein the endometriosis is ovarian endometrioma or deep endometriosis.

43. A method for treating dysmenorrhea or fibroids, comprising: An effective amount of an intravaginal composition comprising a cannabis extract (CE) containing cannabidiol (CBD) is administered to a patient.

44. The method according to any one of claims 40 to 43, wherein the CE comprises between 50% and 99.9% by weight of CBD.

45. Use of a therapeutic agent comprising cannabis extract (CE) for treating a gynecological condition selected from the group consisting of endometriosis, dysmenorrhea, fibroids, and combinations thereof.

46. ​​A therapeutic agent for treating endometriosis, comprising a cannabis extract (CE) having an effective amount of CBD.

47. The therapeutic agent of claim 46, further comprising a carrier.

48. The therapeutic agent of claim 46 or 47, further comprising at least one additional cannabinoid selected from the group consisting of: 9 -THC, THCA, THCV, Δ 8 -THC, CBC, CBCA, CBG, CBGA, CBDA, CBDV, CBN, CBL and combinations thereof.

49. The therapeutic agent of any one of claims 46 to 48, further comprising at least one terpene.

50. The therapeutic agent of claim 49, wherein the terpene is selected from the group consisting of β-myrcene, β-caryophyllene, linalool, α-pinene, citral, D-limonene, eucalyptol, and combinations thereof.

51. The therapeutic agent of any one of claims 46 to 50, further comprising at least one polyphenol.

52. The therapeutic agent of claim 51, wherein the polyphenol is selected from the group consisting of catechin, quercetin, geranylflavone A / B / C, rutin, chlorogenic acid, and combinations thereof.

53. The therapeutic agent of any one of claims 46 to 52, further comprising an essential fatty acid selected from the group consisting of ω3, ω6, ω9, and combinations thereof.

54. The therapeutic agent of any one of claims 46 to 53, further comprising a phytonutrient.

55. The therapeutic agent of claim 54, wherein the phytonutrient is selected from the group consisting of tocopherols, sterols, carotenes, fatty alcohols, minerals, and combinations thereof.

56. The method or therapeutic agent of any preceding claim, further comprising hormone therapy, GnRH therapy, progestin therapy, an aromatase inhibitor, or a combination thereof.

57. A composition for use in a method of treating a non-cancerous gynecological disorder (NCGD), wherein the composition comprises between 1 wt% and 99 wt% cannabis extract (CE).

58. The composition of claim 57, wherein the CE of the composition comprises: a. full spectrum hemp extract (FSHE), broad spectrum hemp extract (BSHE), CBD isolate, CBDA isolate, or a combination thereof; and / or b. wherein the composition comprises between 1% and 99% by weight of the carrier; and / or c. wherein the composition further comprises between 1 wt % and 50 wt % of one or more excipients of the composition.

59. A composition for treating non-cancerous gynecological disorders (NCGD), wherein the composition comprises cannabis extract (CE), wherein the ratio of CE in the composition is between 1 wt % and 100 wt %, and can be all percentages within the said range.

60. The composition according to claim 59, wherein the ratio of the CE in the composition is between 10 wt% and 90 wt%, or between 20 wt% and 90 wt%, and preferably between 40 wt% and 80 wt%.

61. The composition of claim 59 or 60, wherein the CE is preferably full spectrum hemp extract (FSHE), broad spectrum hemp extract (BSHE), CBD isolate or CBDA isolate.

62. The composition of claim 61, wherein the BSHE and / or the FSHE And / or the ratio of the CBD isolate and / or the CBDA isolate in the CE is between 50 wt % and 99.9 wt %.

63. A composition according to any one of claims 59 to 62, comprising a carrier in an amount between 1% and 99% by weight of the composition.

64. A composition according to any one of claims 59 to 63, further comprising at least one or more additional excipients.

65. A composition according to any one of claims 59 to 64, wherein the composition is a mucosal composition.

66. A composition according to any one of claims 59 to 65 comprising between 20 mg and 4,250 mg of CBD.

67. A method of treating a non-cancerous gynecological disorder (NCGD) comprising administering to a patient an effective amount of a composition according to any one of claims 57 to 66.

68. The method of claim 67, wherein the effective amount is between 20 mg and 4,250 mg of cannabidiol (CBD).

Images