WO2022029813A1 - Compositions gynécologiques à base de cannabidiol et de terpènes en combinaison avec des vasodilatateurs périphériques - Google Patents

Compositions gynécologiques à base de cannabidiol et de terpènes en combinaison avec des vasodilatateurs périphériques Download PDF

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WO2022029813A1
WO2022029813A1 PCT/IT2021/050241 IT2021050241W WO2022029813A1 WO 2022029813 A1 WO2022029813 A1 WO 2022029813A1 IT 2021050241 W IT2021050241 W IT 2021050241W WO 2022029813 A1 WO2022029813 A1 WO 2022029813A1
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terpenes
composition
cannabidiol
cbd
visnadine
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PCT/IT2021/050241
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English (en)
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Tommaso PELAGATTI
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Agora' Pharma S.R.L.
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Priority to EP21766009.1A priority Critical patent/EP4188362A1/fr
Publication of WO2022029813A1 publication Critical patent/WO2022029813A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/01—Hydrocarbons
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/01—Hydrocarbons
    • A61K31/015—Hydrocarbons carbocyclic
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
    • A61K31/05—Phenols
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/365—Lactones
    • A61K31/366—Lactones having six-membered rings, e.g. delta-lactones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0014—Skin, i.e. galenical aspects of topical compositions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0034—Urogenital system, e.g. vagina, uterus, cervix, penis, scrotum, urethra, bladder; Personal lubricants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/22—Anxiolytics

Definitions

  • the present invention relates to gynaecological compositions based on cannabidiol and terpenes in combination with peripheral vasodilators. More particularly, the invention relates to compositions containing cannabidiol and one or more of the terpenes present in Cannabis sativa or in other plant species, in combination with herbal active principles with vasodilatory, vasokinetic and/or spasmolytic activity such as coumarins, which has been found to be capable of synergistically potentiating the activity of cannabidiol and terpenes in the treatment of various gynaecological conditions, such as vulvar atrophy and vaginal dryness.
  • Cannabis sativa or hemp original from Central Asia, has been known as a medicinal plant for several millennia, so much so that it is considered sacred by Malawi peoples.
  • THC tetrahydrocannabinol
  • the compounds contained in the hemp plant are made up of an important variety of chemicals: some of the hundreds of elements identified to date, such as the at least 113 cannabinoids, are found exclusively in cannabis, while others, such as terpenes, even more abundant in number, are spread across the whole plant kingdom.
  • cannabidiol a group of terpenophenohc compounds are referred to, which are uniquely found in Cannabis sativa.
  • the two most abundant and studied cannabinoids are represented by tetrahydrocannabinol (Ag-Thc, THC), known as the most important tetrahydrocannabinol for its psychoactive properties, and cannabidiol (CBD), best known for its anti-inflammatory and anti-psychoactive properties, belonging to the cannabidiols family.
  • THC tetrahydrocannabinol
  • CBD cannabidiol
  • THC and CBD are closely, but not univocally, related to the endocannabinoid system, a complex endogenous system of communication between cells present in living organisms, composed of endocannabinoid receptors, their endogenous ligands (endocannabinoids) and proteins involved in the metabolism and transport of endocannabinoids. It is known that this system, of great importance for the normal functioning of the organism, takes its name from the cannabis plant because some phytocannabinoids present in it, including THC, mimic the effects of endocannabinoids, by binding themselves to the same receptors.
  • cannabinoids bind to CBi and CB2 receptors, which are both coupled to Gi proteins.
  • CB1 is found constitutively expressed in high concentrations at the level of the central nervous system, especially in the cerebral cortex, in the hippocampus, in the basal ganglia, in the cerebellum and in some peripheral nervous tissues, such as sensory nerves and some fibers of the autonomous nervous system.
  • CB2 on the other hand, is found mainly expressed on cells of the immune system, such as B lymphocytes, T lymphocytes, natural killer cells, monocytes and macrophages, and has recently been identified in the central nervous system, expressed by microglia.
  • THC the main cannabinoid
  • THC the main cannabinoid
  • THC In addition to binding with CB2 and CB1, THC exerts its effects by interacting with a considerable number of other receptors and transmission systems: it is an agonist of PPAR-y and TRPA1 receptors, antagonist of 5-HT3A receptors, it mediates the activation of glycine receptors, and interacts with the TRPA1 and TRPV2 vanilloid receptors.
  • CBD represents the most promising active ingredient from a pharmacological point of view, thanks to its lack of psychoactive effects, together with its proven anti-inflammatory, antioxidant, anxiolytic and neuroprotective efficacy.
  • cannabidiol has been proposed (European patent EP 1071417B1 , The Mathilda and Terence Kennedy Institute of Rheumatology and Yissum Research Development Company of the Hebrew University of Jerusalem) for use as an anti-inflammatory in the treatment of rheumatoid arthritis, multiple sclerosis, ulcerative colitis and Crohn's disease.
  • Cannabidiol shows an extreme pharmacological versatility: it manages, even at nanomolar concentrations, to displace THC from the binding sites of the CBi receptor, despite having a low affinity for said receptor.
  • CBD does not interact with the endocannabinoid system alone: it seems, in fact, that other receptor and enzymatic systems are affected by its activity.
  • CBD acts as an agonist against TPRV1 , and as an allosteric modulator of the cd and cd [3 glycine receptors. This suggests a role thereof in chronic inflammatory pain, considering the inhibitory neurotransmitter action that glycine exerts at the level of the dorsal horns of the spinal cord (Boychuk DG et al., The effectiveness of cannabinoids in the management of chronic non malignant neuropathic pain: a systematic review, J Oral Facial Pain Headache, 2015, 29: 7-14).
  • CBD anti-inflammatory action
  • vanilloid receptors The anti-inflammatory action of CBD is mediated both by the interaction with the vanilloid receptors and by the inhibition of lipoxygenase and cyclooxygenase.
  • terpenes are a class of plant organic compounds made up of multiples of the isoprene unit (and more specifically called terpenoids when their molecule contains one or more heteroatoms, generally oxygen or nitrogen). Terpenes represent the largest group of volatile substances, an integral part of the cannabis essential oil, best extractable by steam distillation. Unlike cannabinoids, terpenes determine the characteristic aroma of the plant.
  • terpenes are very versatile compounds: they are lipophilic, they interact with membrane ion channels at the level of muscle and neuronal cells, of neuro-receptor systems, of protein-coupled receptors. Like any other active substance, they each have their own biological activity, but their possible synergistic role with cannabinoids is becoming increasingly interesting, in amplifying some of their properties, such as the antiinflammatory, analgesic, anxiolytic, antidepressant and antibacterial activity. Most of the data collected comes from preclinical studies in animal models and in vitro studies (Pellati F. et al., New Methods for the Comprehensive Analysis of Bioactive Compounds in Cannabis sativa L. (hemp), Molecules, 2018, 23, 2639).
  • Myrcene normally contained in the essential oil of cannabis in a percentage of 22-23% by weight, is the most common of the monoterpenes present. It has an important anti-inflammatory, analgesic and anxiolytic activity, and is also widely used in the cosmetics industry.
  • Myrcene is known to reduce inflammation via the prostaglandin pathway (PGE-2) (Van Cleemput M., et aL, Hop(Humulus /upu/us)-derived bitter acids as multipotent bioactive compounds, J Nat Prod. 2009, 72: 1220-1230). Furthermore, again in laboratory studies performed on rodents, it has been shown that it acts as a muscle relaxant, managing at high doses to enhance the effect of barbiturates in terms of sleep length (do Vale TG et aL, Central effects of citral, myrcene and limonene, constituents of essential oil chemotypes from Lip- pia alba (Mill.) Brown, Phytomedicine 2002, 9: 709-714).
  • PGE-2 prostaglandin pathway
  • Beta-caryophyllene in turn, is a bicyclic sesquiterpene that is also found in cinnamon, cloves, black pepper, oregano, basil, rosemary and hops, while in cannabis essential oil it can represent about 18-20% by weight.
  • Caryophyllene has also shown efficacy as an analgesic and antioxidant, and its anti-inflammatory activity via PGE-1 , similar to that exerted by indomethacin, is remarkable.
  • caryophyllene has shown a cytoprotective effect towards the gastric mucosa (Klauke AL et aL, The cannabinoid CB2 receptor- selective phytocannabinoid beta-caryophyllene exerts analgesic effects in mouse models of inflammatory and neuropathic pain, Eur Neuropsy-chophar- macol, 2014, 24: 608-620; Singh B. et aL, Plant terpenes: defense re-sponses, phylogenetic analysis, regulation and clinical applications, 3 Biotech. 2015, 5: 129-151 ).
  • CBD female sexual dysfunction
  • This generic term refers to those difficulties which occur during the sexual response cycle, and which prevent a woman from deriving full satisfaction from sexual activity.
  • This disorder differs from those known with the definition of “female dyspareunia and vaginismus”.
  • the latter manifest themselves as real pathologies, such as sexual pain disorders, characterized by the fear (often unconscious) of penetration in the mildest cases (dyspareunia: intercourse is possible but causes pain), and “vaginismus” in the most severe cases, when the muscular spasms are so intense as to prevent intercourse.
  • desire disorders are common to men and women, such as the so-called “hypoactive” sexual desire, in which there is a reduction or total absence of sexual desire.
  • cannabis oil, or specific components extracted from the plant have already been used in the past to formulate compositions intended to increase sexual desire or to be used as aphrodisiacs.
  • visnadine is an active principle of the fruit of Ammi vis- naga, a plant belonging to the Umbelliferae family, traditionally used as a systemic vasodilator in cardiovascular disorders, and in particular in the treatment of angina pectoris and various obliterating peripheral arteriopathies. It is also known that visnadine gels, topically applied in the vulva, are able to promote sensitivity at the local level, resulting in an increase in microcirculation. This increase is accompanied by a significant increase in local turgor and a pleasant sensation of well-being.
  • Indena S.p.A. discloses a composition of vasoactive substances and oestrogens for the treatment of female sexual dysfunctions which includes natural vasokinetic coumarin (such as visnadine), anti-phosphodiesterase agents (such as for- skolin) and phytoestrogens (such as ferutinin).
  • natural vasokinetic coumarin such as visnadine
  • anti-phosphodiesterase agents such as for- skolin
  • phytoestrogens such as ferutinin
  • the present invention aims to provide a preparation for topical gynaecological application which may exploit the beneficial activity of cannabidiol (CBD) in combination with terpene compounds and in the absence of tetrahydrocannabinol (THC), and at the same time has the sexual function-enhancing effects typical of a local vasodilating agent, without however presenting their drawbacks.
  • CBD cannabidiol
  • THC tetrahydrocannabinol
  • the invention relates to therapeutic formulations which are characterized by being based on CBD in combination with one or more terpenes or terpenoids, preferably but not necessarily derived from the hemp plant, in particular, [3-myrcene and/or [3-caryophyllene, with one or more herbal active ingredients with vasodilatory, vasokinetic and/or spasmolytic activity such as coumarins, in particular visnadine, aesculetin and esculoside.
  • terpenes or terpenoids preferably but not necessarily derived from the hemp plant, in particular, [3-myrcene and/or [3-caryophyllene, with one or more herbal active ingredients with vasodilatory, vasokinetic and/or spasmolytic activity such as coumarins, in particular visnadine, aesculetin and esculoside.
  • Coleus barbatus also known as Coleus forskolii or Plectranthus barbatus, a typical plant of traditional Indian medicine, was used in the past for the vasodilatory and cardiostimulatory properties of the compound extracted from it, forskolin.
  • forskolin has found use as an agent for the treatment of congestive cardiomyopathy, glaucoma and asthma.
  • This active ingredient was initially studied as an intraca- vernous vasoactive agent in the management of vasculogenic impotence, and subsequent studies led to it being considered a potential natural alternative to Viagra.
  • extracts of Coleus barbatus or forskolin can also be advantageously present in the proposed gynaecological formulations.
  • the present invention specifically provides is a gynaecological composition for topical use in the treatment of conditions selected between vulvar atrophy and vaginal dryness, said composition comprising cannabidiol and one or more terpenes in combination with one or more herbal active ingredients having vasodilatory, vasokinetic and/or spasmolytic activity, said composition being free of tetrahydrocannabinol.
  • said one or more herbal active ingredients with vasodilata- tory, vasokinetic and/or spasmolytic activity comprise a coumarin, and specifically said coumarin is selected from visnadine, aesculetin and esculoside. More preferably, said coumarin is visnadine.
  • said one or more terpenes are selected from p-myrcene, p-caryophyllene and their mixtures.
  • the weight ratio of CBD to the one or more terpenes in the proposed formulation can vary between 5:1 and 1 :5, and is preferably between 3:1 and 1 : 3.
  • the topical gynaecological compositions to be used in the topical treatment of vulvar atrophy and vaginal dryness according to the invention can be formulated in any form suitable for application to the genital area, in particular as ovules, sprays or gels, and preferably in the form of a vaginal oleogel.
  • cannabi-diol in the composition for use in the topical treatment of vulvar atrophy and vaginal dryness, cannabi-diol is combined with myrcene.
  • the composition also contains visnadine, and in some cases also Coleus forskolii extract (Plectranthus barbatus), and is formulated as a vaginal oleogel.
  • a preferred example of a gynaecological gel composition based on CBD and p-myrcene contains from 0.8% to 1 .2% by weight of cannabidiol, from 0.8 to 1 .2% by weight of myrcene, and from 0.8 to 1 .2% by weight of visnadine.
  • This composition in addition to promoting sexual arousal and providing a feeling of well-being and warmth (hyperemia) in the concerned area, helps the natural production of vaginal secretion, performs a lubricating action and stimulates the release of dopamine.
  • topical composition particularly indicated for the treatment of vulvar atrophy and vaginal dryness contains from 1 .8% to 2.2% by weight of cannabidiol, from 0.8 to 1 .2% by weight of myrcene, from 0.8 to 1.2% by weight of visnadine and from 0.8% to 1.2% by weight of Coleus forskolii extract (Plectranthus barbatus).
  • cannabidiol contains from 1 .8% to 2.2% by weight of cannabidiol, from 0.8 to 1 .2% by weight of myrcene, from 0.8 to 1.2% by weight of visnadine and from 0.8% to 1.2% by weight of Coleus forskolii extract (Plectranthus barbatus).
  • composition of active ingredients was as follows:
  • the product has been formulated as an oily gel, consisting of sweet almond oil, medium chain triglyceride (MCT) oil, wheat germ oil and micronized silica as excipients.
  • MCT medium chain triglyceride
  • composition of active ingredients was as follows:
  • the product was formulated as an oily gel, consisting of sweet almond oil, medium chain triglyceride oil (MCT), wheat germ oil, micronized silica and alcohol as excipients. Again, for optimal use in the treatment of vulvar atrophy and vaginal dryness, it is recommended to apply 2-4 drops of the product directly to the vulvar or clitoral area a few minutes before sexual activity.
  • MCT medium chain triglyceride oil
  • Human osteoblastic cells SaOS-2 (osteoblastic type cells of human osteosarcoma) were treated with H2O2 (100, 200 and 250 pM) to simulate strong conditions of oxidative stress, and the consequent inflammatory response.
  • H2O2 100, 200 and 250 pM
  • Different concentrations of CBD, [3-myrcene and [3-caryophyllene were tested, in order to evidence the antioxidant and anti-inflammatory power of the three active ingredients.
  • the cells were washed twice with phosphate buffered saline (PBS) and incubated in 100 pl/well of serum-free medium supplemented with 10 pl of MTT solution (5 mg/ml) at 37 °C. After 4 hours, the supernatant was removed, and formazan crystals were dissolved by incubating with 150 pl/well of DMSO for 20 minutes. The plate was then stirred, and the absorbance at 570 nm was measured in a microplate reader.
  • PBS phosphate buffered saline
  • Protein carbonyl content is in fact a commonly used oxidative protein modification marker, which provides significant evidence of oxidative stress.
  • the cells were collected and lysed in a RIPA (radioimmunoprecipitation assay) buffer added with protease inhibitors. Protein concentrations were determined using the bicinchoninic acid assay (BCA) kit. The proteins were separated by electrophoresis and transferred to a nitrocellulose membrane. The membrane was blocked with a 5% milk solution in 0.1 % TBS (tris-buffered saline)-Tween for 1 hour, and incubated with the primary antibody overnight at 4 °C.
  • RIPA radioimmunoprecipitation assay
  • the membrane was rinsed with distilled water, incubated with the secondary antibody for 1 hour at room temperature and washed again. The revelation was achieved through chemiluminescence.
  • the expression levels of inflammation markers (COX2 and iNOS) were quantified by Western blotting. Each experiment was performed three times, and the protein expression levels were normalized to the expression level of glyceraldehyde 3-phosphate dehydrogenase (GAPDH).
  • GPDH glyceraldehyde 3-phosphate dehydrogenase
  • nitrites (NO) in the supernatants of SaOS-2 have been measured with Griess reagent (1 % sulfanilamide, 0.1 % naphthylenediamine dihydrochloride and 2.5% of phosphoric acid).
  • RNA samples containing equal amounts of mRNA were subjected to real-time PCR to quantify the expression of pro-inflammatory cytokines.
  • the synthesis of cDNA was performed using 1 mg of total RNA treated with DNase.
  • the obtained cDNA mixture was subjected to real-time PCR, using SYBR Green I dye and primers for: IL-1 [3, IL-6, IL-8, IL-10, TNFa.
  • Each real-time PCR was performed three times, and the mRNA expression levels were calculated and normalized to the glyceraldehyde-3-phosphate dehydrogenase (GAPDH) mRNA level each time.
  • GPDH glyceraldehyde-3-phosphate dehydrogenase
  • Lipid peroxidation is commonly used as an indicator of ROS mediated damage (reactive oxygen species) to cell membranes.
  • the level of lipid peroxidation was measured using the TBARS assay.
  • the cells were homogenized with 0.5% Triton X-100, and cell homogenates were mixed with 1 ml of 0.67% thiobarbituric acid (TBA), 1 ml of 20% trichloroacetic acid and 1.5. ml of 0.04% butylated hydroxytoluene (BHT). The mixtures were incubated in a boiling water bath for 20 minutes. After cooling to room temperature, the reaction mixtures were centrifuged at 4000 g for 10 minutes, and the absorbances of the supernatants were measured at 532 nm. The TBARS concentrations were calculated using malondialdehyde (MDA) as the reference standard.
  • MDA malondialdehyde
  • the synergistic effect of the CBD-myrcene and CBD-caryophyllene combinations is undoubtedly significant, and the activity of the triple combination of CBD with the two terpenes is surprisingly enhanced for all IL-1 [3 cytokines, IL-6, IL-8, IL-10 and TNFa.
  • An occlusive epicutaneous test in single application (duration 48 h) was carried out on the intact skin of the back of 20 volunteers aged between 18 and 65 years of both sexes with sensitive skin.
  • the general principle of this study is the single application of approximately 0.07-0.1 ml of both products under examination on the back skin of each volunteer.
  • the skin was left in contact with the test products in occlusive mode for 48 hours (Curatest® F model, patch for skin tests, Lohmann and Rauscher International GMBH and Co., Rengsdorf, Germany), in sufficient quantity to fill a 5 reaction disk with a surface of 1 cm 2 (approximately 0.07-0.1 ml).
  • the skin reactivity to the test was evaluated by analyzing the following parameters: erythema, desquamation, edema and blistering.
  • the scores assigned for the parameters considered were recorded for each volunteer. Data were cumulatively considered for the entire panel of volunteers, and their average was
  • the pacth test for the product with visnadine, CBD and myrcene did not show any irritating effect on the sensitive skin of the volunteers, while the patch test with the product only visnadine showed an MH index of 2.24 15 minutes after removing the patch, and of 1 .87 after 24 hours.

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Abstract

L'invention concerne des compositions à base de cannabidiol et d'un ou de plusieurs des terpènes contenus dans Cannabis sativa ou dans d'autres espèces végétales, en combinaison avec des vasodilatateurs périphériques naturels. Les terpènes sont de préférence choisis parmi le β-myrcène et le β-caryophyllène, et sont combinés avec des principes actifs végétaux présentant une activité vasodilatatrice, vasocinétique et/ou spasmolytique comme les coumarines, en particulier la visnadine et éventuellement la forskoline. Les compositions proposées se sont révélées être aptes à améliorer l'activité du cannabidiol, des terpènes et des vasodilatateurs périphériques dans le traitement de divers états gynécologiques, tels que l'atrophie vulvaire et la sécheresse vaginale, sans provoquer d'inconfort ou d'effets secondaires indésirables.
PCT/IT2021/050241 2020-08-03 2021-08-03 Compositions gynécologiques à base de cannabidiol et de terpènes en combinaison avec des vasodilatateurs périphériques WO2022029813A1 (fr)

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009003631A1 (fr) * 2007-07-03 2009-01-08 Indena S.P.A. Combinaisons de matières vasoactives et d'oestrogènes, et utilisation de celles-ci dans le traitement de dysfonctionnements sexuels féminins
US20200038366A1 (en) * 2018-07-16 2020-02-06 ECS Health Sciences, Inc. Compositions and methods related to cannabinoids, terpenoids and essential oils
US20200345686A1 (en) * 2019-04-30 2020-11-05 Vcp Ip Holdings, Llc, Limited Liability Company Delaware Compositions and methods for treating skin and neuropathic conditions and disorders

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009003631A1 (fr) * 2007-07-03 2009-01-08 Indena S.P.A. Combinaisons de matières vasoactives et d'oestrogènes, et utilisation de celles-ci dans le traitement de dysfonctionnements sexuels féminins
US20200038366A1 (en) * 2018-07-16 2020-02-06 ECS Health Sciences, Inc. Compositions and methods related to cannabinoids, terpenoids and essential oils
US20200345686A1 (en) * 2019-04-30 2020-11-05 Vcp Ip Holdings, Llc, Limited Liability Company Delaware Compositions and methods for treating skin and neuropathic conditions and disorders

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