WO2022027122A1 - Compositions contenant des cannabinoïdes de cannabis sativa pour le traitement du dysfonctionnement érectile et sexuel - Google Patents

Compositions contenant des cannabinoïdes de cannabis sativa pour le traitement du dysfonctionnement érectile et sexuel Download PDF

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WO2022027122A1
WO2022027122A1 PCT/CA2020/051069 CA2020051069W WO2022027122A1 WO 2022027122 A1 WO2022027122 A1 WO 2022027122A1 CA 2020051069 W CA2020051069 W CA 2020051069W WO 2022027122 A1 WO2022027122 A1 WO 2022027122A1
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compositions
cbd
sexual
extract
citrulline
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PCT/CA2020/051069
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Natalia RAMADE LORENTE
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Ramade & Cia Holding Corp.
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
    • A61K31/198—Alpha-amino acids, e.g. alanine or edetic acid [EDTA]
    • 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
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/21—Amaranthaceae (Amaranth family), e.g. pigweed, rockwort or globe amaranth
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/23—Apiaceae or Umbelliferae (Carrot family), e.g. dill, chervil, coriander or cumin
    • A61K36/232—Angelica
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/28—Asteraceae or Compositae (Aster or Sunflower family), e.g. chamomile, feverfew, yarrow or echinacea
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/48—Fabaceae or Leguminosae (Pea or Legume family); Caesalpiniaceae; Mimosaceae; Papilionaceae
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A61P15/10—Drugs for genital or sexual disorders; Contraceptives for impotence
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
    • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D311/78—Ring systems having three or more relevant rings
    • C07D311/80—Dibenzopyrans; Hydrogenated dibenzopyrans

Definitions

  • compositions containing only natural products for the treatment of erectile and sexual dysfunction More specifically relates to compositions containing Cannabis extract, and other herbal extracts.
  • the compositions herein described can be used as medical Cannabis to treat ESD in a subject in need thereof.
  • the present invention has been challenged by the problems of finding natural compositions and methods for prevention, treatment and inhibition of ED in men and sexual dysfunction in women that are practical for short and long term routine administration, while avoiding side effects of existing formulations, enable treatment of and prevention of ESD in patients that cannot utilize prior art ED treatments, and/or provide new practical and cost effective compositions to prevent as well as treat ED.
  • FIELD OF THE INVENTION Current invention relates to herbal over-the-counter formulation for treating, inhibiting the onset, and/or slowing the rate of development of erectile and sexual dysfunction. In some embodiments Cannabis or extract thereof, is administrated in an amount of 1 mg to about 200mg. Current invention does not involve anti-erectile and sexual dysfunction drugs (AED).
  • other herbal extracts may comprise Baccharis trimera or extract thereof, L-citrulline/L-arginine extract, Mucuna pruriens or extract thereof, Angelica sinensis or extract thereof, Turnera Diffusa or extract thereof, Pfaffia extacts or extract thereof, Achyrocline Satureioides or extract thereof.
  • the Cannabis extract comprises at least one cannabinoid of Cannabisplant.
  • the Cannabis extract comprises tetrahydrocannabinol and/or its acidic form (THC, THCA).
  • the Cannabis extract comprises cannabigerol and/or its acidic form (CBG, CBGA).
  • the Cannabis extract comprises cannabichromene and/or its acidic form (CBC, CBCA). In some embodiments, the Cannabis extract comprises cannabidiol and/or its acidic form (CBD, CBDA). In some embodiments, the Cannabis extract comprises cannabicyclol and/or its acidic form (CBL, CBLA). In some embodiments, the Cannabis extract comprises cannabielsoin and/or its acidic form (CBE, CBEA). In some embodiments, the Cannabis extract comprises cannabinol and/or its acidic form (CBN, CBNA). In some embodiments, the Cannabis extract comprises cannabinodiol and/or its acidic form (CBND, CBNDA).
  • the Cannabis extract comprises cannabitriol and/or its acidic form (CBT, CBTA).
  • the Cannabis extract comprises cannabivarin and/or its acidic form (also known as cannabivarol; CBV, CBVA).
  • cannabivarin and/or its acidic form also known as cannabivarol; CBV, CBVA.
  • erectile dysfunction is not just a physical problem, but it can also be a psychological problem.
  • Mental disorders are a common cause of ED.
  • anxiety and depression are highly prevalent in those with erectile dysfunction and other sexual disorders.
  • the present invention contains compounds that target different phycological components of the problem. 3.
  • Figure 1 shows sex response cycle, highlighting responsive desire experienced during the sexual experience as well as variable initial (spontaneous) desire.
  • Figure 2 shows Oral administration cannabidiol (CBD) dose-normalized concentration-time profiles.
  • Figure 3 shows Diagnostic plots of oral administration model.
  • Figure 4 shows the comparison of oral l-citrulline (nutraceutical grade l-citrulline or watermelon products) versus oral l-arginine.
  • Figure 5 shows the relationship between the 12 groups of men (Group 1 received Formulation 1, Group 2 received Formulation 2, and so on) and the CA PSV.
  • Figure 6 shows the difference between CA PSV baseline values and CA PSV values after treatment with each formulation. 4. BACKGROUND 4.1.
  • Impotence is a serious clinical problem in adult men.
  • Impotence or erectile dysfunction (ED) is a problem that most men will face at some time in their life. In fact, by the time a man reaches 50 years of age, he has about a 1 in 2 chance of having some problem with his erection. The problem could be either attaining and/or maintaining his erection long enough to complete the sexual act. As men get older, the chance of getting ED increases such that a 60-year-old man has approximately a 60% chance of having ED, a 70-year-old man has about a 70% chance, etc.
  • Erectile dysfunction is not always just a physical problem, it can also be a psychological problem.
  • Mental disorders are a common cause of ED.
  • anxiety and depression are highly prevalent in those with erectile dysfunction and other sexual disorders.
  • the major reason ED manifests itself, regardless of the age of onset, is due to an alteration in the corpus cavernosum smooth muscle (CSM), which is located within the cavernosum or corporal bodies of the penis.
  • CSM corpus cavernosum smooth muscle
  • the function of the CSM in the erectile process is to receive and trap blood entering the corporal bodies. This is accomplished when the CSM undergoes relaxation that allows it to open and create spaces or sinusoids into which the entering blood pools. The pooling of this blood in sinusoidal spaces increases the pressure within the corporal bodies and when a certain intracorporeal pressure is reached, the pressure closes off the veins that drain the blood out of the corporal bodies, essentially trapping it within the corporal bodies. Clinically, this is how the CSM tissue can attain (by creating spaces for the blood to pool into) and maintain (by closing off the veins) an erection.
  • Flaccidity is due to corpus cavernosum smooth-muscle cells ("CSM") being contracted and helicine arterioles being sufficiently contracted to limit blood flow to corpus cavernosum sinuses; the sympathetic nervous system and tonic adrenergic discharge maintain baseline contraction of smooth muscle cells and arteriole blood supply (e.g., adrenergic, cholinergic, and nonadrenergic-noncholinergic pathways). Therefore, a combination of metabolic pathways is involved in inducing the erectile processes involving smooth muscle relaxation, arterial dilation, and venous occlusion.
  • CSM corpus cavernosum smooth-muscle cells
  • nNOS neuronal nitric oxide synthase
  • nNOS This NO from nNOS is the major chemical that is involved in the relaxation of the CSM cells and hence is required for the initiation and maintenance of a normal erection. Therefore, while nNOS is normally present in the nerves innervating the penis, iNOS is normally not present in the CSM cells of the penis and is only induced by the CSM cells themselves when the cells experience oxidative stress. However, when iNOS is induced, human erectile dysfunction can be ameliorated by treatment with nNOS or inducers of nNOS. Thus, there remains a ubiquitous and long-felt need to treat ED before it progresses to the point where pharmacological and/or other medical intervention is required in order to have desired sexual performance.
  • PDE5 Type 5 phosphodiesterase
  • cGMP cyclic guanosine monophosphate
  • PDE5 inhibitors like Viagra, Cialis and Levitra prevent the cGMP from breaking down so the effect of the cGMP on the tissues is enhanced.
  • cGMP is formed within the CSM from a reaction that is initiated by the NO that is released from the cavernosal nerve following sexual stimulation. The NO that begins the erectile response comes from the enzyme nNOS located in the nerve endings.
  • NO activates the enzyme soluble guanylyl cyclase (sGC) in the cytoplasm of the CSM and this enzyme in turn converts guanosine triphosphate (GTP) into cyclic guanosine monophosphate (cGMP).
  • GTP guanosine triphosphate
  • cGMP cyclic guanosine monophosphate
  • An increase in cGMP stimulates protein kinase G to phosphorylate potassium and calcium channels causing a decrease in cytosolic calcium, dilation of the helicine arterioles, and the relaxation of the trabecular smooth muscle where all the CSM cells are located.
  • the relaxation of the smooth muscle leads to an increase in the intracavernosal volume, initiating the erectile process.
  • endogenous PDE5 enzyme degrades cGMP which reverses the relaxation of the smooth muscle cells and leads to loss of erection whereas the intake of these PDE5 inhibitors prior to sexual stimulation prevent the degradation of the cGMP that is formed thereby prolonging any CSM relaxation and enhancing any erectile response.
  • PDE5 inhibitors like Viagra, Cialis and Levitra depend on the specificity of the compound.
  • PDE5 inhibitors are considered the "first line treatment of ED," there are notable side effects (headache, flushing, dyspepsia, rhinitis, visual disturbances, back pain, etc.) and adverse interactions that can limit or bar their use (e.g., patients taking nitrates with a PDE5i can experience hypotension and syncope.
  • sexual dysfunction can constitute an adverse event of antidepressant use, especially among patients who had low levels of sexual enjoyment before the onset of their depression (Clayton AH, et al.2002).
  • patients are specifically asked about sexual side-effects, they are acknowledged by as many as 70% (Montejo AL, et al.2001).
  • Sexual dysfunction is also a common side-effect of treatment with antidepressants.
  • Oestrogenised female animals change their sexual behaviour when administered progesterone; studies have shown that the same changes can result from dopamine or the presence of a male animal (Mani SK et al.1994 and Blaustein JD et al.2003).
  • bupropion a dopaminergic drug; average dose 389 mg/ d
  • improvements in pleasure, arousal and orgasm were statistically significant for those administered the active drug.
  • these changes were unaccompanied by increased desire (Segraves RT, et al.2004).
  • ECS endocannabinoid system
  • eCB endocannabinoids
  • AEA anandamide
  • eCB-responsive receptors e.g., a complex enzyme and transporter apparatus.
  • Cannabinaceae-derived “classical” and other plants-derived “non-classical phytocannabinoids (pCBs) represent another important, and ever-growing group of cannabinoids.
  • pCBs phytocannabinoids
  • eCBs and pCBs are able to activate/antagonize/inhibit a remarkably wide-variety of cellular targets including several metabotropic (e.g., CB1 or CB2), ionotropic (certain transient receptor potential [TRP] ion channels) and nuclear (peroxisome proliferator-activated receptors [PPARs]) receptors, various enzymes, and transporters.
  • metabotropic e.g., CB1 or CB2
  • TRP transient receptor potential
  • PPARs nuclear (peroxisome proliferator-activated receptors]) receptors
  • each ligand can be characterized by a unique, molecular fingerprint, and in some cases, they can even exert opposing biological actions on the same target molecule (Molecules 2019, 24, 918).
  • CANNABIS SATIVA The plant Cannabis sativa grows in tropical climate.
  • cannabinoids that causes psychoactive manifestations following ingestion or inhalation of smoke.
  • cannabinoids that causes psychoactive manifestations following ingestion or inhalation of smoke.
  • Cannabis sativa produces unique secondary metabolites consisting of alkyl resorcinol and monoterpene groups.
  • the plant Cannabis sativa contains more than 60 terpenophenolic compounds, named phytocannabinoids.
  • Cannabis may contain over 140 cannabinoid (tricyclic dibenzopyran) compounds and some, such as cannabidiol, may modulate the response to THC.
  • Cannabinoids cannabigerol (CBG), cannabichromene (CBC), cannabidiol (CBD), cannabicyclol (CBL), cannabielsoin (CBE), cannabinol (CBN), cannabinodiol (CBND), cannabitriol (CBT), and more) nitrogenous compounds, amino acids, proteins, enzymes, glycoproteins, sugars, hydrocarbons, simple alcohols, simple aldehydes, simple ketones, simple acids, fatty acids, simple esters, lactones, steroids, terpenes, non-cannabinoid phenols, flavonoids, vitamins, pigments and elements are the chemical classes compounds of Cannabis sativa which has been identified.
  • THC The two major cannabinoids are THC and CBD.
  • THC 4.6. ⁇ 9 ⁇ TETRAHYDROCANNABINOL
  • THC The Cannabis plant (Cannabis sativa) contains many compounds, but ⁇ 9 ⁇ tetrahydrocannabinol (THC) is the main psychoactive ingredient (Figure 1). THC breaks down to produce cannabinol and was identified along with cannabidiol (the main non-psychoactive component). However, THC was not isolated, synthesised, and stereochemically defined until the 1960s. THC is concentrated in the flowering head of the female plant and selective growing in the past 5– 10 years has substantially increased THC content from 1-3% THC in the “flowerpower” era to 6–13% and above. Figure 1.
  • Tetrahydrocannabinol molecular structure Pharmacokinetics of Cannabis ⁇ 9 ⁇ THC which is highly lipophilic get distributed in adipose tissue, liver, lung and spleen. Hydroxylation of ⁇ 9 ⁇ THC generates the psychoactive compound 11 ⁇ hydroxy ⁇ 9_Tetrahydrocannabinol (11 ⁇ OH ⁇ THC) and further oxidation generates the inactive 11 ⁇ nor ⁇ 9 ⁇ carboxy ⁇ 9 ⁇ tetrahydrocannbinol (THCCOOH). THCCOOH is the compound of interest for diagnostic purposes. It is excreted in urine mainly as a glucuronic acid conjugate. ⁇ 9 ⁇ THC is rapidly absorbed through lungs after inhalation. It quickly reaches high concentration in blood.
  • THC in blood is circulated in plasma and rest in red blood cells. Following inhalation, ⁇ 9 ⁇ THC is detectable in plasma within seconds after the first puff and the peak plasma concentration is attained within 3-10 minutes. However, the bioavailability of ⁇ 9 ⁇ THC varies according to the depth of inhalation, puff duration and breath-hold. Considering that approximately 30% of THC is assumed to be destroyed by pyrolysis, the systemic bioavailability of THC is ⁇ 23-27 % for heavy users and 10-14 % for occasional users (Iranian J Psychiatry 7:4, Fall 2012). 4.7.
  • CBD CANNABIDIOL
  • Figure 2 CANNABIDIOL
  • CBD Cannabidiol
  • Figure 2 was isolated in 1940 and is the major non-psychoactive component of Cannabis sativa.
  • Cannabis sativa Over the centuries, several medicinal preparations derived from C. sativa have been employed for a variety of disorders, including gout, rheumatism, malaria, pain, and fever. These preparations were widely employed as analgesics by Western medical practitioners in the 19th century. More recently, there is clinical evidence suggesting efficacy in HIV-associated neuropathic pain, as well as spasms associated with multiple sclerosis Figure 2.
  • Cannabinol molecular structure Cannabinol molecular structure.
  • Cannabidiol pharmacological effects are mediated through G protein coupled receptors, cannabinoid type I (CB1) and cannabinoid type II (CB2), which are highly expressed in the hippocampus and other parts of the central nervous system.
  • CB1 receptors When activated, CB1 receptors inhibit synaptic transmission through action on voltage-gated calcium and potassium channels.
  • CB2 receptors are primarily expressed in the immune system and have limited expression in the central nervous system.
  • the effects of CBD are CB2 receptor independent. Studies have demonstrated that CBD has a low affinity for the CB1 receptors, but even at low concentrations, CBD decreases G-protein activity.
  • Cannabinoids are highly lipophilic, allowing access to intracellular sites of action, resulting in increases in calcium in a variety of cell types including hippocampal neurons. CBD actions on calcium homeostasis may provide a basis for CBD neuroprotective properties. Toxicology CBD is well tolerated in humans with doses up to 600 mg not resulting in psychotic symptoms. In the few small placebo-controlled studies performed, no significant CNS effects were noted. Oral CBD undergoes extensive first-pass metabolism via CYP3A4, with a bioavailability of 6%. Following single doses in humans, the half-life of CBD when taken orally is about 1 to 2 days.
  • CBD is a potent inhibitor of multiple CYP isozymes, including CYP 2C and CYP3A. Whether these in vitro observations are relevant at plasma concentrations likely to be seen in patients is unclear (Epilepsy Currents, Vol.14, No.5 (September/October) 2014 pp.250–252). Plasma levels of CBD were increased when CBD was administered with food or in a fed state, or when a meal is consumed post-administration. Oral capsules with piperine pro- nanolipospheres also increased AUC and Cmax.
  • Cannabinoids (CBD, THC, CBC, CBN, CBG, and other minor cannabinoids) from Cannabis Sativa plant haven’t been proposed as a mean of treating erectile and sexual dysfunction as only active.
  • Herbal formulations have been proposed as a mean of treating erectile dysfunction. See e.g. EP2637505B1.
  • the disclosed compositions do not include cannabis or cannabis derivatives, for instance, the only ingredient that they mention is L-citrulline.
  • Other administration routes for cannabinoids compositions have been disclosed. See e.g. CA30026274.
  • the proposed compositions do not mention oral administration or any other way of administration other than nasal. Thus, their focus in not natural products.
  • compositions with cannabis have been proposed as a mean of treating erectile dysfunction and sexual performance. See e.g. US2018/0161284A1.
  • the proposed compositions include cannabis or cannabis derivatives + anti-erectile dysfunction medication as sildenafil (VIAGRA®), tadalafil (CIALIS®) and vardenafil (LEVITRA®), avanafil, alprostadil.
  • VIAGRA® sildenafil
  • CIALIS® tadalafil
  • LEVITRA® vardenafil
  • avanafil alprostadil.
  • damiana horny got weed and yohimbine as added extra.
  • Patent application US2020/0009107A1 discloses compositions including cannabis or cannabis derivatives + anti-erectile dysfunction medication as sildenafil (VIAGRA®), tadalafil (CIALIS®) and vardenafil (LEVITRA®) AND/OR herbal supplements as damiana, horny got weed, yohimbe root (yohimbine), garlic with vitamin C, gingko biloba, ginseng, goosefoot, Chenopodium ambrosioides (wormseed), Chlorophytum borivilianum (musli) and L-citrulline/L-arginine ; the only herbal product mentioned in above mentioned patent application and that coincides with current invention is L-citrulline/L-arginine.
  • Patent application WO2009/121687 discloses compositions for the treatment of erectile dysfunction comprising L-citrulline and/or Viscum album and/or NADPH.
  • CBD is a non-psychotropic component of Cannabis sativa that binds to CB1 receptors with only comparably very low affinity (Petitet F et al. 1998 and Thomas A et al. 2007) and is devoid of overt cannabimimetic or propsychotic properties (Petitet F et al. 1998).
  • cannabidiol may enhance endogenous anandamide signalling indirectly, by inhibiting the intracellular degradation of anandamide catalysed by the enzyme fatty acid amide hydrolase (FAAH) (Petitet F et al.1998). It has been shown that the endocannabinoid anandamide potentiates the neurogenic relaxation of rat corpus cavernosum, possibly through either CB1 or vanilloid receptors (Hartmann U, et al. 2002). Others observed that both CB1 and CB2 receptors activation potentiated neurogenic relaxation of rabbit corpus cavernosum (I. M. Vural, et al.2009).
  • FAAH fatty acid amide hydrolase
  • anandamide inhibits neurogenic relaxation of corpus cavernosum of human and primates (Van den Bossche et al.2000).
  • the potent vasodilatory influence of anandamide has been shown in a variety of isolated vascular preparations. Its mechanism of action, however, is complex and the subject of intense investigation. In rabbit pail arterioles and mesenteric arteries, the anandamide- induced dilation was blocked by indomethacin and diclofenac, respectively, suggesting it was mediated by generation of vasodilator eicosanoids.
  • anandamide stimulated the release of nitric oxide via an activation of CB1 receptors, and vasodilation could be blocked by inhibition of NO-synthase.
  • anandamide stimulated CB1 receptor-mediated NO release.
  • anandamide was reported to directly induce vasorelaxation, unrelated to its metabolism or to NO-release.
  • anandamide can have actions unrelated to cannabinoid receptor stimulation, such as decreasing gap junctional permeability in astrocytes, an effect which is not induced by other cannabinoid receptor agonists and which is insensitive to SR141716A.
  • the cellular effects of cannabinoids were mostly investigated in neural cells. These include inhibition of adenylyl cyclase, inhibition of Ca 2+ -current through N-type, and P/Q-type Ca 2+ channels, activation of inward rectifier K+ current and of voltage-dependent A-type K+current.
  • compositions or dosage forms of current invention may include one or more of the following types of CBD extract: Full spectrum, broad spectrum or isolate: A.
  • Full-Spectrum CBD as an extract that contains all phytochemicals naturally found in the Cannabis sativa plant (comprising any strain type of Cannabis sativa plant), including CBD, trace cannabinoids (which can include any of the following: THC (tetrahydrocannabinol), THCA (tetrahydrocannabinolic acid), CBD (cannabidiol), CBDA (cannabidiolic acid), CBN (cannabinol), CBG (cannabigerol), CBC (cannabichromene), CBL (cannabicyclol), CBV (cannabivarin), THCV (tetrahydrocannabivarin), CBDV (cannabidivarin), ,CBCV (cannabichromevarin), CBGV (cannabigerovarin), CBGM (cannabigerol monomethyl ether), CBE (cannabielsoin), CBT (cannabicitran) among others), terpenes, and essential oils.
  • THC
  • Full-spectrum extracts from hemp also might come with a negligible THC content — below 0.3% (worldwide compliance).
  • the full spectrum of the active compounds extracted from hemp work together to amplify the health benefits of each individual cannabinoid. This phenomenon is referred to as the “entourage effect” (synergy achieved by all the components in Cannabis).
  • broad-spectrum extracts contain multiple cannabinoids - which can include any of the following: CBD (cannabidiol), CBDA (cannabidiolic acid), CBN (cannabinol), CBG (cannabigerol), CBC (cannabichromene), CBL (cannabicyclol), CBV (cannabivarin), THCV (tetrahydrocannabivarin), CBDV (cannabidivarin), ,CBCV (cannabichromevarin), CBGV (cannabigerovarin), CBGM (cannabigerol monomethyl ether, CBE (cannabielsoin), CBT (cannabicitran) among others-, they also might produce the “entourage effect” but without the THC.
  • CBD isolate as the purest form of CBD; made by pulling it from its natural environment and removing it from all other ingredients. Isolates are usually 99% pure, meaning that one gram of isolate powder carries about 990 mg of CBD. Same applies for isolates of any other type of cannabinoid. 2. OTHER EFFECTIVE HERBAL DRUGS FOR ERECTILE DYSFUNCTION 2.1. BACCHARIS TRIMERA (CARQUEJA) Experiments in vitro demonstrated that BACCHARIS TRIMERA induces vascular smooth muscle relaxation (Table 1). Effect/ Result References Chloroform extracts from the plant have shown to induce vascular O.
  • R.M. Gene et al.1996 Demonstration of the arterial smooth muscle vasorelaxant properties of the infusion of B. trimera towards rat aortic rings, which are likely to be H. Heinzen et al.2016 due to endothelium dependent and independent mechanisms. The effect might correlate with the fall in blood pressure referred in folk medicine. Table 1. In vivo essays. 2.2.
  • L-CITRULINE l-Citrulline is a neutral, non-essential alpha-amino acid that is an important component of the urea cycle in the liver and kidneys (Curis E. et al.2005). As a non-protein amino acid, l-citrulline is rarely found in food, but is highly concentrated in watermelon. The concentration of l-citrulline in watermelon grown in the United States can range from 1.6 to 3.5 g/kg of fresh watermelon.
  • Figure 4 presents the comparison of oral l-citrulline (nutraceutical grade l-citrulline or watermelon products) versus oral l-arginine (Allerton T.D. et al.2018).
  • the activity of the arginase enzyme located in the enterocytes of intestines and liver substantially reduces the availability of oral l-arginine, instead yielding increased urea and l-ornithine production.
  • l-citrulline is not acted on by arginase enzyme or first-pass extraction but is converted to l-arginine by argininosuccinate lyase in the kidneys.
  • Increased circulating l-arginine serves a substrate for the eNOS to produce nitric oxide (NO) and increase smooth muscle vasodilation.
  • l-citrulline may directly activate inducible nitric oxide synthase (iNOS) in skeletal muscle and increase protein synthesis via mTOR activation.
  • l-citrulline may indirectly activate neuronal nitric oxide synthase (nNOS) in skeletal muscle leading to increases in NO and stimulation of mitochondrial biogenesis.
  • l-citrulline has reported actions on adipose tissue to increase lipolysis, fatty acid oxidation, and uncoupling protein 1 (UCP1) expression.
  • l-citrulline has also been reported to indirectly activate iNOS in activated macrophages and increase NO production.
  • l-citrulline s systemic effects positively impact hypertension, atherosclerosis, inflammation, insulin resistance, type 2 diabetes, and cardiovascular disease. Emerging evidence also suggests that l -citrulline itself can positively impact skeletal muscle and adipose tissue to improve metabolic syndrome.
  • Figure 4 was partially modified from Irving and Spielmann (2016). Both l-arginine and l-citrulline levels have been shown to get lowered in severe ED/ arteriogenic ED (Barassi A et al. 2017).
  • l-citrulline and l-arginine supplementations have been shown to rapidly and effectively increase NO bioavailability and cyclic guanosine monophosphate (cGMP) concentrations (Morita M, et al. 2014).
  • L-citrulline supplementation has been shown to improve erectile function in rats with acute arteriogenic ED, and one study has shown improved erection in mild ED patients (Cormio L, et al.2011), though there have been no studies in humans with l-citrulline and l-arginine combination.
  • the advantage of l-citrulline over l-arginine is that it does not undergo first-pass metabolism, nor it is metabolized by intestinal bacteria. 2.3.
  • MUCUNA PRURIENS M. pruriens seeds are rich source of L-DOPA and its metabolites, which include epinephrine and norepinephrine. It’s been proven that an increase in dopamine level in the brain following M. pruriens treatment may not only induce the activation of sexual behavior but it may also increase plasma testosterone level. It has been reported that L-DOPA and its metabolite dopamine stimulate the hypothalamus and forebrain to secrete gonadotropin-releasing hormone (GnRH) (Vermes I, et al.1979).
  • GnRH gonadotropin-releasing hormone
  • pruriens may also contribute to proper functioning of male genital system and facilitate sperm transport, contraction of seminal vesicles and inhibition of lipid peroxidation of spermatozoa (Fait G, et al.2008).
  • ANGELICA SINENSIS Coumarins, and Osthole in particular have been identified as bioactives of Angelica sinensis, which display activities such as, inhibition of platelet aggregation, inhibition of Smooth muscle contraction, Smooth muscle relaxation (Che-Ming et al.1994), inhibition of calcium flux, cyclic nucleotide (such as cGMP and cAMP) phosphodiesterase inhibition, increase in cAMP and cGMP levels, anti-proliferative, anti-inflammatory, enhancement of the increase of cAMP induced by forskolin, vasorelaxation, neurotransmitter receptor binding, such as GABA, 5HT-1A, D-2, and D-1 receptors.
  • Alpha-angelica-lactone also possesses various activities, including, e.g., calcium antagonism.
  • Ferulic acid another component of Angelica root also has been shown to scavenge oxygen free radicals and increase intracellular cAMP and cGMP.
  • Preferred activities of Angelica are cyclic nucleotide phosphodiesterase inhibition, calcium antagonism, oxygen free radical Scavenging, Smooth muscle modulation, as either vasorelaxant or vasodilatory (July 2013 EMA/HMPC/614586/2012 Committee on Herbal Medicinal Products (HMPC) Assessment report on Angelica sinensis (Oliv.) Diels, radix). 2.5.
  • ACHYROCLINE SATUREIOIDES (MARCELA) Ethanol extract of the aerial parts of Achyrocline satureioides (Lam.) DC. (Asteraceae) showed a significant, dose dependent, relaxant effect on the smooth muscle of corpus cavernosum strips, obtained from Guinea pig (65.5 +/- 4.1% of relaxation at the dose of 25.0 mg/ml). Bioassay guided fractionation of this extract furnished two flavonoids, quercetin and quercetin 3-methyl ether, with important vasorelaxing effects on the corpus cavernosum strips (79.8 +/- 8.4 and 66.0 +/- 4.8% of relaxation respectively at the dose of 0.075 mg/ml).
  • TURNERA DIFFUSA and PFAFFIA PANICULATA Sexually potent and sexually sluggish/impotent male rats were treated orally with different amounts of Turnera diffusa and Pfaffia paniculata fluid extracts (0.25, 0.50, 1.0 ml/kg). While having no effect on the copulatory behavior of sexually potent rats, both plant extracts--singly or in combination--improved the copulatory performance of sexually sluggish/impotent rats.
  • the present invention surprisingly discovered that the most effective treatment is the one that treats every aspect and angle of the problem from a holistic point of view, targeting different physiological and phycological components of the problem.
  • the tested formulations induce vascular smooth muscle relaxation of the corpus cavernosum which can treat and/or prevent ED and SD effectively.
  • the precise dosage will vary according to a variety of factors such as subject-dependent variables (e.g. age, gender, medical history, etc.), the disorder or condition and the type of treatment.
  • subject-dependent variables e.g. age, gender, medical history, etc.
  • the aspects herein described are not limited by the illustrated ordering of acts or events, as some acts may occur in different order and/or concurrently with other acts or events.
  • compositions of the present inventions do not contain compounds that require a prescription and avoid side effects of current "first line” treatments for ED (AED).
  • AED current "first line” treatments for ED
  • the combination therapy of cannabis extract with other herbal extracts elicits the desired biological and medical, when administrated in therapeutically effective amounts.
  • compositions comprising the following herbal drugs: Cannabis, cannabis extracts or one or more cannabinoid, and three other herbal drugs or herbal extracts listed herein.
  • oral dosage composition for use in the treatment of male erectile dysfunction (ED) and/or related erectile dysfunction (RED), wherein the composition comprises 1-200 mg of a chosen cannabinoid or combination of cannabinoids, provided in the form of a Full spectrum extract, broad spectrum extract or isolate extract - said extract could be in liquid, semi-liquid or solid form, plus, 400 mg of a composition consisting of at least one member of the group consisting of L-citrulline and L-arginine; the amount of arginine or a compound that can produce arginine in vivo in a daily formulation is preferably from about 100 mg to about 3 g for treatment of erectile dysfunction.
  • ED male erectile dysfunction
  • RED erectile dysfunction
  • the arginine is L-arginine and the compound that can produce arginine in vivo is citrulline, preferably L-citrulline. Some or all the L-arginine can be replaced with L-citrulline.
  • the composition comprises also at least 200 mg of Baccharis trimera or derivative of Baccharis trimera; the derivative may comprise or is derived from dried extract of aerial parts and leaves of Baccharis trimera; the extract may be used fresh or may be partially or completely dehydrated.
  • the formulation for the treatment of erectile dysfunction also comprises at least 400 mg of Mucuna pruriens or derivative of Mucuna pruriens; the derivative may comprise or is derived from dried extract of seeds of Mucuna pruriens; the extract may be used fresh or may be partially or completely dehydrated.
  • An embodiment of the present formulation may also comprise at least 200 mg of Angelica Sinensis or derivative; the derivative may comprise the dried root of Angelica sinensis; the extract may be used fresh or may be partially or completely dehydrated.
  • the present formulation may also comprise at least 200 mg of Turnera diffusa and/or Pfaffia paniculataor derivative; the derivative may comprise the leaves and stems of Turnera diffusa and/or Pfaffia paniculate; the extract may be used fresh or may be partially or completely dehydrated.
  • the composition may comprise also at least of 200 mg Achyrocline Satureioidesor derivative, the derivative may comprise inflorescences of Achyrocline Satureioides; the extract may be used fresh or may be partially or completely dehydrated.
  • a dosage form of the composition contains an amount of each ingredient sufficient when administered for a sufficient period of time to produce a beneficial effect in treating ED or SD, wherein the beneficial effect includes at least one of slowing, stopping or reversing worsening symptoms of ED or SD, slowing, stopping or reversing the appearance of symptoms of ED or SD, shortening refractory period between erections, and/or reducing, slowing or stopping increases in refractory period between erections.
  • indicia of ED or SD are treated and/or indicia of satisfactory sexual experience are improved.
  • compositions of the present invention When determining the efficacy of a composition of the present invention in treating ED or RED by IIEF score, the presence of all ingredients CBD extract, THC extract, CBN extract, CBG extract, CBC extact, L-Citrulline, Baccharis trimera extract, Mucuna pruriens extract, Angelica Sinensis extract, Turnera Diffusa and Pfaffia extacts, Achyrocline Satureioides extract, were tested.
  • the active ingredients of compositions of the present invention can be combined using well known and standard processes and agents.
  • a gelatine capsule contains the combined ingredients in powder form. Exemplary compositions for base formulations are presented below.
  • the ingredients, in powder form, are inspected, weighed, blended and encapsulated in gelatine capsules.
  • the blending process includes standard screening, blending and metal detection at standard temperatures and in a sterile environment at least sufficient for food supplements.
  • the compositions or dosage forms may include optional pharmaceutically acceptable excipients as fillers, binders, and colorants, and can be packaged in standard gelatine capsules (hard or soft gelatine) or formed into solid tablets, taken in particulate form, or mixed into and/or suspended in solution.
  • the composition might comprise other optional ingredients, such as a binding agent, an agent that increases dissolution and digestion in vivo, preservatives and/or colorants.
  • Standard ingredients in powder formulations are used for preparing and compounding preferred exemplary formulations of the present inventions.
  • carrier silica can be used to convert liquids into free-flowing powders and/or can be used to enhance flowability and shelf life of powdered products.
  • Desintegrants are an excipient used to enhance the disintegration process of tablet formulation when they make contact with gastrointestinal fluid, for example: starch, croscarmellose sodium, crospovidone, and sodium starch glycolate.
  • Magnesium stearate can be used as a diluent with lubricating properties helpful to prevent the composition and its ingredients from sticking to manufacturing equipment and can also serve as a binding agent.
  • an oral dosage form comprises a composition in accordance with the first, second and third aspects of the inventions, wherein the dosage form is selected from the group consisting of a tablet, capsule, lozenge, powder or suspension comprising the foregoing ingredients.
  • Preferred suspensions are aqueous and/or alcohol (ethanol) based.
  • Flavourings or taste masking agents may be employed.
  • Tablets or other dosage forms may include diluents (for example lactose), desintegrants, for example cross-carmelose sodium or binders, for example, polyvinylpyrrolidone.
  • Lubricants for example magnesium stearate, or other conventional excipients may be employed (e.g., silicas, carbohydrates, etc.).
  • Film coated tablets may be provided.
  • the extracts may be used fresh or may be partially or completely dehydrated.
  • Fresh natural products used for ingredients of the present invention may be chopped, pulped or otherwise comminute before incorporation into a dosage form.
  • an ingredient may be concentrated to facilitate transportation, storage, and administration.
  • the raw materials and ingredient extracts may be dried, for example by freeze-drying or vacuum drying, before compounding into oral dosage forms.
  • Individual dosage forms may comprise compressed tablets, capsules, lozenges or may be provided in sachets. Suspension formulations may be provided.
  • CBD extract, THC extract, CBN extract, CBG extract, CBC extact, L-Citrulline, Baccharis trimera extract, Mucuna pruriens extract, Angelica Sinensisextract, Turnera Diffusa and Pfaffia extacts, Achyrocline Satureioides extract are all commercially available, with preferred sources and analyses provided.
  • the ingredients are combined and encapsulated in hard gelatine capsules, but other dosage forms are anticipated that will produce equivalent results.
  • Example 1 One hundred and sixty men over the age of 40 (40 years ⁇ x) with sexual dysfunction based on history were entered in this open-label, nonrandomized study. Different patients received randomly capsules containing one of the 12 FORMULATIONS presented above or placebo enough for 12 weeks treatment, 2 capsules/day. Efficacy was assessed at weeks 4, 8, and 12 using the International Index of Erectile Function Questionnaire. By use of this standard questionnaire, many patient histories, with identities redacted, can be combined with questionnaire results to generate statistically significant data when compared with questionnaire results following administration of different compositions (or placebo). Echo-doppler studies have been performed before and after treatment with each formulation; an increase in blood flow can be appreciated through CA PSV values on Figure 5 and Figure 6.
  • CA PSV Cavernosal artery peak systolic velocity
  • Example 3 Two double-blind parallel studies (placebo – FORMULATION 2 and placebo - Sildenafil) in men with organic and psychogenic erectile dysfunction or mixed causes was performed for 24 weeks to evaluate the efficacy and of FORMULATION 2 for sexual dysfunction in men when compared with sildenafil.250 men over the age of 20 (20 years ⁇ x) received treatment with FORMULATION 1, one hour or more before sexual activity, which allowed them to have satisfactory activity in 86% of cases.
  • we performed echo-doppler studies before and after FORMULATION 2 treatment highlighting an increase in blood flow that varied from 30% to 40%. Greater penile stiffness was observed in those in whom FORMULATION 2 was administered. Results: A total of 250 patients signed consent to participate in the study.
  • the mean age of the patients was 56 years. Seventy-five patients were assigned to receive FORMULATION 2 and 50 were assigned to receive placebo, with 70 patients who received FORMULATION 2 completed the treatment and 57 who were assigned to receive placebo completed the treatment. Seventy-five patients were assigned to receive sildenafil and 50 were assigned to receive placebo, with 68 patients who received sildenafil completed the treatment and 59 who were assigned to receive placebo completed the treatment.
  • dosage form comprises at least about 25mg CBD or CBD derivative and at least about 400 mg of L-citrulline or L-arginine or a mixture thereof, at least about 200mg of Baccharis trimera and at least about 400mg of Mucuna pruriens; said dosage form can be administered at least once a day, preferably twice a day, for a sufficient period of time to treat erectile dysfunction or age related erectile dysfunction.

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Abstract

La présente invention concerne des compositions contenant uniquement des produits naturels pour le traitement du dysfonctionnement érectile et sexuel (ESD). Plus spécifiquement elle concerne des compositions contenant un extrait de cannabis, et d'autres extraits d'herbes. Selon la présente invention, les compositions ci-inclus décrites peuvent être utilisées en tant que cannabis médical pour traiter l'ESD chez un sujet.
PCT/CA2020/051069 2020-08-06 2020-08-06 Compositions contenant des cannabinoïdes de cannabis sativa pour le traitement du dysfonctionnement érectile et sexuel WO2022027122A1 (fr)

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