WO2018205038A1 - Compositions comprenant des cannabinoïdes et des terpènes utiles pour le traitement du cancer et de troubles oculaires vasculaires par inhibition de la signalisation hedgehog - Google Patents

Compositions comprenant des cannabinoïdes et des terpènes utiles pour le traitement du cancer et de troubles oculaires vasculaires par inhibition de la signalisation hedgehog Download PDF

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WO2018205038A1
WO2018205038A1 PCT/CA2018/050572 CA2018050572W WO2018205038A1 WO 2018205038 A1 WO2018205038 A1 WO 2018205038A1 CA 2018050572 W CA2018050572 W CA 2018050572W WO 2018205038 A1 WO2018205038 A1 WO 2018205038A1
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pharmaceutical composition
cannabinoids
composition defined
terpenoids
cancer
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Randy RINGUETTE
Charles Campbell
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Tetra Bio-Pharma Inc.
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    • 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
    • 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
    • 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
    • A61K31/13—Amines
    • A61K31/15—Oximes (>C=N—O—); Hydrazines (>N—N<); Hydrazones (>N—N=) ; Imines (C—N=C)
    • 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
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/164—Amides, e.g. hydroxamic acids of a carboxylic acid with an aminoalcohol, e.g. ceramides
    • 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
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • 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
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
    • 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
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5383—1,4-Oxazines, e.g. morpholine ortho- or peri-condensed with heterocyclic ring systems
    • 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

Definitions

  • compositions comprising cannabinoids and terpenes useful in the treatment of cancer and vascular ocular disorders via inhibition of Hedgehog signalling
  • the present invention generally relates to pharmaceutical compositions and their use for preventing, inhibiting and/or reversing tumorigenesis, neovascularization and/or angiogenesis in a mammal, in particular in the treatment of cancers, or ocular neovascularization and angiogenesis related ocular diseases.
  • the Hedgehog (HH) signaling pathway is a developmental signaling pathway, highly conserved from flies to mammals, that is indispensable in the proper patterning and development of various tissues by influencing expression of target genes involved in proliferation, differentiation, self-renewal, angiogenesis, cell migration, and axon guidance.
  • HH promotes carcinogenesis by promoting tumour cell proliferation, survival, and metastasis; as well as recruitment of blood vessels by promoting angiogenesis.
  • HH dependent tumours include medulloblastoma, basal cell carcinoma (BCC), rhabdomyosarcoma, chronic myeloid leukemia, multiple myeloma, lymphoma, breast cancer, prostate cancer, small cell lung cancer, colorectal cancer, liver cancer, or stomach cancer (reviewed by Wu, et al. 2017).
  • the hedgehog signaling pathway consists of the secreted HH ligands, Sonic, Desert, and Indian HH (SHH, DHH, IHH), which interact with their receptor Patched (PTCH) to activate an intracellular signaling cascade, culminating in the translocation of the GLI transcription factors to the nucleus, where they activate target gene expression.
  • PTCH receptor Patched
  • SMO transmembrane protein Smoothened
  • SUFU Suppressor of Fused
  • PC primary cilium
  • GLIs are phosphorylated by kinases at the base of the PC, resulting in proteolytic processing and conversion to their repressor forms (GLI R ), which are targeted to the nucleus to downregulate target genes.
  • GLI R repressor forms
  • HH HH signaling pathway reviewed by Briscoe and Therond 2013.
  • Vasculogenesis refers to the formation of endothelial tubes or blood vessels de novo from newly differentiational angioblasts or endothelial precursor cells
  • angiogenesis refers the formation or remodelling of new blood vessels from existing vasculature (Byrd & Grabel, 2004).
  • overexpression of Shh causes hypervascularization of the neuroectoderm (Ro witch, et al., 1999), while Shh-mx ⁇ mutants have decreased vascularization of the lung tissues (Pepicelli, et al, 1998).
  • Vessel differentiation in the mouse visceral yolk sac is also regulated by Hh, such that Smo loss -of-function mutants display no ability to remodel vessels with dense endothelial tubules containing clusters of primitive erythrocytes attributing to early lethality (Zhang, et al, 2001; Coultas, et al, 2010).
  • Ihh ' mutant yolk sacs display a less severe phenotype compared to Smo ⁇ ' ⁇ embryos, which is characterized by small, under developed or collapsed visceral yolk sac vessels (Byrd, et al., 2002) and a 50% survival beyond midgestational stages (St-Jacques, et al, 1999).
  • the difference in phenotype severity between Smo ' ' ' and Ihh 'A may be due partial compensation by Dhh derived from yolk sac mesoderm (Farrington, et al, 1997). Ptch-/- embryos also die embryonically due to vascular defects (Coultas, et al, 2010). In vitro embryonic stem cell models derived from Ihh ⁇ A or Smo ' mutant mice or treated with pharmacological Hh inhibitors have an apparent lack of endothelial cells and primitive blood formation (Byrd, et al., 2002; Maye, et al, 2000), consistent with in vivo data.
  • Hh signaling components that disrupt Hh signaling from the midline have dysfunctional circulation and vascularization (Lawson, et al, 2002; Brown, et al., 2000), and Shh ligand from the endoderm promotes the organization of angioblasts into tube-shaped vessels (Vokes, et al, 2004).
  • Hh also has a described role in regulating angiogenesis in adult tissues.
  • cardiac and vascular tissues express Ptchl and respond to exogenous Hh (Pola, et al., 2001).
  • Shh is a potent angiogenic factor in corneal and ischemic limb models, where it promotes vessel formation and improves tissue function post-injury, respectively (Pola, et al, 2001; Pola, et al, 2003).
  • Hh pathway activation is known to promote tumorigenesis
  • Hh-responsive stromal perivascular cells drive tumor angiogenesis (Chen, et al., 2001; Pinter, et al, 2013).
  • Hh regulates angiogenesis appears to be indirect through upregulation of pro-angiogenic growth factors, including vascular endothelial growth factor and angiopoietin-1 and -2, in support cells, such as adventitious fibroblasts (Chen, et al, 2001; Nagase, et al., 2006; Moran, et al, 2012; Pola, et al, 2001).
  • pro-angiogenic growth factors including vascular endothelial growth factor and angiopoietin-1 and -2
  • support cells such as adventitious fibroblasts (Chen, et al, 2001; Nagase, et al., 2006; Moran, et al, 2012; Pola, et al, 2001).
  • the Notch (Lawson, et al, 2002; Moran, et al, 2012) and Bone morphogenic protein (BMP) (Astorga & Carlsson, 2007) pathways have also been implicated in distinct
  • endothelial cells can respond to Hh directly, promoting endothelial progenitor proliferation, migration, adhesion, and capillary formation (Vokes, et al., 2004; Asai, et al, 2006) through the regulation of Rho/ROCK kinase signaling and by inducing the target genes matrix metalloprotease and osteopontin (Renault, et al, 2010).
  • Aberrant blood vessel growth is implicated in several human diseases, particularly in the eye, such as diabetic retinopathy, age-related macular degeneration, neovascular glaucoma, retinal vein occlusion and retinopathy of prematurity (Chirco, et al, 2017; Shin, et al, 2014; Liou, et al, 2009; Laouri, et al, 2011 ; Shazly & Latina, 2009). While disease mechanisms in each case differ, the eye is extremely vulnerable to neovascularization and inappropriate angiogenesis, which often leads to irreversible vision loss.
  • Neovascularization in the retina is causative in many retinal diseases, including diabetic retinopathy, age-related macular degeneration, neovascular glaucoma, retinal vein occlusion and retinopathy of prematurity.
  • Diabetic retinopathy is a common complication of diabetes mellitus, a metabolic disease distinguished by elevated blood glucose levels, that affects the microvasculature of the retina (Shin, et al., 2014).
  • the earliest detectable type of DR termed non-proliferative diabetic retinopathy, is characterized early by microaneurysms and retinal venous dilation, followed by intraretinal hemorrhaging and edema, which if left untreated can lead to irreversible vision loss (Liou, et al., 2009).
  • Ischemia-induced blood vessel proliferation marks the progression of the disease to proliferative diabetic retinopathy, where new fragile and leaky vasculature is formed resulting in vitreous hemorrhaging (Liou, et al, 2009). Over time these new blood vessels tend to undergo fibrosis and contract, leading to retinal detachments, and new vessels can invade the anterior chamber causing neovascular glaucoma (Liou, et al, 2009). In addition to vascular dysfunction and edema, inflammation and oxidative stress lead to neuronal dysfunction and contribute to the disease (Shin, et al, 2014).
  • Neovascular Glaucoma is a severe form of glaucoma characterized by the development of neovascularization within the iris that obstructs aqueous humor outflow and elevates intraocular pressure, leading to vision loss (Rodrigues, et al., 2016).
  • NVG is usually secondary to posterior segment disease involving hypoxia in the retina, which promotes the growth of new blood vessels in the anterior chamber (Shazly & Latina, 2009), and thus several ocular and systemic disorders may lead to the disease.
  • Retinal vein occlusion is an obstruction of the retinal venous system, classified according to where the occlusion is located, that is often caused by external compression or disease of the vein wall that can lead to visual morbidity and blindness (Laouri, et al, 2011).
  • RVO can also be further subdivided into ischemic, where there is significant inhibition of blood flow, and non-ischemic, where there is no area of capillary non-perfusion (Laouri, et al, 2011).
  • ischemic RVO ocular neovascularization is a well-established, serious complication that contributes to disease progression (Laouri, et al, 2011).
  • AMD Age-related macular degeneration
  • AMD has two major forms: atrophic, non-exudative or dry AMD and wet, neovascular or exudative AMD.
  • Dry AMD broadly describes all forms of AMD that are not neovascular and it is characterized by the build up of cellular debris, or drusen, between the retina and choroid layer that causes retinal pigment epithelium (RPE) geographical atrophy and retinal scarring (Chakravarthy, et al, 2010).
  • RPE retinal pigment epithelium
  • phyto-derived and endogenous cannabinoids potently inhibit the hedgehog pathway by directly antagonizing SMO activity (Khaliullina, et al., 2015).
  • addition of either endocannabinoids, including 2-acylglycerol an anandamide, or the phytocananbinoids THC or CBD inhibited Gli-dependent Hh signaling in both an invertebrate fly and mammalian cell model (Khaliullina, et al., 2015), which points to an evolutionarily conserved role of cannabinoids in the regulation of Hh signaling.
  • the endocannabinoid system is an endogenous signaling system consisting of secreted neuromodulatory lipids (termed “endocannabinoids”) anandamide and 2- Arachidonoylglycerol (2 -AG) and their receptors, cannabinoid receptor 1 and cannabinoid receptor 2 (CB1 and CB2), plus a number of alternative receptors.
  • the ECS is active in many tissues with CB1 receptors found predominantly found in neurons in the CNS, while CB2 receptors are found in numerous peripheral tissues, including the peripheral nervous system and the immune system (Turcotte, et al. 2016; Kendall and Yudowski, 2017).
  • CBRs CB receptors
  • cannabinoids and phytocannabinoids are additionally potently targeted by synthetic cannabinoids and phytocannabinoids, the latter of which are found predominantly in various species of the Cannabis genus.
  • Cannabis also contains numerous flavonoids, terpenoids, and phenolic compounds.
  • Terpenoids are unique essential oil components found within plants with diverse pharmacology (Russo, 2001). Terpenoids represent thelargest group of plant chemicals, with approximately 20 000 fully characterized (Langenheim, 1994).
  • Exogenous cannabanoids and terpenoids have been identified as potent anti -tumour agents in many preclinical studies, acting via four common mechanisms: promoting apoptosis, inhibiting proliferation, inhibiting metastasis, and inhibiting angiogenesis (Ladin, et al. 2016).
  • extracts containing a mixture of cannabinoids and terpenoids exert more potent anti-carcinogenic effects than do single purified cannabinoids (Ladin, et al. 2016).
  • cancer there are many types of cancer that have been shown in the art to be sensitive to cannabinoids and terpenoids, including prostate cancer, cervical cancer, glioblastoma multiforme, neuroblastoma, astrocytoma, esophageal squamous cell carcinoma, hepatocellular carcinoma, colorectal cancer, breast cancer, lung cancer, lymphoma, and bladder cancer (Ladin, et al. 2016).
  • cannabinoids can modulate the HH signaling pathway, a known oncogenic pathway when aberrantly upregulated, provides an interesting novel class of therapeutic molecules that to date have not been investigated in terms of their effectiveness in treating HH mediated diseases.
  • small molecule inhibition of the HH pathway and its effectiveness in treating human disease is well known in the art, however additional molecules need to be identified and developed to provide more appropriate therapies.
  • the objective of the present invention was to identify a novel combination of molecules, in particular a synergistic combination of cannabinoids and terpenoids, that can down regulate hedgehog (HH) pathway, in particular HH-pathway mediated cellular proliferation leading to tumour growth and cancer, and Hh pathway mediated cellular proliferation, differentiation, adhesion, and/or migration leading to ocular neovascularization and angiogenesis.
  • HH hedgehog
  • compositions comprising a synergistic combination of one or more cannabinoids and one or more terpenoids, and their use for down regulating hedgehog (HH) pathway in a mammal, in particular in a human being, in order to prevent, inhibit and/or reverse cell proliferation, adhesion, differentiation and/or migration in a mammal.
  • HH hedgehog
  • compositions of plant extracts comprising a combination of at least one cannabinoid and at least one terpenoid, and their use for down regulating hedgehog (HH) pathway in a mammal, in particular in a human being.
  • HH hedgehog
  • the present invention is not limited to pharmaceutical compositions of plant extracts as pharmaceutical compositions using synthetic plant extract such as synthetic cannabinoids may be used.
  • compositions of plant extracts comprising a combination of at least one cannabinoid and at least one terpenoid, and their use as anti-carcinogenic agents.
  • compositions of plant extracts comprising a synergistic combination of at least one cannabinoid and at least one terpenoid, for treating tumours dependent on deregulated Hedgehog signaling pathway.
  • compositions of plant extracts comprising a synergistic combination of at least one cannabinoid and at least one terpenoid, for inhibiting and/or reversing ocular disease related with ocular neovascularization and/or angiogenesis in a mammal.
  • a method of preventing, inhibiting and/or reversing tumour proliferation in a mammalian subject by administering to said subject a therapeutically effective amount of a pharmaceutical composition comprising a synergistic combination of one or more cannabinoids and one or more terpenoids that interfere with the hedgehog signaling pathway, to prevent, inhibit and/or reverse cancer.
  • the pharmaceutical compositions described herein are used in the treatment of HH-dependent medulloblastoma, basal cell carcinoma, rhabdomyosarcoma, chronic myeloid leukemia, multiple myeloma, lymphoma, breast cancer, prostate cancer, small cell lung cancer, colorectal cancer, liver cancer, or stomach cancer.
  • the treatment of said tumours with the medicaments results in a reduction, amelioration, and or reversal in tumour cell proliferation, survival, or metastasis, or a reduction, amelioration, and or reversal in blood vessel invasion to the tumour.
  • a method of preventing, inhibiting and/or reversing ocular disease related with ocular neovascularization and angiogenesis in a mammalian subject by administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising a synergistic combination of one or more cannabinoids and one or more terpenoids that interfere with the hedgehog signaling pathway, to prevent, inhibit and/or reverse ocular disease.
  • a therapeutically effective amount of a pharmaceutical composition comprising a synergistic combination of one or more cannabinoids and one or more terpenoids that interfere with the hedgehog signaling pathway, to prevent, inhibit and/or reverse tumour proliferation in a mammal.
  • a therapeutically effective amount of a pharmaceutical composition comprising a synergistic combination of one or more cannabinoids and one or more terpenoids that interfere with the hedgehog signaling pathway, to make a medicament to prevent, inhibit and/or reverse tumour proliferation in a mammal.
  • a method of preventing, inhibiting and/or reversing ocular disease related with ocular neovascularization and angiogenesis in a mammalian subject by administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising a synergistic combination of one or more cannabinoids and one or more terpenoids that interfere with the hedgehog signaling pathway, to prevent, inhibit and/or reverse ocular disease.
  • a therapeutically effective amount of a pharmaceutical composition comprising a synergistic combination of one or more cannabinoids and one or more terpenoids that interfere with the hedgehog signaling pathway, to prevent, inhibit and/or reverse ocular neovascularization and angiogenesis related ocular diseases in a mammal.
  • a therapeutically effective amount of a pharmaceutical composition comprising a synergistic combination of one or more cannabinoids and one or more terpenoids that interfere with the hedgehog signaling pathway, to make a medicament to prevent, inhibit and/or reverse ocular neovascularization and angiogenesis related ocular diseases in a mammal.
  • said ocular neovascularization and angiogenesis related ocular diseases may be selected from the group consisting of age-related macular degeneration, diabetic retinopathy, retinopathy of prematurity, neovascular glaucoma and retinal vein occlusion.
  • said pharmaceutical compositions comprise a synergistic combination of one or more endogenous, synthetic, or phyto-derived cannabinoids and one or more terpenoids.
  • said one or more phytocannabinoids are selected from the group consisting of Cannabichromene (CBC), Cannabichromenic acid (CBCV), Cannabidiol (CBD), Cannabidiolic acid (CBDA), Cannabidivarin (CBDV), Cannabigerol (CBG), Cannabigerol propyl variant (CBGV), Cannabicyclol (CBL), Cannabinol (CBN), Cannabinol propyl variant (CBNV), Cannabitriol (CBO), Tetrahydrocannabinol (THC), Tetrahydrocannabinolic acid (THCA), Tetrahydrocannabivarin (THCV), Tetrahydrocannabivarinic acid (THCVA), and a mixture thereof.
  • said one or more terpenoids is a mono-, di-, or sesquiterpene.
  • the pharmaceutical composition may be derived from combinations of isolated cannabinoids or terpenoids derived from the flowers, roots, seeds, or leaves of species of the Cannabis genus. Understandably, the cannabinoids may be from various origins, such as but not limited to plant extract or synthetically derived.
  • the medicament is derived from inhaling smoke from combusting dried flowers from the Cannabis plant.
  • the medicament is derived from inhaling vapour from heating an extract from the Cannabis plant.
  • the medicament is in a form of a cream, ointment, solution or foam applied topically and is comprised of combinations of cannabinoids and terpenoids; and optionally at least one pharmaceutical acceptable carrier or excipient.
  • the medicament is in a form of a pill comprising a combination of cannabinoids and terpenoids and at least one pharmaceutical acceptable carrier or excipient.
  • the medicament is in a form of a suppository comprising a combination of cannabinoids and terpenoids and at least one pharmaceutical acceptable carrier or excipient.
  • the medicament is in a form of a strip or tablet, such as a mucoadhesive strip or tablet comprising a combination of cannabinoids and terpenoids and at least pharmaceutical acceptable carrier or excipient.
  • the medicament further comprises one or more Fatty Acid Amide Hydrolase inhibitor (FAAH), a monoacylglycerol lipase (MAGL) inhibitor and/or one or more HH pathway inhibitor.
  • Fatty Acid Amide Hydrolase inhibitor FAAH
  • MAML monoacylglycerol lipase
  • the medicament is used in combination or as an adjunct therapy to a chemotherapeutic agent.
  • said pharmaceutical composition is delivered by intraocular injection.
  • said pharmaceutical composition is delivered by intraocular implant.
  • said pharmaceutical composition is delivered by direct contact with the cornea via eye drops or gels.
  • said pharmaceutical composition contains one or more terpenoids and cannabinoids encapsulated in a liposome.
  • said pharmaceutical composition downregulates or inhibits one or more components of the hedgehog signaling pathway within retinal vasculature and surrounding support cells of the ocular tissue.
  • % or wt.% means weight % unless otherwise indicated. When used herein % refers to weight % as compared to the total weight percent of the phase or composition that is being discussed.
  • room temperature it is meant the temperature where the compositions are made and stored. A room temperature of between about 15 and 25 °C is generally accepted.
  • compositions of plant extracts comprising a combination of at least one cannabinoid and at least one terpenoid.
  • the one or more phytocannabinoids are selected from the group consisting Cannabichromene (CBC), Cannabichromenic acid (CBCV), Cannabidiol (CBD), Cannabidiolic acid (CBDA), Cannabidivarin (CBDV), Cannabigerol (CBG), Cannabigerol propyl variant (CBGV), Cannabicyclol (CBL), Cannabinol (CBN), Cannabinol propyl variant (CBNV), Cannabitriol (CBO), Tetrahydrocannabinol (THC), Tetrahydrocannabinolic acid (THCA), Tetrahydrocannabivarin (THCV), Tetrahydrocannabivarinic acid (THCVA), and a mixture thereof.
  • CBC Cannabichromene
  • CBCV Cannabichromenic acid
  • CBDV Cannabidiol
  • CBDA Cannabidiolic acid
  • CBDV Cannabidivarin
  • CBDV Cannabidivarin
  • the one or more cannabinoids are selected from those that bind and activate the endocannabinoid receptors to influence the Hh receptor SMO, or those have an inhibitory effect on Hh signaling pathway, such as:
  • ⁇ phytocannabinoids preferably showing an inhibitory effect on Hh signaling in Light II cells and drosophila wing discs, such as, but not limited to:
  • the inhibition of Hh signaling may indirectly occur through the modulation of endocannabinoid metabolism or through modulation of any other pathways/molecular targets.
  • the inhibition of Hh signaling may further directly occur a through Hh pathway modulation via the Hh receptor SMO.
  • an effective amount of said one or more cannabinoids ranging from, but not limited to, about ⁇ to about lOOmM.
  • the one or more terpenoids are, but not limited to:
  • Linalool (3,7-dimethylocta-l,6-dien-3-ol); f. ⁇ -caryophyllene: (lR,4E,9S)-4,l l,l l-Trimethyl-8-methylidene- bicyclo[7.2.0]undec-4-ene
  • Betulinic acid (3P)-3-Hydroxy-lup-20(29)-en-28-oic acid
  • the above-listed terpenoids are abundant in cannabis or other plant sources, and have previously described anti-cancer or angiogenic properties.
  • the pharmaceutical composition may further comprise one or more pharmaceutical acceptable carrier or excipient comprising: antiadherents, binders, coatings, colours, disintegrants, flavors, glidants, lubricants, preservatives, sorbents, sweeteners, vehicles.
  • Topical sonic hedgheog ene therapy accelerates wound healing in diabetes by enhancing endothelial progenitor cell-mediated microvascular remodeling.. Circulation, 113(20), pp. 2413-24.
  • Sonic hedgehog is an indirect angiogenic agent upregulating two families of angiogenic growth factors. Nat Med, 7(6), pp. 706-11. [00114] Renault, M. A. et al, 2010. Sonic hedgehog induces angiogenesis via Rho kinase-dependent signaling in endothelial cells.. JMol Cell Cardiol, 49(3), pp. 490-8.

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  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

L'invention concerne des compositions pharmaceutiques comprenant un mélange de cannabinoïdes et de terpènes et leur utilisation dans le traitement de troubles sélectionnés médiés par la voie de signalisation Hedgehog (HH). Dans des modes de réalisation préférés, les constituants de la composition inhibent de manière synergique la signalisation HH de sorte qu'ils permettent le traitement du cancer et de troubles oculaires associés à une néovascularisation aberrant (telle que la dégénérescence maculaire liée à l'âge). Les cannabinoïdes à employer comprennent les phytocannabinoïdes (tels que tétrahydrocannabinol et cannabidiol), les cannabinoïdes endogènes (tels que N-acyléthanolamides) ou des cannabinoïdes de synthèse. Les terpènes préférés à employer comprennent ceux naturellement présents dans les végétaux Cannabis (tels que pinène, limonène, linalool et phytol).
PCT/CA2018/050572 2017-05-12 2018-05-14 Compositions comprenant des cannabinoïdes et des terpènes utiles pour le traitement du cancer et de troubles oculaires vasculaires par inhibition de la signalisation hedgehog WO2018205038A1 (fr)

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Cited By (8)

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Publication number Priority date Publication date Assignee Title
US11084770B2 (en) 2016-12-07 2021-08-10 Treehouse Biotech, Inc. Cannabis extracts
US11202771B2 (en) 2018-01-31 2021-12-21 Treehouse Biotech, Inc. Hemp powder
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US11260033B2 (en) 2018-12-11 2022-03-01 Disruption Labs Inc. Compositions for the delivery of therapeutic agents and methods of use and making thereof
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WO2020230145A1 (fr) * 2019-05-16 2020-11-19 Technion Research & Development Foundation Limited Cannabinoïdes et utilisations associées
CN110548143A (zh) * 2019-09-17 2019-12-10 武汉大学 大麻素受体cb1在视网膜感光细胞退行性疾病中的应用
CZ309885B6 (cs) * 2022-06-21 2024-01-10 Univerzita Palackého v Olomouci Triterpeny s inhibiční aktivitou na Hedgehog signální dráhu pro použití při léčbě nádorových onemocnění

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