Oleo gel composition and delivery system with active compounds from cannabis sativa and mentha arvensis for reduction of inflammation and pain in deep tissues

Abstract

Disclosed is an oleo gel composition including essential combination of synergistically acting phyto-active materials, non-psychotropic phytocannabinoids from the plant of Cannabis sativa: Cannabidiol, Cannabidiolic acid, Cannabivarin and Cannabigerol in combination with extract of Olive europaea Fruit Oil, Mentha arvensis leaf oil, and Silica colloidal anhydrous ensuring the delivery of cannabinoids to the deep tissues in order to reduce pain and inflammation of skeletal muscles and joints caused by trauma or/and induced by arthritis/osteoarthritis.

Claims

1. A topical composition for the treatment and/or reduction of deep tissue joint and muscle inflammation resulted from mechanical trauma of skeletal muscles or arthritis/osteoarthritis (OA), the topical composition comprising: 82% olive oil; about 8.2% silica colloidal anhydrous; about 0.5% mint oil; and 12% Cannabis sativa extract, wherein the Cannabis sativa extract contains Cannabidiol (CBD), Cannabidiolic acid (CBDA), Cannabivarin (CBV), and Cannabigerol (CB-G) in an amount equal to 2% of a total mass of cannabis extract, the phytocannabinoids being introduced with a ratio of CBDA and CBD 1:1, 1%:1%, respectively.

2. The topical composition according to claim 1, wherein the Cannabis sativa extract is a non-psychotropic Cannabis sativa variety.

3. A method for producing a non-Newtonian fluid oleo gel composition for treatment and/or reduction of deep tissue joint and muscle inflammation resulted from mechanical trauma of skeletal muscles or arthritis/osteoarthritis (OA), the method comprising steps of: a) extraction of Cannabis sativa extract using supercritical extraction with CO.sub.2 with parameters of: pressure at 465 bar, extraction temperature at 70 C., process length of 120 minutes; b) decarboxylation of CBDA resin for 5-6 hours to produce CBD at 160 C.; and c) mixing obtained decarboxylated and non-carboxylated Cannabis sativa extracts with olive oil, mint oil, and Silica colloidal anhydrous to achieve the gel composition comprising: 82% olive oil; about 8.2% silica colloidal anhydrous; about 0.5% mint oil; and 12% Cannabis sativa extract, wherein the Cannabis sativa extract contains Cannabidiol (CBD), Cannabidiolic acid (CBDA), Cannabivarin (CBV), and Cannabigerol (CB-G) in an amount equal to 2% of a total mass of cannabis extract, the phytocannabinoids being introduced with a ratio of CBDA and CBD 1:1, 1%:1%, respectively.

4. A method for relieving human pain and inflammation of deep tissues of skeletal muscles and/or joints resulted from mechanical injury/trauma and/or arthritis/osteoarthritis, the method comprising applying an effective amount of the topical composition of claim 1 to an area to be treated.

5. A pharmaceutical patch comprising a system to release active compounds in a desired location for long-term treatment, the pharmaceutical patch comprising the topical composition of claim 1.

6. The topical composition according to claim 1, wherein Cannabis sativa is a non-psychotropic Cannabis sativa of Benico variety.

7. The method of claim 3, wherein the Cannabis sativa is a non-psychotropic Cannabis sativa variety.

8. The method of claim 3, wherein the Cannabis sativa is a non-psychotropic Cannabis sativa of Benico variety.

9. The method of claim 3, wherein a concentration of the Cannabidiol (CBD) and Cannabidiolic acid (CBDA) in the non-Newtonian fluid oleo gel composition is 20 mg/g, w/w.

Description

BRIEF DESCRIPTION OF DRAWINGS

(1) FIG. 1 Shows data presented as group averagesSN. Differences between control/edema and phytocannabinoid preparation groups are considered significant at p<0.05*.

(2) FIG. 2 Shows data presented as group averagesSN. Differences between control/edema and phytocannabinoid preparation groups are considered significant at p<0.05*.

DETAILED DESCRIPTION OF THE INVENTION

(3) Materials and Methods

(4) Preparation of Cannabis Sativa Extract

(5) Cannabis extract is produced using pulverized, dried (passive drying process for 52 hours at 35-40 C., to reach residual moisture level of approximate 10%) biomass of Cannabis sativa Benico variety which is derived from the mixture comprising upper plant partsblossoms, and leaves. However, other non-psychotropic Cannabis sativa varieties can be used, where THC concentration rages from 0.0001 to 1%. The CBD and CBDA enriched lipophilic fraction (extract) is produced using an approach of supercritical extraction with CO.sub.2 with the following parameters: pressure465 bar, extraction temperature70 C., process length120 minutes. The CBD resin is produced by decarboxylation of CBDA resin at 160 C. for 5-6 hours.

(6) The amount of major cannabinoids: CBD, CBDA, CBG, CBV in the cannabis extract is determined according to the ST/NAR/40 Recommended Methods for the Identification and Analysis of Cannabis Products (United Nations, New York, 2009). 10 mg of the resin is homogenised in the 1 mL mixture of methanol and chloroform (v/v, 9:1), for 15 min in the ultrasound bath. After centrifugation for 10 min at max g to separate insolubilities, the prepared samples were analysed using Shimadzu HPLC chromatography system with 30AC automatic injector, CTO-20AC column thermostat, DGU 20A5 vacuum degas unit, LC-30AD pump and SPD-M20A diode matrix detector. The analysed cannabinoids were fractionated in Supelco Discovery HS C18 (254.6 mm, 5 m) (RP) with C18 pre-column under the isocratic elution conditions. The temperature of the column30 C., mobile phase: acetonitrile 0.1%, flow 0.8 ml/min., separation time 30 min.; injection volume20 l; detection at the two channels 225 nm and 306 nm. The data was analysed by Lab Solutions software. The following internal standards were used from Cerilliant: Cannabinol, 1.0 mg/mL (C-046), Cannabidiolic acid (CBDA), 1.0 mg/mL (C-144), Cannabidivarin (CBDV), 1.0 mg/mL (C-140), Cannabigerol (CBG), 1.0 mg/mL (C-141).

(7) Characteristics of Cannabis sativa extractProtein fraction (Kjeldahl Method)0.63%, Lipids (Soxlet Method)96.60%, water Gravimetric Method (103 dgr centigrade)1.73%, sum of CBD/CBDA/CBDV/CBG 18%, where the extract comprises 80% of CBDA from the total cannabinoids, THC<0.1%.

(8) Preparation of Tropical Composition

(9) TABLE-US-00001 Content Vendor and Compound (%) specifications Silica colloidal anhydrous 8.2 Olive europaea fruit oil 82 Mentha arvensis leaf oil 0.5 Decarboxylated Cannabis sativa 6% 15-18% CBD extract CBD (~20 mg/g WW) CBD resin [Satimed] Non-carboxylated Cannabis sativa 6% 15-18% CBDA extract CBDA (~20 mg/g WW) CBDA resin [Satimed] Phenoxyethanol 0.5

(10) Initially, decarboxylated and non-carboxylated extracts of Cannabis sativa are mixed one by one into the pre-warmed (40 C.) Olive europaea (Olive) Fruit Oil followed by the addition of required amounts of Mentha arvensis leaf oil and Phenoxyethanol. At this point the mixing is increased up to 100 rpm and the amount of Silica colloidal anhydrous is added stepwise to reach the required amounts. The homogenisation is continued for 30-45 minutes at the temperature of 40 C. to acquire required consistency and product is filled into the required vessels.

EXAMPLES

Example 1

(11) Experimental Procedures

(12) The effects of two phytocannabinoid preparations (JSC SATIMED): Preparation 1 (in which the concentration of phytocannabinoids is 40 mg/ml, extract diluted 4.5 fold with raw Cannabis sativa seed oil) and Preparation 2 (10 mg/ml of phytocannabinoids, extract diluted 10 fold with raw Cannabis sativa seed oil), were analysed on the model of acute inflammation (paw edema) in mice. Three single doses of preparation Preparation 1 (0.33 mg/kg, 1 mg/kg and 10 mg/kg phytocannabinoids) and one dose of Preparation 2 (0.23 mg phytocannabinoids) were tested. The experiment was performed on 48 mice (BALB/c strain , 6-7 weeks old, average weight 23 g), which were divided into 6 groups (6 mice per group), and in all of them paw edema was induced:

(13) 1 group. Edema/controlno treatment

(14) 2 group. 50 mg/kg prednisolone/control i.p.

(15) 3 group. 0.33 mg/kg phytocannabinoids Preparation 1 p.o.

(16) 4 group. 1 mg/kg phytocannabinoids Preparation 1 p.o.

(17) 5 group. 10 mg/kg phytocannabinoids Preparation 1 p.o.

(18) 6 group. 0.23 mg phytocannabinoids Preparation 2 (topical application) (i.p.intraperitoneally, p.o.orally)

(19) Prior to the study, the thickness of the right hind foot of each mouse was measured by a digital micrometre (Mitutoyo, Japan). Acute inflammation (paw edema) was induced to all mice by an injection of 20 l of 1% carrageenan into their right paw. The effects of phytocannabinoids on acute inflammation (paw edema) were measured by analysing the differences between the thickness of the affected and unaffected paw. The test and control materials were administered to animals one hour after carrageenan injection. Digital micrometre measurements were carried out after 4, 6 and 24 hours of carrageenan injection.

(20) Results: Cannabis sativa extract of topical composition reduces inflammation of Paw edema in mice model after oral administration and topical treatment.

(21) Paw edema was reduced by all analysed doses of Preparation 1. The most effective inhibition was observed at 1 mg/kg phytocannabinoid dose, which reduced the rates of paw edema (in comparison to the control group) by 43.2%-57.5% depicted in FIG. 1.

(22) Local application of preparation Preparation 2 statistically significantly reduced paw edema (up to 44.4%) as shown in FIG. 2.

REFERENCES

(23) 1. Almekinders, L. C. 1999. Anti-Inflammatory Treatment of Muscular Injuries in Sport. An Update of Recent Studies. Sports Medicine (Auckland, N.Z.) 28 (6): 383-88. 2. Baoge, L., E. Van Den Steen, S. Rimbaut, N. Philips, E. Witvrouw, K. F. Almqvist, G. Vanderstraeten, and L. C. Vanden Bossche. 2012. Treatment of Skeletal Muscle Injury: A Review. ISRN Orthopedics 2012: 689012. doi:10.5402/2012/689012. 3. Bondesen, Brenda A., Stephen T. Mills, Kristy M. Kegley, and Grace K. Pavlath. 2004. The COX-2 Pathway Is Essential during Early Stages of Skeletal Muscle Regeneration.American Journal of Physiology. Cell Physiology 287 (2): C475-83. doi:10.1152/ajpcell.00088.2004. 4. Fisar, Zdenek. 2009. Phytocannabinoids and Endocannabinoids. Current Drug Abuse Reviews 2 (1): 51-75. 5. Fogh, Karsten, Troels Herlin, and Knud Kragballe. 1989. Eicosanoids in Skin of Patients with Atopic Dermatitis: Prostaglandin E 2 and Leukotriene B 4 Are Present in Biologically Active Concentrations. Journal of Allergy and Clinical Immunology 83 (2): 450-55. 6. Hampson, A. J., M. Grimaldi, J. Axelrod, and D. Wink. 1998. Cannabidiol and ()Delta9-Tetrahydrocannabinol Are Neuroprotective Antioxidants. Proc Natl Acad Sci USA 95 (14): 8268-73. 7. Hassan, Samia, Khalil Eldeeb, Paul J. Millns, Andrew J. Bennett, Stephen P. H. Alexander, and David A. Kendall. 2014. Cannabidiol Enhances Microglial Phagocytosis via Transient Receptor Potential (TRP) Channel Activation. Br J Pharmacol 171 (9): 2426-39. doi:10.1111/bph.12615. 8. Izzo, Angelo A., Francesca Borrelli, Raffaele Capasso, Vincenzo Di Marzo, and Raphael Mechoulam. 2009. Non-Psychotropic Plant Cannabinoids: New Therapeutic Opportunities from an Ancient Herb. Trends Pharmacol Sci 30 (10): 515-27. doi:10.1016/j.tips.2009.07.006. 9. Li, Yong, James Cummins, and Johnny Huard. 2001. Muscle Injury and Repair. Current Opinion in Orthopaedics 12 (5): 409-15. 10. Maccarrone, M., and A. Finazzi-Agro. 2003. The Endocannabinoid System, Anandamide and the Regulation of Mammalian Cell Apoptosis. Cell Death & Differentiation 10 (9): 946-55. 11. Malfait, A. M., R. Gallily, P. F. Sumariwalla, A. S. Malik, E. Andreakos, R. Mechoulam, and M. Feldmann. 2000. From the Cover: The Nonpsychoactive Cannabis Constituent Cannabidiol Is an Oral Anti-Arthritic Therapeutic in Murine Collagen-Induced Arthritis. Proceedings of the National Academy of Sciences of the United States of America 97 (17): 9561.doi:10.1073/pnas.160105897. 12. Nderitu, Paul, Lucy Doos, Peter W. Jones, Simon J. Davies, and Umesh T. Kadam. 2013. Non-Steroidal Anti-Inflammatory Drugs and Chronic Kidney Disease Progression: A Systematic Review. Family Practice 30 (3): 247-55.doi:10.1093/fampra/cms086. 13. Neogi, Tuhina, and Yuqing Zhang. 2013. Epidemiology of OA. Rheumatic Diseases Clinics of North America 39 (1): 1.doi:10.1016/j.rdc.2012.10.004. 14. Pertwee, R. G. 2008. The Diverse CB1 and CB2 Receptor Pharmacology of Three Plant Cannabinoids: delta9-Tetrahydrocannabinol, Cannabidiol and delta9-Tetrahydrocannabivarin. Br J Pharmacol 153 (2): 199-215.doi:10.1038/sj.bjp.0707442. 15. Rainsford, K. D., S. C. Roberts, and S. Brown. 1997. Ibuprofen and Paracetamol: Relative Safety in Non-prescription Dosages. Journal of Pharmacy and Pharmacology 49 (4): 345-76.doi:10.1111/j.2042-7158.1997.tb06809. x. 16. Ramer, Robert, Katharina Heinemann, Jutta Merkord, Helga Rohde, Achim Salamon, Michael Linnebacher, and Burkhard Hinz. 2013. COX-2 and PPAR- Confer Cannabidiol-Induced Apoptosis of Human Lung Cancer Cells. Mol Cancer Ther 12 (1): 69-82. doi:10.1158/1535-7163.MCT-12-0335. 17. Roth, Dr Sanford H. 2012. Coming to Terms with Nonsteroidal Anti-Inflammatory Drug Gastropathy. Drugs 72 (7): 873-79.doi:10.2165/11633740-000000000-00000. 18. Ryan, Duncan, Alison J. Drysdale, Carlos Lafourcade, Roger G. Pertwee, and Bettina Platt. 2009. Cannabidiol Targets Mitochondria to Regulate Intracellular Ca2+ Levels. J Neurosci 29 (7): 2053-63.doi:10.1523/JNEUROSCI.4212-08.2009. 19. Samuelsson, B. 1990. Arachidonic Acid Metabolism: Role in Inflammation. Zeitschrift Fur Rheumatologie 50: 3-6. 20. Schneider, Christian. 2011. Traumeelan Emerging Option to Nonsteroidal Anti-Inflammatory Drugs in the Management of Acute Musculoskeletal Injuries. International Journal of General Medicine 4: 225-34.doi:10.2147/IJGM.S16709. 21. Schwitzer, Thomas, Raymund Schwan, Karine Angioi-Duprez, Isabelle Ingster-Moati, Laurence Lalanne, Anne Giersch, and Vincent Laprevote. 2015. The Cannabinoid System and Visual Processing: A Review on Experimental Findings and Clinical Presumptions. Eur Neuropsychopharmacol 25 (1): 100-112.doi:10.1016/j.euroneuro.2014.11.002. 22. Shen, Wei, Yong Li, Ying Tang, James Cummins, and Johnny Huard. 2005. NS-398, a Cyclooxygenase-2-Specific Inhibitor, Delays Skeletal Muscle Healing by Decreasing Regeneration and Promoting Fibrosis. The American Journal of Pathology 167 (4): 1105-17.doi:10.1016/S0002-9440(10)61199-6. 23. Shen, Wei, Victor Prisk, Yong Li, William Foster, and Johnny Huard. 2006. Inhibited Skeletal Muscle Healing in Cyclooxygenase-2 Gene-Deficient Mice: The Role of PGE2 and PGF2alpha. Journal of Applied Physiology (Bethesda, Md.: 1985) 101 (4): 1215-21. doi:10.1152/japplphysio1.01331.2005. 24. Shrivastava, Amit Kumar, and Aparna Pandey. 2012. Inflammation and Rheumatoid Arthritis. Journal of Physiology and Biochemistry 69 (2): 335-47.doi:10.1007/s13105-012-0216-5. 25. Smith, L. L., A. Anwar, M. Fragen, C. Rananto, R. Johnson, and D. Holbert. 2000Cytokines and Cell Adhesion Molecules Associated with High-Intensity Eccentric Exercise. European Journal of Applied Physiology 82 (1-2): 61-67.doi:10.1007/s004210050652. 26. Sumariwalla, Percy F., Ruth Gallily, Susanna Tchilibon, Ester Fride, Raphael Mechoulam, and Marc Feldmann. 2004. A Novel Synthetic, Nonpsychoactive Cannabinoid Acid (HU-320) with Antiinflammatory Properties in Murine Collagen-induced Arthritis. Arthritis & Rheumatism 50 (3): 985-98.doi:10.1002/art.20050. 27. Takeda, Shuso. 2013. [Medicinal chemistry and pharmacology focused on cannabidiol, a major component of the fiber-type cannabis]. Yakugaku Zasshi: Journal of the Pharmaceutical Society of Japan 133 (10): 1093-1101. 28. Takeda, Shuso, Koichiro Misawa, Ikuo Yamamoto, and Kazuhito Watanabe. 2008. Cannabidiolic Acid as a Selective Cyclooxygenase-2 Inhibitory Component in Cannabis. Drug Metab Dispos 36 (9): 1917-21.doi:10.1124/dmd.108.020909. 29. van der Stelt, Mario, and Vincenzo Di Marzo. 2005. Anandamide as an Intracellular Messenger Regulating Ion Channel Activity. Prostaglandins Other Lipid Mediat 77 (1-4): 111-22.doi:10.1016/j.prostaglandins.2004.09.007 30. U.S. Pat. No. 6,949,582B1 31. Patent US20120264818A1 32. Patent EP1186298B1