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(12) Patent Application Publication (10) Pub. No.: US 2013/0059018 A1 Parollaro Et Al US 2013 005901 8A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2013/0059018 A1 ParollarO et al. (43) Pub. Date: Mar. 7, 2013 (54) PHYTOCANNABINOIDS IN THE (86). PCT No.: PCT/GB11ASO487 TREATMENT OF CANCER S371 (c)(1), (75) Inventors: Daniela Parolaro, Varese (IT); Paola (2), (4) Date: Nov. 19, 2012 Massi,Izzo, Naples Milan (IT): (IT); Francesca Angelo Antonio Borelli, (30) Foreign ApplicationO O Priority Data Naples (IT): Gabriella Aviello, Naples Mar. 12, 2010 (GB) ................................... 10041374 (IT): Vincenzo DiMarzo, Pozzuoli (IT): Luciano De Petrocellis, Pozzuoli (IT): Publication Classification Aniello Schiano Moriello, Pozzuoli (IT); Alessia Ligresti, Pozzuoli (IT): (51) Int. Cl. Ruth Alexandra Ross, Aberdeen (GB); A61E36/85 (2006.01) Lesley Ann Ford, Aberdeen (GB); A63L/05 (2006.01) Sharon Anavi-Goffer, Aberdeen (GB); A63L/92 (2006.01) Manuel Guzman, Madrid (ES); A6IPI/00 (2006.01) Guillermo Velasco, Madrid (ES); Mar A 6LX3 L/357 (2006.01) Lorente, Madrid (ES); Sofia Torres, A613 L/443 (2006.01) Madrid (ES); Tetsuro Kikuchi, Osaka A613 L/488 (2006.01) (JP); Geoffrey Guy, Wiltshire (GB); A6IP35/00 (2006.01) Colin Stott, Wiltshire (GB); Stephen A613 L/352 (2006.01) Wright, Salisbury (GB); Alan Sutton, A63L/337 (2006.01) Wiltshire (GB); David Potter, Wiltshire (52) U.S. Cl. ........ 424/725; 514/454: 514/729; 514/568; (GB); Etienne De Meijer, Wiltshire 514/733; 514/456; 514/449; 514/463: 514/338; (GB) 514/393 (73) Assignees: OTSUKA PHARMACEUTICAL CO., (57) ABSTRACT LIMITED, Tokyo (JP); GW PHARMA LIMITED, Salisbury (GB) This invention relates to the use of phytocannabinoids, either in an isolated form or in the form of a botanical drug sub (21) Appl. No.: 13/634,343 stance (BDS) in the treatment of cancer. Preferably the cancer to be treated is cancer of the prostate, cancer of the breast or (22) PCT Filed: Mar. 11, 2011 cancer of the colon. Patent Application Publication Mar. 7, 2013 Sheet 1 of 12 US 2013/0059018 A1 Figure 1: Overview of Botanical Drug Substance (BDS) preparation ... r. --: GroW PlantS. Cuttings taken from "mother" plants After 11 weeks growing Harvest Plants time Good Agricultural < Fractice Dry and remove Controlled temperature StemS : and humidity 1 mm particle size Conversion of Cannabinoid acid to neutral forms by heating in nitrogen atmosphere 100 bar pressure 25°C temperature Storage at -20°C in :ethanol for defined time Good Manufacturing Practice Cold Filtration "CE"R of ioitated y : Recovery of BDS. Solvent Removal of Ethanol and Evaporation residual moisture Patent Application Publication Mar. 7, 2013 Sheet 2 of 12 US 2013/0059018 A1 Figure 2: Effect of cannabinoids on apoptosis in hormone-insensitive prostate cancer cell line (DU-145) and hormone-sensitive prostate cancer cell line (LNCaP) DU145 14000 - 12OOO - 1OOOO - Control CBEDS 1 CBDWBDS25 8OOO - is CBDBOS 10 CBDBOS 25 6OOO - 8 THCWABDS 10 THCWABDS 25 8 THCWEDS 10 4OOO - THCBDS 25 is THC, 10 2OOO - THC, 25 THCA 10 THCWA 25 LNCP 14e5 1.2e-5 Control CBDWBDS 10 CBDWBDS 25 SS CBDBDS 10 S CBDBDS 25 s THCWABDS 10 THCWABDS 25 THCWBDS 10 THCWBOS 25 THCW 10 THCW 25 THCWA THCWA 25 Patent Application Publication Mar. 7, 2013 Sheet 3 of 12 US 2013/0059018 A1 Figure 3: Effect of cannabinoid BDS real and reconstituted on TRPM8 antagonism Reconstituted BDS 100 S CBGBDS c CBG 75 E CBG-Free BDS 5. SO O 9. 8 25 SS O O m -7.O -6.5 -6.0 -5.5 -50 log antagonist, M Real BDS OO g O CBG-Free BDS c CBGBDS s 75 CBG s s 50 O O. 8 25 Y SS log antagonist, M Patent Application Publication Mar. 7, 2013 Sheet 4 of 12 US 2013/0059018 A1 Figure 4: Effect of cannabinoids alone or in combination with a chemotherapeutic agent in hormone-insensitive prostate cancer cell line (DU-145) and hormone sensitive prostate cancer cell line (LNCaP) in a subcutaneous xenograft model. a) CBGBDS alone or in combination with Taxotere in the LNCaP xenograft model 18OO 1600 1400 NY c 1200 SO 1000 - 3 800 E 6OO 3 400 > paO.C. skS.SS&S 2OO O 10 15 2O 25 3O 35 40 45 Time (days) -H Group 1: Vehicle - Group 2: 1mg/kg CBGBDS i.p. daily, ''' Group 3: 10mg/kg CBGBDS i.p. daily, resses Group 4: 100mg/kg CBGBDS i.p. daily. -- Group 5: 5mg/kg Taxotere i.v. weekly ri- Group 6: 100mg/kg CBGBDS i.p. daily & 5mg/kg Taxotere i.v. weekly Patent Application Publication Mar. 7, 2013 Sheet 5 of 12 US 2013/0059018 A1 b) CBD BDS alone or in combination with Taxotere in the LNCaP xenograft model 18OO 6 O O 400 200 10 12 14 16 18 20 22 24 26 28 30 32 34 36 .38 40 Time (days) -H Group 1: Vehicle -k- Group 2: 1mg/kg CBD BDS i.p. daily. - Group 3: 10mg/kg CBD BDS i.p. daily. sesser Group 4: 100mg/kg CBD BDS i.p. daily. -- Group 5: 5mg/kg Taxotere i.v. weekly rt Group 6: 100mg/kg CBD BDS i.p. daily & 5mg/kg Taxotere i.v. weekly Patent Application Publication Mar. 7, 2013 Sheet 6 of 12 US 2013/0059018 A1 c) CBGBDS alone or in combination with Taxotere in the DU-145 xenograft model 1500 1400 13OO 1200 1100 1000 900 800 700 600 500 400 300 200 1OO O 10 15 20 25 30 35 40 45 50 55 60 65 Time (days) -H Group 1: Vehicle i.p. daily -- Group 2: 1mg/kg CBGBDS i.p. daily & Group 3: 10mg/kg CBGBDS i.p. daily r^ss Group 4: 100mg/kg CBGBDS i.p. daily -- Group 5: 5mg/kg Taxotere i.v. weekly rsr Group 6: 100mg/kg CBGBDS i.p. daily & 5mg/kg Taxotere i.v. weekly Patent Application Publication Mar. 7, 2013 Sheet 7 of 12 US 2013/0059018 A1 d) CBD BDS alone or in combination with Taxotere in the DU-145 xenograft model CSUZO3: DU45 O 8 O 7 O E. O 4. 3 O - OO Time days) 'ehicle imgkg (CED EDS i.p. daily, imgkg. CED EDS ip, daily, img/kg (CED EDS i.p. daily. 5mgkg Taxotere iw, Weekly lmgkg (EC) E3 ip, daily & Smg'kg Taxotre iw, Weekly Patent Application Publication Mar. 7, 2013 Sheet 8 of 12 US 2013/0059018 A1 Figure 5: Effect of the cannabinoids isolated CBD and CBD BDS on colon carcinogenesis in the mouse a) Number of aberrant crypt focus (ACF) per mouse % Control CBD 1 CBD 5 CBD BDS Cel AOM b) Number of polyps per mouse 1.5 | 1.0 % O.O 3: Control CBD 1 CBD 5 CBD BDS Ce AOM Patent Application Publication Mar. 7, 2013 Sheet 9 of 12 US 2013/0059018 A1 c) Number of tumours per mouse Control CBD 1 CBD 5 CBD BDS Ce AOM Patent Application Publication Mar. 7, 2013 Sheet 10 of 12 US 2013/0059018 A1 Figure 6: Effect of the cannabinoids isolated CBG, isolated CBDV, CBGBDS and CBDV BDS on colon carcinogenesis in the mouse a) Number of aberrant crypt focus (ACF) per mouse S S. sS. 8S. &Sis : 8S. b) Number of aberrant crypt focus (ACF) with 4 or more crypts per mouse Patent Application Publication Mar. 7, 2013 Sheet 11 of 12 US 2013/0059018 A1 º,º Patent Application Publication Mar. 7, 2013 Sheet 12 of 12 US 2013/0059018 A1 c) Number of tumours per mouse US 2013/00590 18 A1 Mar. 7, 2013 PHYTOCANNABINOIDS IN THE be used. The cell line LNCaP are hormone-sensitive prostate TREATMENT OF CANCER cancer cells which were derived from a supraclavicular lymph node metastasis in a 50 year old male in 1977. The cell 0001. This invention relates to the use of phytocannab line DU-145 are hormone-insensitive prostate cancer cells inoids, either in an isolated form or in the form of a botanical which were derived from a brain metastasis. drug substance (BDS), as a prophylactic or in the treatment of 0009. It is known that expression levels of both cannab cancer. Typically the cancer to be treated is a cancer of the: inoid receptors, CB1 and CB2, were significantly higher in prostate, breast, skin, glioma, colon, lung or a bone or lymph CA-human papillomavirus-10 (virally transformed cells metastasis. The phytocannabinoids may be used in combina derived from adenocarcinoma of human prostate tissue), and tion with other cancer treatments. other human prostate cells LNCaP. DU-145, PC3, and CWR22RN1 than inhuman prostate epithelial and PZ-HPV-7 BACKGROUND (virally transformed cells derived from normal human pros 0002 Cancer is a class of diseases which occurs because tate tissue) cells (Sarfaraz, 2005). cells become immortalised; they fail to heed customary sig (0010. Additionally it is known that WIN-55.212-2 (mixed nals to turn off growth which is a normal function of remod CB1/CB2 agonist) treatment with hormone sensitive LNCaP elling in the body that requires cells to die on cue. Apoptosis, cells resulted in a dose- (1-10 Mmol/L) and time-dependent or programmed cell death, can become defective and when (24-48 hours) inhibition of cell growth. Blocking of CB1 and this happens malignant transformation can take place. The CB2 receptors by their antagonists SR141716 (CB1) and immortalised cells grow beyond their normal limits and SR 144528 (CB2) significantly prevented this effect. invade adjacent tissues. The malignant cells may also 0011. These results suggested that WIN-55,212-2 or other metastasise and spread to other locations in the body via the cannabinoid receptor agonists could be developed as novel bloodstream or lymphatic system.
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