(19) United States (12) Patent Application Publication (10 ...

[Pages:35](19) United States (12) Patent Application Publication

Parolaro et al.

US 20130059018A1

(10) Pub. N0.2 US 2013/0059018 A1

(43) Pub. Date:

Mar. 7, 2013

(54) PHYTOCANNABINOIDS IN THE TREATMENT OF CANCER

(75) Inventors: Daniela Parolaro, Varese (IT); Paola

Massi, Milan (IT); Angelo Antonio

IZZO' Naples (IT); Francesca Boreiii'

Naples (IT); Gabriella Aviello, Naples

(IT); Vincenzo Di Marlo' POZZuOh (IT);

Luciano De Petrocellis, PoZZuoli (IT); Aniello Schiano Moriello, PoZZuoli (IT); Alessia Ligresti, PoZZuoli (IT); Ruth Alexandra Ross, Aberdeen (GB); Lesley Ann Ford, Aberdeen (GB); Sharon Anavi-Goffer, Aberdeen (GB); Manuel Guzman, Madrid (ES); Guillermo Velasco, Madrid (ES); Mar Lorente, Madrid (ES); So?a Torres, Madrid (ES); Tetsuro Kikuchi, Osaka

(JP); Geoffrey Guy, Wiltshire (GB); Colin Stott, Wiltshire (GB); Stephen Wright, Salisbury (GB); Alan Sutton, wlltshlre?GB); DaVid__P?"er; wlltshlre (GB); Etlenne De M611", Wlltshlre (GB)

(73) Assignees: OTSUKA PHARMACEUTICAL C0., LIMITED, Tokyo (JP); GW PHARMA

LIMITED, Salisbury (GB)

(21) Appl. No.: 13/634,343

(22) PCT Filed: Mar. 11, 2011

(86) PCT No.:

PCT/GB11/50487

? 371 (0X1),

(2)' (4) Date: NOV` 19' 2012

.

. .

. .

(30)

Foreign Application Priority Data

M 12 2010 GB

1004137 4

ar. ,

( ) ................................. ..

.

Publication Classi?cation

(51) Int_ CL A61]; 36/185 A61]; 31/05 A61]; 31/192 A611) 1/00 A61]; 31/357 A61]; 31/443 A61]; 31/4188 A61P 35/00 A61]; 31/352 A61K 31/337

(200601) (200601) (200601) (200601) (200601) (200601) (200601) (2006.01) (200601) (2006.01)

(52) us. Cl. ...... .. 424/725; 514/454; 514/729; 514/568; 514/733; 514/456; 514/449; 514/463; 514/338; 514/393

(57)

ABSTRACT

This invention relates to the use of phytocannabinoids, either in an isolated form or in the form of a botanical drug sub stance (BDS) in the treatment of cancer. Preferably the cancer to be treated is cancer of the prostate, cancer of the breast or cancer of the colon.

Patent Application Publication Mar. 7, 2013 Sheet 1 0f 12 US 2013/0059018 A1

Figure 1: Overview of Botanical Drug Substance (BDS) preparation

BRM ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~

GrowPlants

Cuttings taken from "mother" plants

Good Agricultural

Practice

Harvest Plants After 11 Weeks growing

`

time

Dry and remove

- stems

Controlled temperature and humidity

`

1 mm particle size

~~ ExtractieniProsess ~~~~

Decab-oxylate

Conversion of cannabinoid

' acid to neutral forms by

heating in nitrogen atmosphere

100 bar pressure 25?C temperature

Good

Manufacturing

Practice

Storage at -20?C in ?ethanol for defined time

Cold Filtration

Removal of precipitated Waxy material

`Sol-vent I

Evaporation

. Recovery of BDS.

Removal of Ethanol and

'

residual moisture

Patent Application Publication Mar. 7, 2013 Sheet 2 0f 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)

14000 i

Bil-145

ma0

m3>QCUwxE0LO mww m w, 54_O

?\_ . _

?\

1

CcB DDUVB DDSS 12O5

- THCVABDS 25

THCVBDS 25

: : THCV 10

m THCV 25 m THCVA 10 - THCVA 25

P.

\

g

CBDVBDS 1 O C B DV BDS 25

11+ CBDBDS1D

m CBDBDS 25 m THCVABDS 10 - THCVABDS 25 III'I'I'I'I'I' TH CV BDS 10

m THCVA 1U - THCVA 25

Patent Application Publication Mar. 7, 2013 Sheet 3 0f 12 US 2013/0059018 A1

Figure 3: Effect of cannabinoid BDS real and reconstituted on TRPM8 antagonism

Reconstituted BDS

100

g

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