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.GW has achieved this.StabilityStability studies are ongoing to assess the stability of Tetranabinex®,Nabidiolex® and the finished product Sativex® in order to establish a suitableshelf-life for the product.Such studies include temperature cycling and photo-stability, in compliance with international regulatory (InternationalConference on Harmonisation) conditions.Additionally, studies are being per-formed to investigate forced degradation.Profile of a BDSTypically, a GW Pharmaceuticals BDS contains the following." Principal cannabinoids"9-THC (>90% of the cannabinoid fraction in THC BDS)CBD (>85% of the cannabinoid fraction in CBD BDS)" Minor cannabinoidsCannabichromene (CBC)Cannabigerol (CBG)Cannabinol (CBN)Tetrahydrocannabivarin (THC-V)Cannabidivarin (CBD-V)Tetrahydrocannabinolic acid (THCA)Cannabidiolic acid (CBDA)Cannabicyclol (CBL)Cannabitriol (CBO)Cannabielsoin (CBE)Cannabichromivarin (CBC-V)" TerpenesMonoterpenes: myrcene, limonene, linalool, ±-pineneSequiterpenoids: trans-caryophyllene, ±-caryophyllene, caryophyllene 244 G.W.Guy and C.G.Stottoxide, cis-nerolidol, trans-nerolidolDiterpenoids: phytolTriterpenoids: squalene" Fatty acidsLinolenic acid, palmitoleic acid, linoleic acid, palmitic acid, oleic acid,stearic acid, myristic acid, arachidic acid and behenic acid" Sterols²-Sitosterol, Campesterol and Stigmasterol" Carotenoids²-Carotene, lutein" Chlorophylls and related compoundsPhaeophytin" VitaminsVitamin E" Phenolic compoundsFlavonoids, coumarins, cinnamic acids and psoralensFinished product BDP: formulation and fillingThe dosage form for Sativex® is a solution, consisting of a vehicle of ethanol,propylene glycol and peppermint, containing Tetranabinex® and Nabidiolex®extracts, that is sprayed into the oral cavity, on to the oromucosal surface.Sativex® contains Tetranabinex® and Nabidiolex® extracts of C.sativaequivalent to 27 mg/ml "9-THC and 25 mg/ml CBD per actuation.The con-tainer is an amber Type I glass vial, with a sealed pump, designed to deliver auniform 100 µl volume.An actuator is used to produce the spray (Fig.3).Administration of Sativex®: achieving the therapeutic windowAppropriate delivery of the active components of a cannabis-based medicineis important in terms of patient acceptability, and achieving optimal and pre-dictable effect.The rate of delivery of constituents to the site of action is asimportant as the amount delivered.Hence, the formulation selected to delivercannabinoids is very important.The fact that cannabinoids are extremelylipophilic compounds limits the number of excipients that may be used to for-mulate cannabis-based medicines.Sativex® is self-titrated by patients.Its frequency of use is determined bythe type, severity and frequency of symptoms that patients endure.As patientsvary enormously in terms of the symptoms they exhibit upon presentation totheir physician, the administration of Sativex® is unique in each individualpatient.The ability of Sativex® to relieve a variety of single primary symptomsacross different patient populations, coupled with its ability to relieve clus- The development of Sativex® a natural cannabis-based medicine 245Figure 3.Administration of Sativex®.ters of symptoms in individual patients as reported in GW s clinical pro-gramme, demonstrates the real strength and potential of Sativex® as a medi-cine.These beneficial effects are not only due to the pharmacological actionsof the medicine but also due to the flexibility of dosing that the medicineoffers.It accommodates inter-individual variation, but also allows each patientto establish a dose regimen that provides patient benefits with minimalunwanted side effects.It allows patients the opportunity to develop their owndosing regimen, including dosing interval and acceptable dose range, and alsoenables them to assess the time course of symptom relief, using their own per-sonal endpoints as markers of efficacy and tolerability.In this way, the patientis able to optimize the relief of their symptoms, while minimising and resolv-ing the occurrence of any side effects that they may experience (i.e.patiens cantarget the therapeutic window).By utilizing this approach, a number of significant clinical benefits ofSativex® have been reported in GW s clinical trial programme.Clinical effects of Sativex®The clinical effects of Sativex® have undergone investigation in an interna-tional clinical trials programme, with centres in UK, Romania, Belgium, 246 G.W.Guy and C.G.StottIreland and Canada.More than 1400 subjects have participated in the clinicalprogramme, which has initially targeted MS patients who have symptoms, andpatients with neuropathic pain.A summary of the programme is presented in Table 1.A total of 13 phase Istudies have been undertaken to investigate the pharmacokinetics of Sativex®Table 1
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