Patent Abstract:
the present disclosure relates to the use of cannabidiol for the treatment of tuberous sclerosis complex . in particular the tsc is treatment resistant and is characterised by generalised seizures or focal seizures with impairment . the disclosure further relates to the use of cbd in combination with one or more anti - epileptic drugs .

Detailed Description:
the following describes the production of the highly - purified (& gt ; 98 % w / w ) cannabidiol extract which has a known and constant composition which was used for the expanded access trials described in examples below . in summary the drug substance used in the trials is a liquid carbon dioxide extract of high - cbd containing chemotypes of cannabis sativa l . which had been further purified by a solvent crystallization method to yield cbd . the crystallisation process specifically removes other cannabinoids and plant components to yield greater than 95 % cbd w / w , typically greater than 98 % w / w . the cannabis sativa l . plants are grown , harvested , and processed to produce a botanical extract ( intermediate ) and then purified by crystallization to yield the cbd ( drug substance ). the plant starting material is referred to as botanical raw material ( brm ); the botanical extract is the intermediate ; and the active pharmaceutical ingredient ( api ) is cbd , the drug substance . both the botanical starting material and the botanical extract are controlled by specifications . the drug substance specification is described in table 5 below . distinct chemotypes of cannabis sativa l . plant have been produced to maximize the output of the specific chemical constituents , the cannabinoids . one type of plant produces predominantly cbd . only the (−)- trans isomer occurs naturally , furthermore during purification the stereochemistry of cbd is not affected . an overview of the steps to produce a botanical extract , the intermediate , are as follows : high cbd chemovars were grown , harvested and dried and stored in a dry room until required . the botanical raw material ( brm ) was finely chopped using an apex mill fitted with a 1 mm screen . the milled brm was stored in a freezer for up to 3 months prior to extraction . decarboxylation of cbda to cbd was carried out using a large heraeus tray oven . the decarboxylation batch size in the heraeus is approximately 15 kg . trays were placed in the oven and heated to 105 ° c . ; the brm took 96 . 25 minutes to reach 105 ° c . held at 105 ° c . for 15 minutes . oven then set to 150 ° c . ; the brm took 75 . 7 minutes to reach 150 ° c . ; brm held at 150 ° c . for 130 minutes . total time in the oven was 380 minutes , including 45 minutes cooling and 15 minutes venting . extraction no 1 was performed using liquid co 2 at 60 bar / 10 ° c . to produce botanical drug substance ( bds ) which was used for crystallisation to produce the test material . the crude cbd bds was winterised in extraction no 2 under standard conditions ( 2 volumes of ethanol at minus 20 ° c . for around 50 hours ). the precipitated waxes were removed by filtration and the solvent evaporated using the rotary evaporator ( water bath up to 60 ° c .) to yield the bds . the manufacturing steps to produce the drug substance from the intermediate botanical extract are as follows : intermediate botanical extract ( 12 kg ) produced using the methodology above was dispersed in c5 - c12 straight chain or branched alkane ( 9000 ml , 0 . 75 vols ) in a 30 litre stainless steel vessel . the mixture was manually agitated to break up any lumps and the sealed container then placed in a freezer for approximately 48 hours . the crystals were isolated by vacuum filtration , washed with aliquots of cold c5 - c12 straight chain or branched alkane ( total 12000 ml ), and dried under a vacuum of & lt ; 10 mb at a temperature of 60 ° c . until dry before submitting the drug substance for analysis . the dried product was stored in a freezer at minus 20 ° c . in a pharmaceutical grade stainless steel container , with fda food grade approved silicone seal and clamps . the drug product is presented as an oral solution . the oral solution presentation contains 25 mg / ml or 100 mg / ml cbd , with the excipients sesame oil , ethanol , sucralose and flavouring . two product strengths are available to allow dose titration across a wide dose range . the 25 mg / ml solution is appropriate at lower doses and the 100 mg / ml solution at higher doses . the drug product formulation is as described in table 6 below : the composition can be substantially equivalent , by which is meant the functional ingredients can vary from the qualitative composition specified in table 6 by an amount of up to 10 %. example 1 below describes the use of a highly purified cannabis extract comprising cannabidiol ( cbd ) in an expanded access treatment program in children with tre . efficacy of cannabidiol reducing seizures in children and young adults with tuberous sclerosis complex of 137 children and young adults with severe , childhood onset treatment - resistant epilepsy ( tre ), twelve suffered from tuberous sclerosis complex ( tsc ). these subjects were tested with a highly purified extract of cannabidiol ( cbd ) obtained from a cannabis plant . the participants in the study were part of an expanded access compassionate use program for cbd . all of these patients diagnosed with tsc presented with one or more types of seizure including tonic , tonic - clonic , atonic , absence , focal seizures with impairment and focal seizures which evolve to secondary generalised seizures . all patients entered a baseline period of 4 weeks when parents / caregivers kept prospective seizure diaries , noting all countable seizure types . the patients then received a highly purified cbd extract ( greater than 98 % cbd w / w ) in sesame oil , of known and constant composition , at a dose of 5 mg / kg / day in addition to their baseline anti - epileptic drug ( aed ) regimen . the daily dose was gradually increased by 2 to 5 mg / kg increments until intolerance occurred or a maximum dose of 25 mg / kg / day was achieved . patients were seen at regular intervals of 2 - 4 weeks . laboratory testing for hematologic , liver , kidney function , and concomitant aed levels was performed at baseline , and after cbd therapy . all patients were taking at least two concomitant anti - epileptic drugs . these included clobazam ; diazepam ; lacosamide ; lamotrigine ; levetiracetam ; lorazepam ; nordiazepam ; n - desmethylclobazam ; phenytoin ; valproic acid ; zonisamide . the average number of concomitant antiepileptic drugs being taken was 2 . 7 . the majority took either clobazam and / or valproic acid . there were 12 children and young adult patients who received at least 3 months of treatment all of whom suffered from treatment - resistant epilepsy with a diagnosis of tuberous sclerosis complex ( tsc ). a summary of the percentage change from baseline in total number of seizures after 12 weeks treatment are summarized in table 7 below . table 7 shows that after 3 months of therapy , there was a decrease in total seizure frequency with ten out of 12 of the tsc patients . furthermore six of the 12 experienced a greater than 50 % reduction in total seizures over the 12 weeks of treatment . the average reduction in the total number of seizures in these patients was 80 . 4 %. these data infer that the cbd is effective at treating this intractable and difficult to treat patient group and was surprisingly able to reduce the total seizure frequency in over 80 % of the patients treated . table 8 summarises the reduction in the number of focal seizures and focal seizure sub - types , and table 9 summarises the reduction in the number of generalised seizure sub - types . as can be seen from tables 8 and 9 above the treatment with cbd was able to dramatically reduce the incidence of the generalised seizure types tonic , atonic , tonic - clonic and absence seizures . in addition the cbd treatment also markedly reduced the number of focal seizures with impairment . from the 12 patients with tsc that were treated with cbd , ten of these patients experienced seizures which were focal with impairment . these data therefore suggest that treatment with cbd is likely to be a significant treatment option for tsc patients . these data indicate that cbd significantly reduces the number of seizures in a high proportion of patients that do not respond well to existing aed . it was surprising that in this group of patients which are treatment - resistant such a high number were able to gain an effect . the fact that half of the patients benefitted from at least a fifty percent reduction in the total number of seizures that they suffered from was remarkable . furthermore the fact that in this group of responders the average reduction in the number of seizures was 80 % is very surprising . it was also demonstrated that treatment with cbd was able to virtually eliminate the generalised seizures that a tsc patient suffers from . again this is very surprising particularly in this group of patients that were resistant to existing medications . ames f r and cridland s ( 1986 ). “ anticonvulsant effects of cannabidiol .” s afr med j 69 : 14 . consroe p , martin p , eisenstein d . 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