Patent Application: US-201514741829-A

Abstract:
the present disclosure relates to the use of cannabidiol in the treatment of absence seizures . in particular , the disclosure relates to the use of cbd for reducing absence seizures in patients suffering with etiologies that include : lennox - gastaut syndrome ; tuberous sclerosis complex ; dravet syndrome ; doose syndrome ; cdkl5 ; dup15q ; jeavons syndrome ; myoclonic absence epilepsy ; neuronal ceroid lipofuscinoses and brain abnormalities . the disclosure further relates to the use of cbd in combination with one or more anti - epileptic drugs .

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 the 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 98 % cbd . 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 ). 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 , which was then used for crystallisation to produce the test material . 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 , sweetener 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 ). cannabidiol is the most abundant non - psychoactive cannabinoid in the selected chemovar . previous studies in animals have demonstrated that cbd has anticonvulsant efficacy in multiple species and models . example 1 describes data produced in an expanded access treatment program in children with tre . efficacy of cannabidiol reducing absence seizures in children and young adults with intractable epilepsy of 137 children and young adults with severe , childhood onset treatment - resistant epilepsy ( tre ), forty - two suffered from epilepsy that was characterised by absence seizures . these subjects were tested with a highly purified extract of cannabidiol ( cbd ) obtained from a cannabis plant . all subjects presented with absence type seizures , often in addition to other generalised and / or focal seizures . the participants in the study were part of an expanded access compassionate use program for cbd . the epileptic syndromes that these patients suffered from were as follows : lennox - gastaut syndrome ; myoclonic absence epilepsy ; tuberous sclerosis complex ; dravet syndrome ; doose syndrome ; jeavons syndrome ; cdkl5 ; dup15q ; neuronal ceroid lipofuscinoses ( ncl ) and brain abnormalities . seizure types experienced by these patients included : tonic , clonic , tonic - clonic , myoclonic , atonic , absence , myoclonic - absence , focal seizures without impairment , focal seizures with impairment and focal seizures evolving to bilateral convulsive 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 every 4 weeks of cbd therapy . the patients on the study were all taking at least one concomitant aed . these included clobazam , clonazepam , clorazepate , desmethylclobazam , diazepam , ethosuximide , felbamate , gabapentin , ketogenic diet , lacosamide , lamotrigine , levetiracetam , lorazepam , midazolam , n - desmethylclobazam , nordiazepam , phenytoin , stiripentol , topiramate , trazodone , vagus nerve stimulation , valproic acid , vigabatrin , and zonisamide . of the 42 children and young adult patients who received treatment with cbd , there were 28 patients who received treatment for at least 12 weeks of treatment all of whom suffered from absence type seizures . a summary of the 50 % responders , based on 12 weeks of treatment are summarized in table 7 below . table 7 shows that after 3 months of therapy , a remarkable 64 % of patients had an equal to or greater than & gt ; 50 % reduction in absence seizures , these data infer that the cbd is very effective at reducing this type of seizure . these data indicate that cbd significantly reduces the number of absence type 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 nearly two thirds of the patients ( 64 %) benefitted from at least a fifty percent reduction in the number of absence seizures that they suffered from was remarkable . efficacy of cannabidiol reducing myoclonic absence seizures in children and young adults with intractable epilepsy of 137 children and young adults with severe , childhood onset treatment - resistant epilepsy ( tre ), ten suffered from epilepsy that was characterised by myoclonic absence seizures . these subjects were tested with a highly purified extract of cannabidiol ( cbd ) obtained from a cannabis plant . all subjects presented with myoclonic absence type seizures , often in addition to other generalised and / or focal seizures . the participants in the study were part of an expanded access compassionate use program for cbd . the epileptic syndromes that these patients suffered from were as follows : myoclonic absence epilepsy ; doose syndrome ; and epilepsy of unknown cause . 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 every 4 weeks of cbd therapy . the patients on the study were all taking at least one concomitant aed . these included clobazam , clonazepam , clorazepate , diazepam , ethosuximide , ketogenic diet , lacosamide , lamotrigine , levetiracetam , lorazepam , midazolam , and valproic acid . of the 10 children and young adult patients who received treatment with cbd , there were 8 patients who received treatment for at least 12 weeks of treatment all of whom suffered from myoclonic absence type seizures . a summary of the 50 % responders , based on 12 weeks of treatment are summarized in table 8 below . table 8 shows that after 3 months of therapy , a remarkable 75 % of patients had an equal to or greater than & gt ; 50 % reduction in absence seizures , these data infer that the cbd is very effective at reducing this type of seizure . these data indicate that cbd significantly reduces the number of myoclonic absence 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 nearly three quarters of the patients ( 75 %) benefitted from at least a fifty percent reduction in the number of myoclonic absence seizures that they suffered from was remarkable . 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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