Methods for the treatment of migraine and related headache conditions using tricaprylin

Abstract

The present disclosure relates to a method for treating or preventing headaches, such as migraine and associated headaches. The method comprises administering a composition comprising at least one compound (e.g., a ketogenic compound) capable of increasing ketone body concentration in a subject in need thereof, administered in an amount effective for treating or preventing headaches, such as migraine and associated headaches. In one embodiment, the composition comprises a medium chain triglyceride (MCT), such as tricaprylin.

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of U.S. Provisional Patent Application No. 63 / 233,552, filed August 16, 2021, U.S. Provisional Patent Application No. 63 / 343,893, filed May 19, 2022, and U.S. Provisional Patent Application No. 63 / 351,684, filed June 13, 2022, the disclosures of each of which are incorporated by reference in their entirety into this specification.

[0002]

[0002] The present invention relates to the field of migraine treatment and prevention. More specifically, the present invention relates to the use of ketogenic drugs to treat and prevent the occurrence of migraine headaches. [Background technology]

[0003]

[0003] Migraine is an extremely common, disabling, and costly neurological disorder. Its recurrent form is characterized by recurrent (0-14 headache days per month) moderate to severe headache attacks lasting 4-72 hours. The headaches are exacerbated by physical activity and are accompanied by either photophobia, phonophobia or odour phobia, nausea, or a combination of these. Migraine has the highest incidence in young adults during the prime of their working lives and imposes a substantial cost on society. Current migraine treatment options generally have limited efficacy and often have side effects.

[0004]

[0004] The primary pathogenesis of migraine is still largely unknown, but the ketogenic diet has shown some limited efficacy in treating migraine. The ketogenic diet (KD) was introduced in 1921 for the treatment of drug-resistant epilepsy. The ketogenic diet is a high-fat, low-carbohydrate, low-protein diet that mimics fasting and induces a state of ketosis in subjects. The ketogenic diet has also been shown to be beneficial for weight loss and has shown potential in other neurological conditions.

[0005] The first known report of a KD in migraine appears to have been made in 1928 by Schnabel, who tested the KD in 23 migraine patients. Nine of the 23 patients reported some improvement, but one patient who had three recurrent attacks that interrupted his eating and urinary intake had no detectable ketosis. The authors concluded that "judging from our group of patients, maintaining a ketogenic diet appears to be a difficult problem for adults" and that they were "well encouraged to continue with the high-fat regimen."

[0006] In 2010, Kossoff and coauthors examined the efficacy of the modified Atkins diet in adolescents with frequent headaches. The modified Atkins diet induces ketosis similar to the traditional ketogenic diet but does not impose protein restriction. The study examined eight subjects with at least 15 headaches per week for at least a three-month period. Three of the subjects reported improvements in headache severity and quality of life, but continued to have daily migraines and required pharmacological therapy. The authors concluded that "there appears to be no clear benefit of the modified Atkins diet in treating adolescents with chronic daily migraines. In addition, although improvements were noted in this pilot study, the diet was perceived as too restrictive, and many adolescents refused to try it."

[0007] In 2013, Di Lorenzo et al. reported two pairs of twin sisters who each started a KD for weight loss. The sisters also suffered from frequent migraines, each with 5-6 attacks per month. The patients complained of severe throbbing headaches of up to 72 hours duration. The severity increased with movement, and the attacks were accompanied by photophobia, nausea, and occasional vomiting. The patients maintained a careful migraine diary, and the migraines were not considered chronic (longer than 15 months) and did not meet the criteria for medication-overuse headache (MOH), a clinical condition in which multiple symptomatic sedatives taken to treat headache attacks are the cause of pain. The patients were also overweight with BMIs of 28.65 and 26.81. To lose weight, the patients began a controlled weight loss KD using a meal replacement product manufactured by SDM Genola consisting of less than 1 g / kg / day carbohydrate, 1.2-1.6 g / kg / day protein, with three meals per day and one meat or fish meal per day. The patients continued this diet for 4 weeks and then transitioned to a low-calorie, non-ketogenic, low-carbohydrate diet for 2 months. This cycle was repeated three times until the desired BMI (approximately 21) was reached. In both cases, the patients reported disappearance of migraines during the ketogenic diet and recurrence during the transition diet.

[0008]

[0008] In the same 2013 report by Di Lorenzo et al., the authors described preliminary data presented at the Italian Society for the Study of Headaches. In this study, 108 migraine patients (52 treated with a KD and 56 with a hypocaloric diet) were deemed to show that "ketogenesis improves migraine headaches, whereas weight loss does not: during the 1-month KD there was a very high responder rate (about 90%), whereas during the 2 months following the 4-week period of ketogenesis the KD group did not differ from the standard diet group in terms of headache relief."

[0009] In a follow-up study by Di Lorenzo et al. in 2015, 96 overweight female migraineurs were enrolled in a diet clinic to receive either a 1-month KD followed by a low-calorie standard diet (SD) or a 6-month SD. The mean monthly frequency of attacks, number of headache days, and pill intake were assessed before the diet and at 1, 2, 3, and 6 months after starting the diet. In the KD group, baseline attack frequency (2.9 attacks per month), number of headache days (5.11 days per month), and pill intake (4.91 pills per month) were significantly reduced after the first month of the diet (0.71, 0.91, 0.51, respectively; overall, KD vs. baseline, P<0.0001).

[0010]

[0010] During the transition period (first month vs. second month), the KD group showed a temporary worsening of each clinical headache variable (2.60, 3.60, and 3.07, respectively), despite continued improvement up to 6 months (2.16, 2.78, and 3.71, respectively).

[0011] In the SD group, a significant reduction in headache and number of days with tablet intake was observed only from the third month onwards (P<0.0001) and in attack frequency at the sixth month (P<0.0001).

[0012] In 2015, Bracaglia et al. investigated potential mechanisms that may be responsible for the effectiveness of the ketogenic diet in migraine. The authors recorded visual evoked potentials (VEPs) and somatosensory evoked potentials (SSEPs) in 16 migraine patients before and one month after intervention with a KD. One month after the KD, a significant reduction in the mean frequency of migraines (from an average of 4.1 attacks / month to 1.4 attacks / month, p<0.001) and duration (from 51.9 hours / month to 16.3 hours / month, p<0.001) was observed.

[0013]

[0013] KD did not alter the first SSEP and VEP block of 100 sweeps, but significantly induced a habitual normalization of paroxysmal depressed VEPs (+0.09 to -0.14, p = 0.017) and SSEPs (0.38 to -0.48, p = 0.002) during subsequent blocks.

[0014]

[0014] The authors concluded, "We found evidence of KD-induced changes at the cortical level that paralleled the improvement of migraine. Because the KD was able to restore normal EP habituation curves during repetitive stimulation without significantly altering the early amplitude response, we hypothesize that the KD acts on habituation via enhancing late GABA inhibition."

[0015]

[0015] A further study by Di Lorenzo et al. in 2018 examined the effect of a 3-month modified Atkins diet (MAD) in drug-resistant cluster headache. Eighteen drug-resistant cluster headache patients were given the MAD for 12 weeks. Of the 18 patients, 15 were considered responders and 11 experienced complete resolution of headaches. The average monthly number of headaches decreased from 108.71 to 31.44 at the end of the 12 weeks.

[0016]

[0016] The mechanism of action (MOA) of KD for relieving migraine and cluster headaches is not fully defined, but several authors have speculated about the MOA and noted increases in two major pathways: dopaminergic stimulation and GABAergic activity.

[0017]

[0017] Di Lorenzo et al. in 2018 speculated about two mechanisms mediating improvement in migraine and cluster headache. First, KD can induce an increase in brain dopaminergic activity in mice, which corrects the impairment of dopaminergic stimulation associated with cluster and migraine headaches. Second, ketone bodies can increase GABAergic activity in rat brains, and GHB is a GABA agonist and has been shown to prevent CH attacks. GABA and glutamate are the main inhibitory and excitatory neurotransmitters in the central nervous system. Among other functions, they regulate pain thresholds in the CNS. For this reason, it has been hypothesized that abnormalities in GABA and glutamate turnover may play a role in the pathogenesis of migraine. Additional MOAs are also possible, including reduced inflammation, inhibition of oxidative stress, improvements in ATP levels, and improvements in cerebral blood flow.

[0018]

[0018] US Patent Application Publication No. 2018 / 0200220 discloses the use of ketogenic medium-chain triglycerides (KMCT) as follows: "The inventors have surprisingly discovered that providing ketogenic medium-chain triglycerides (KMCT) to patients suffering from frequent migraine attacks can reduce the frequency of migraine attacks and alleviate migraine symptoms without the side effects of drugs currently used for this purpose. KMCT is metabolized in the liver to provide a rich source of ketone bodies, which can be metabolized as a carbon and energy source for the body, particularly the brain." However, the application is limited to speculation regarding the efficacy of the disclosed mixture of KMCT. Summary of the Invention [Problem to be solved by the invention]

[0019]

[0019] Further research and treatment options regarding the use of ketogenic diets and ketogenic drugs are needed. [Means for solving the problem]

[0020]

[0020] In one aspect, the present disclosure relates to a method for treating or preventing headache in a subject in need thereof, comprising administering to a subject in need thereof an effective amount of a composition comprising at least 95% pure tricaprylin.

[0021] In certain aspects, the methods are for the treatment or prevention of migraine and related headaches (e.g., trigeminal autonomic cephalgia). In some embodiments, the methods are for the treatment or prevention of chronic migraine in a subject, the subject experiencing at least 15 migraine headaches over a consecutive 30-day period at baseline.

[0022]

[0022] According to the methods of the present disclosure, treatment or prevention may include treating, preventing or ameliorating one or more symptoms of headache, reducing the number of headache days, reducing the use of headache medications, and the like.

[0023] In some embodiments, the methods provide a reduction in the number of migraine headache days per month (30 consecutive days) by at least 1 day, at least 2 days, at least 2.5 days, at least 3 days, at least 3.5 days, at least 4 days, at least 4.5 days, at least 5 days, at least 6 days, at least 7 days, at least 8, at least 9 days, at least 10 days, at least 11 days, at least 12 days, at least 13 days, at least 14 days, at least 15 days, after at least 1 month, at least 2 months, at least 3 months, etc. of treatment.

[0023]

[0024] In other embodiments, the method includes measuring the change from baseline in duration of migraine headaches during treatment months 1, 2, or 3; the change from baseline in duration of migraine headaches of moderate to severe intensity during treatment months 1, 2, or 3; the percentage of participants with a 50% reduction from baseline in number of migraine headache days during treatment months 1, 2, or 3; the percentage of participants with a 75% reduction from baseline in number of migraine headache days during treatment months 1, 2, or 3; the percentage of participants with a 90% reduction from baseline in number of migraine headache days during treatment months 1, 2, or 3; the change from baseline in use of acute migraine medication once a month during treatment months 1, 2, or 3; the change from baseline to time to first use of acute migraine medication during treatment months 1, 2, or 3; the change from baseline Headache Impact Test (HIT-6) score at the end of months 1, 2, or 3 (see, e.g., Yang M, Rendas-Baum R, Varon SF, Kosinski M. Validation of the Headache Impact Test (HIT-6™) across months 1, 2, or 3). episodic and chronic migraine. Cephalalgia. 2011 Feb;31(3):357-67, the disclosure of which is incorporated herein in its entirety); provides improvement or amelioration of one or more symptoms of migraine selected from the occurrence of migraine-related adverse events, including aura, nausea, and vomiting.

[0024]

[0025] In some aspects, tricaprylin is administered in an amount ranging from about 10 g / kg / day to about 60 g / kg / day of the compound in a composition administered orally in a single dose or in divided doses. In some embodiments, the composition is administered once, twice, or three times daily.

[0025]

[0026] In some aspects, the composition comprises at least about 30% tricaprylin by weight of the total composition, and one or more emulsion-forming excipients present in a concentration sufficient to form an emulsion that is stable under ambient conditions for at least one month.

[0026]

[0027] In some embodiments, the emulsion-forming excipient(s) of the composition is selected from the group consisting of lecithin, hydrogenated castor oil, caprylic acid esters, sodium oleate, glycerol, citric acid esters of mono- and diglycerides, mono- and diglycerides of fatty acids including propylene glycol monocaprylate, and combinations thereof.

[0027]

[0028] In some embodiments, tricaprylin is present in the composition in an amount of about 30% to about 60% by weight of the total composition. In some embodiments, one or more emulsion-forming excipients are present in the composition in an amount of about 1% to about 10% by weight of the total composition. In some embodiments, the stable emulsion exhibits an average particle size of less than 0.5 μm at ambient conditions for at least one month, preferably less than 0.3 μm at ambient conditions for at least one month, and preferably less than 0.2 μm at ambient conditions for at least one month.

[0028]

[0029] While multiple aspects are disclosed, still other aspects of the present disclosure will become apparent to those skilled in the art from the following detailed description, which shows and describes illustrative aspects of the present disclosure. As will be understood, the present invention is capable of modification in various aspects without departing from the spirit and scope of the present disclosure. Accordingly, the detailed description is to be regarded as illustrative in nature and not restrictive. [Brief description of the drawings]

[0029] [Figure 1]

[0030] FIG. 1 illustrates an exemplary dosing and titration scheme according to the clinical protocol of the present disclosure. [Diagram 2]

[0031] FIG. 2 illustrates baseline demographics (FAS) showing that the treatment arms were largely balanced; the tricaprylin arm had a higher proportion of men, according to embodiments of the present disclosure. [Diagram 3]

[0032] FIG. 3 illustrates baseline demographics (FAS) showing that the tricaprylin arm had a higher average weight, although BMI was similar, in accordance with an embodiment of the present disclosure. [Figure 4]

[0033] FIG. 4 illustrates baseline migraine headache days showing a higher percentage of subjects in the tricaprylin arm with chronic migraine headaches, according to an embodiment of the present disclosure. [Diagram 5]

[0034] FIG. 5 illustrates the primary efficacy analysis: Efficacy Evaluable Set (EEITS) at Initial Titration showing efficacy at 2 months, positive trend at 3 months, according to an embodiment of the present disclosure. [Figure 6]

[0035] FIG. 6 illustrates the primary efficacy analysis: EEITS subgroup with MHD of 4-24 at baseline, according to an embodiment of the disclosure. [Figure 7]

[0036] FIG. 7 illustrates the results of MMRM analysis on primary endpoints: EES and EEITS, according to an embodiment of the disclosure. [Figure 8]

[0037] 8A-8B illustrate the primary endpoint: change from baseline in recurrent (FIG. 8A) and chronic (FIG. 8B) subjects (EES4-24MHD) according to an embodiment of the disclosure. [Figure 9]

[0038] FIG. 9 illustrates the secondary endpoint: change from baseline in acute migraine medication use (EES) according to embodiments of the present disclosure. [Figure 10]

[0039] FIG. 9 illustrates the secondary endpoint: change from baseline in acute migraine medication use (EEITS) according to an embodiment of the disclosure. [Figure 11]

[0040] FIG. 11 illustrates secondary endpoints: responder analysis MHD50, MHD75, MHD90 (EES), according to an embodiment of the disclosure. [Figure 12]

[0041] FIG. 12 illustrates secondary endpoints: Responder Analysis MHD50, MHD75, MHD90 (EEITS), according to an embodiment of the disclosure. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0030]

[0042] In one aspect, the present disclosure relates to a method for the treatment or prevention of headache in a subject in need thereof, comprising administering an effective amount of a composition comprising a compound capable of increasing ketone body levels in the body of a subject in need thereof.

[0031]

[0043] In some embodiments, the method is for the treatment or prevention of migraine or associated headaches (eg, trigeminal autonomic headaches).

[0044] In some embodiments, the method is for the treatment of chronic migraine in a subject, where the subject experiences at least 15 migraine headaches (or more than 14 migraine headaches) for any consecutive 30 days at baseline.

[0032]

[0045] According to the methods of the present disclosure, treatment or prevention may include treating, preventing or ameliorating one or more symptoms of headache, reducing the number of headache days, reducing the use of headache medications, and the like.

[0046] In some embodiments, the methods provide a reduction in the number of migraine headache days by at least 1 day, at least 2 days, at least 2.5 days, at least 3 days, at least 3.5 days, at least 4 days, at least 4.5 days, at least 5 days, at least 6 days, at least 7 days, at least 8 days, at least 9 days, at least 10 days, at least 11 days, at least 12 days, at least 13 days, at least 14 days, at least 15 days per month (30 consecutive days) after at least 1 month, at least 2 months, at least 3 months, etc. of treatment.

[0033]

[0047] In some embodiments, the methods provide improvement or remission of one or more symptoms of migraine selected from: change from baseline in duration of migraine headaches during treatment months 1, 2, or 3; change from baseline in duration of migraine headaches of moderate to severe intensity during treatment months 1, 2, or 3; percentage of participants with a 50% reduction from baseline in number of migraine headache days during treatment months 1, 2, or 3; percentage of participants with a 75% reduction from baseline in number of migraine headache days during treatment months 1, 2, or 3; percentage of participants with a 90% reduction from baseline in number of migraine headache days during treatment months 1, 2, or 3; change from baseline in use of acute migraine medication once a month during treatment months 1, 2, or 3; change from baseline to time to first use of acute migraine medication during treatment months 1, 2, or 3; change from baseline Headache Impact Test (HIT-6) score at the end of months 1, 2, or 3; occurrence of migraine-related adverse events including aura, nausea, vomiting, and the like.

[0034]

[0048] In some embodiments, compositions useful in connection with the methods of the present disclosure may include tricaprylin. Tricaprylin belongs to a family of compounds known as medium chain triglycerides (MCTs). MCTs are triacylglycerols, and the fatty acids are 6-12 carbons in length. In the case of tricaprylin, greater than 95%, 97%, 98%, 99%, etc. of the fatty acids are octanoic acid, which consists of eight carbons (C8). The remaining fatty acids may be C6, C10, etc. In certain embodiments, less than 5%, 4%, 3%, 2%, or 1% of the fatty acids are C10.

[0035]

[0049] The MCTs of the present disclosure may be prepared by any process known in the art, such as direct esterification, rearrangement, resolution, transesterification, and the like. Sources of MCTs include any suitable source, semi-synthetic, synthetic, or natural. Exemplary sources of tricaprylin include MIGLYOL® 808 or NEOBEE® 895. Examples of natural sources of MCTs include vegetable sources such as coconut and coconut oil, palm kernel and palm kernel oil, and animal sources such as any of a variety of species, e.g., goat's milk. For example, lipids may be prepared by rearrangement of vegetable oils such as coconut oil. Length and chain length distribution may vary depending on the source oil. For example, MCTs containing 1-10% C6, 30-60% C8, 30-60% C10, 1-10% C10 are typically derived from palm oil and coconut oil. Exemplary sources of tricaprylin include MIGLYOL® 808 or NEOBEE® 895.

[0036]

[0050] In certain embodiments, tricaprylin can be administered as a pharmaceutical composition.In certain aspects, tricaprylin can be administered as a pharmaceutical composition comprising high drug loading of tricaprylin and at least one surfactant.In some embodiments, the pharmaceutical composition can comprise high drug loading of tricaprylin and at least two surfactants.In some embodiments, the pharmaceutical composition forms an emulsion that is stable at least about 4 hours at ambient conditions, at least 24 hours at ambient conditions, at least 2 weeks at ambient conditions, at least 1 month at ambient conditions, etc.

[0037]

[0051] In certain embodiments, the emulsions may have an average droplet diameter less than about 1000 nm but greater than about 100 nm, such as from about 100 nm to 500 nm, from about 200 nm to about 300 nm, from about 160 nm to about 190 nm, etc. In some embodiments, the stable emulsions exhibit an average particle size less than 0.5 μm at ambient conditions for at least one month, preferably less than 0.3 μm at ambient conditions for at least one month, preferably less than 0.2 μm at ambient conditions for at least one month. In other aspects, the emulsions may have an average particle size less than about 1000 nm but greater than about 100 nm, such as from about 100 nm to 500 nm, from about 200 nm to about 300 nm, from about 160 nm to about 190 nm, etc.

[0038]

[0052] In certain embodiments, pharmaceutical compositions of the present disclosure may comprise spray-dried particles having an average diameter of about 5 μm to about 50 μm in diameter, about 5 μm to about 30 μm in diameter, about 5 μm to about 20 μm in diameter, about 5 μm to about 10 μm in diameter, etc.

[0039]

[0053] In certain embodiments, the pharmaceutical compositions may comprise a high drug loading of tricaprylin, such as at least about 20% of the total compositions, at least about 25% of the total compositions, at least about 30% by weight of the total compositions, at least about 40% by weight of the total compositions, from about 30% by weight of the total compositions to about 65% by weight of the total compositions, from about 30% by weight of the total compositions to about 60% by weight of the total compositions, from about 40% by weight of the total compositions to about 50% by weight of the total compositions, or from about 40% by weight of the total compositions to about 45% by weight of the total compositions.

[0040]

[0054] As used herein, unless otherwise specified, "wt %" refers to "wt % of the total composition."

[0055] In certain embodiments, tricaprylin and / or pharmaceutical compositions can be administered orally.The therapeutically effective amount of tricaprylin is any amount or dose that is sufficient to produce the desired effect, and can depend in part on the severity and stage of the condition, the size and condition of the patient, and other factors that are readily known to those skilled in the art.Dosage can be administered as a single dose or multiple doses, such as once a day, twice a day, three times a day, etc., as described elsewhere herein.

[0041]

[0056] In certain aspects, tricaprylin can be administered in a pharmaceutical composition that includes tricaprylin with high drug loading and one or more emulsion-forming excipients that are present at sufficient concentration to form an emulsion at room temperature.The pharmaceutical composition can include components in the amounts described herein.In some embodiments, the pharmaceutical composition can form a stable liquid emulsion.

[0042]

[0057] As described herein, the pharmaceutical composition of the present disclosure may form a liquid emulsion. An emulsion refers to a composition that, when diluted with water or other aqueous medium and gently mixed, gives a stable oil / water emulsion with an average droplet diameter of less than about 5 μm but greater than about 100 nm (e.g., 0.35-1.2 μm), generally polydisperse. Such emulsions are stable, meaning that they have no visually detectable phase separation and no visually detectable crystals.

[0043]

[0058] "Gentle mixed," as used herein, is understood in the art to refer to the formation of an emulsion by gentle hand (or mechanical) mixing, such as by repeated inversion in a standard laboratory mixer. High shear mixing is not required to form an emulsion. Such emulsion compositions generally emulsify more or less spontaneously when introduced into an aqueous use environment.

[0044]

[0059] As explained above, the pharmaceutical compositions of the present disclosure can form stable emulsions when administered in an aqueous use environment, such as water, a pharma- ceutical suitable aqueous solution, or in vivo. By way of example, the emulsions can be stable at ambient conditions for at least about 24 hours, at least about 1 day, at least about 5 days, at least about 10 days, at least about 1 month, etc. In certain embodiments, the emulsions formed do not phase separate during the period of stability. In certain embodiments, the emulsions can have an average droplet diameter of less than about 5 μm but greater than about 100 nm (e.g., 0.35-1.2 μm).

[0045]

[0060] In certain embodiments, the emulsion formed may be stable at a pH of the stomach, such as a pH of about 1 to about 3, such as about 1.2 to about 2.9. In certain embodiments, the emulsion formed may be stable at a pH of the intestine and / or colon, such as a pH of about 5 to about 7, such as about 5.5 to about 6.9. In certain embodiments, the emulsion formed may begin to degrade or phase separate at a pH of the stomach after about 0.5 hours to about 1 hour, but does not release the encapsulated tricaprylin until the pH of the intestine or colon. In this regard, without intending to be bound by theory, in vitro digestion assays indicate that the encapsulated tricaprylin is released from the emulsion at pH of the intestine and / or colon, which are the primary locations of lipid digestive enzymes. In accordance with certain aspects of the present disclosure, preferential release of tricaprylin in the intestine and / or colon rather than the stomach may increase the bioavailability of tricaprylin given the location of lipid digestive enzymes in these regions.

[0046]

[0061] In certain aspects of the present disclosure, the pharmaceutical composition provides the preferential release of tricaprylin with high drug loading in the lower gastrointestinal tract of the user.Without intending to be bound by theory, the preferential release of tricaprylin in the lower gastrointestinal tract, including the colon, may result in reduced stomach upset and related adverse events compared to the standard administration of non-formulated MCT oil.Furthermore, the improved bioavailability of tricaprylin may generally result in increased ketone body production in vivo compared to the standard administration of non-formulated MCT oil.

[0047]

[0062] In certain aspects, the pharmaceutical composition of the present disclosure includes one or more emulsion-forming excipients. In certain embodiments, the one or more emulsion-forming excipients can be any emulsifier capable of forming an emulsion including MCT oil. Examples are lecithin (e.g., phosphoripon 90G), hydrogenated castor oil including polyoxyl 40 castor oil (e.g., Kolliphor RH40), caprylic acid esters, sodium oleate, glycerol, citric acid esters of mono- and diglycerides (e.g., Citrem), mono- and diglycerides of fatty acids including propylene glycol monocaprylate (e.g., Capmul PG-8), and combinations thereof. The emulsion-forming excipients can be present in an amount sufficient to result in the formation of a desired emulsion. For example, in certain embodiments, the emulsion-forming excipients can be present in an amount of about 1% to about 10% by weight, such as about 1.3% to about 10% by weight of the total composition.

[0048]

[0063] In certain embodiments, the emulsion-forming excipients may include a combination of lecithin, Kolliphor RH40, and caprylic acid ester emulsifiers. In other embodiments, the emulsion-forming excipients may include a combination of lecithin, sodium oleate, and glycerol. In yet other embodiments, the emulsion-forming excipients may include Citrem alone or a combination of mono- and diglycerides of fatty acids.

[0049]

[0064] By way of non-limiting example, Table 1 below shows attributes and properties of exemplary liquid pharmaceutical formulations.

[0050] [Table 1]

[0051]

[0065] By way of non-limiting example, suitable lecithins useful as excipients for forming emulsions of the present disclosure can be derived from any suitable source, such as eggs or soybeans. By way of non-limiting example, suitable lecithins can be selected from Soy PC, 95%, Avanti No. 441601; Egg PC, 95%, Avanti No. 131601, and the like.

[0052]

[0066] Any suitable mono- or diglyceride of fatty acids may be used as an emulsion former of the present disclosure, such as, for example, citric acid esters of mono- and diglycerides of fatty acid (Citrem) E472C; mono- and diglycerides of fatty acid E471; and the like.

[0053]

[0067] In other embodiments, the pharmaceutical composition may comprise high drug loading tricaprylin; at least one surfactant; adsorbent and film-forming polymer.The pharmaceutical composition may further comprise a co-surfactant.In some embodiments, the pharmaceutical composition comprises at least two surfactants.In certain embodiments, the composition is a self-emulsifying spray-dried composition.

[0054]

[0068] In other aspects, the at least one surfactant is selected from polyoxyl hydrogenated castor oil, polyoxyl stearate, polyoxyl hydroxystearate, lecithin, phosphatidylcholine, and combinations thereof. In certain embodiments, the solid composition comprises at least two surfactants, and the at least two surfactants can be selected from polyoxyl hydrogenated castor oil, polyoxyl stearate, polyoxyl hydroxystearate, lecithin, phosphatidylcholine, and combinations thereof. In certain embodiments, at least one of the at least two surfactants is a polyoxyl hydrogenated castor oil or a polyoxyl stearate surfactant. The at least two surfactants can be present in a ratio of 2:1 to 1:1 relative to each other.

[0055]

[0069] In certain aspects, the adsorbent is a silica compound, such as colloidal silicon dioxide (AEROSIL®, CAB-O-SIL®), amorphous silica gel (SYLOID®, SYLYSIA®), granular silicon dioxide (AEROPERL®), silica aerogel, magnesium aluminometasilicate (NEUILIN®), calcium silicate (FLORITE®), and ordered mesoporous silicates.

[0056]

[0070] In certain aspects, the film-forming polymer can be polyvinylpyrrolidone (PVP), polyvinylpyrrolidone-vinyl acetate copolymer (PVP-VA), hydroxypropyl methylcellulose (HPMC), hydroxypropyl methylcellulose acetate succinate (HPMCAS), dextrans of various molecular weights (e.g., 10,000, 40,000, 70,000, 500,000, etc.), etc. In certain embodiments, the film-forming polymer is PVP or PVP-VA, and in other embodiments, the film-forming polymer is PVP-VA.

[0057]

[0071] Any suitable method for making the pharmaceutical compositions of the present disclosure may be used.

[0072] The pharmaceutical compositions of the present disclosure, in one embodiment, are administered in a dosage required to treat symptoms of migraine and associated headaches (e.g., trigeminal-autonomic cephalopathy) and headaches. Appropriate dosages can be determined by one of skill in the art. In one embodiment, oral administration of the pharmaceutical compositions of the present disclosure results in hyperketonemia. Hyperketonemia, in one embodiment, results in ketone bodies that are utilized to treat symptoms of migraine and associated headaches (e.g., trigeminal-autonomic cephalopathy) and headaches.

[0058]

[0073] Administration can be, for example, once a month, once a week, daily, or more than once a day, as needed or desired.Similarly, administration can be every other day, every week, or every month, every 3 days, every 3 weeks, or every 3 months, every 4 days, every 4 weeks, or every 4 months, etc. Administration can be multiple times a day. Administration can be provided with or without food.

[0059]

[0074] The pharmaceutical compositions provided herein are, in one embodiment, intended for "long-term" consumption, sometimes referred to herein as "long" periods. "Long-term" administration, as used herein, generally refers to periods greater than one month. Periods greater than 2, 3, or 4 months include an embodiment of the invention. Also included are embodiments that include longer periods, including periods greater than 5, 6, 7, 8, 9, or 10 months. Periods greater than 11 months or one year are also included. More long-term use over periods of 1, 2, 3, or more years is also contemplated herein. "Regularly," as used herein, refers to dosing with or consuming the composition at least once a week. More frequent dosing or consumption, such as two or three times a week, is included. Also included are regimens that include consumption at least once a day. Those skilled in the art will appreciate that blood levels of ketone bodies or specific ketone bodies achieved can be a useful measure of dosing frequency. Any frequency that allows for the maintenance of blood levels of the measured compound within an acceptable range, whether or not specifically exemplified herein, may be considered useful herein. Those skilled in the art will understand that dosing frequency is a function of the composition consumed or administered, and that some compositions may require more frequent or less frequent dosing to maintain a desired blood level of the measured compound (e.g., ketone bodies).

[0060]

[0075] Administration can be carried out periodically, for example, as part of a patient treatment regimen. The treatment regimen can include causing the patient to take the pharmaceutical composition of the present disclosure periodically in an amount effective to improve the patient's cognitive function, memory, and behavior. The periodic intake can be daily or weekly, once a day, or 2, 3, 4 or more times a day. Similarly, the periodic administration can be every other day or week, every 3 days or week, every 4 days or week, every 5 days or week, or every 6 days or week, and in such a regimen, administration can be multiple times a day. The goal of the periodic administration is to provide the patient with an optimal dose of the pharmaceutical composition of the present disclosure, as exemplified herein.

[0061]

[0076] In one embodiment, the composition increases the circulating concentration of at least one ketone body in a mammal or patient. In one embodiment, the circulating ketone body is D-beta-hydroxybutyrate. The amount of circulating ketone bodies can be measured multiple times after administration, in one embodiment at a time point expected to be near the peak concentration in the blood, but also before and after the expected peak blood concentration level. These off-peak measured amounts are then optionally adjusted to reflect the expected level at the expected peak. In one embodiment, the expected peak time is about 2 hours. The peak circulating blood level and timing can vary depending on factors known to those skilled in the art, including individual digestive speed, simultaneous or pre- or post-ingestion of meals, beverages, etc., as known to those skilled in the art. In one embodiment, the peak blood level reached of D-beta-hydroxybutyrate is about 0.05 millimolar (mM) to about 50 mM. Another method of determining whether blood levels of D-beta-hydroxybutyrate are elevated to about 0.05 to about 50 mM is by measuring urinary excretion of D-beta-hydroxybutyrate in the range of about 5 mg / dL to about 160 mg / dL. In other embodiments, maximum blood levels are elevated to about 0.1 to about 50 mM, about 0.1 to about 20 mM, about 0.1 to about 10 mM, about 0.1 to about 5 mM, and more preferably about 0.15 to about 2 mM, about 0.15 to about 0.3 mM, and about 0.2 to about 5 mM, although variations will necessarily occur depending on the composition and host, e.g., as described above. In other embodiments, the maximum blood level of D-beta-hydroxybutyrate achieved is at least about 0.05 mM, at least about 0.1 mM, at least about 0.15 mM, at least about 0.2 mM, at least about 0.5 mM, at least about 1 mM, at least about 1.5 mM, at least about 2 mM, at least about 2.5 mM, at least about 3 mM, at least about 4 mM, at least about 5 mM, at least about 10 mM, at least about 15 mM, at least about 20 mM, at least about 30 mM, at least about 40 mM, and at least about 50 mM.

[0062]

[0077] The effective dosage of the compound for the composition of the present invention, i.e., the compound capable of increasing the ketone body concentration in an amount useful for treating the symptoms of migraine and / or associated headaches, will be clear to those skilled in the art. As explained herein above, such effective amount can be determined in light of the disclosed blood ketone levels.

[0063]

[0078] In one embodiment, the amount of tricaprylin administered ranges from about 0.05 g / kg / day to about 60 g / kg / day. In other embodiments, the amount of tricaprylin administered is at least 10 g / day, 15 g / day, 20 g / day, 30 g / day, 40 g / day, 50 g / day, 60 g / day. In other embodiments, the dose of tricaprylin ranges from about 0.25 g / kg / day to about 20 g / kg / day. In other embodiments, the dose of tricaprylin ranges from about 0.5 g / kg / day to about 20 g / kg / day. In other embodiments, the dose ranges from about 0.1 g / kg / day to about 10 g / kg / day. In other embodiments, the dose of tricaprylin is at least about 0.05 g / kg / day, at least about 0.1 g / kg / day, at least about 0.15 g / kg / day, at least about 0.2 g / kg / day, at least about 0.5 g / kg / day, at least about 1 g / kg / day, at least about 1.5 g / kg / day, at least about 2 g / kg / day, at least about 2.5 g / kg / day, at least about 3 g / kg / day, at least about 4 g / kg / day, at least about 5 g / kg / day, at least about 10 g / kg / day, at least about 15 g / kg / day, at least about 20 g / kg / day, at least about 30 g / kg / day, at least about 40 g / kg / day, and at least about 50 g / kg / day. Administration can be in a single dose or in divided doses, for example, once, twice, or three times daily.

[0064]

[0079] Convenient unit dose containers and / or compositions include, among others, sachets or containers of spray-dried particles, tablets, capsules, lozenges, troches, hard candies, nutritional bars, nutritional drinks, metered sprays, creams, and suppositories. The compositions may be combined with pharma- ceutically acceptable excipients, such as gelatin, oils, and / or other pharma- ceutically active agents. For example, the compositions may be advantageously combined with and / or used in combination with other therapeutic or prophylactic agents that are different from the subject compounds. In many cases, administration in combination with the subject compositions improves the efficacy of such agents. For example, the compounds may be advantageously used in combination with other migraine or headache medications (e.g., triptans or CGRP antagonists), or compounds that improve the efficiency of glucose utilization, and mixtures thereof.

[0065]

[0080] The daily dose of tricaprylin may also be measured in terms of grams of tricaprylin per kg of body weight (BW) of the subject. The daily dose of tricaprylin may range from about 0.01 g / kg to about 10.0 g / kg of the subject's BW. Preferably, the daily dose of tricaprylin is from about 0.1 g / kg to about 5 g / kg of the subject's BW. More preferably, the daily dose of tricaprylin is from about 0.2 g / kg to about 3 g / kg of the subject. Even more preferably, the daily dose of tricaprylin is from about 0.5 g / kg to about 2 g / kg of the subject.

[0066]

[0081] The following examples are provided for illustrative purposes only and are not intended to limit the scope of the present invention. EXAMPLES

[0067]

[0082] Accordingly, it is to be understood that the embodiments of the invention described herein are merely illustrative of the application of the principles of the invention. References herein to details of exemplary embodiments are not intended to limit the scope of the claims, but as such recite those features regarded as essential to the invention.

[0068]

[0083] Key Definitions:

[0084] Migraine defined by ICHD-3 criteria adapted according to industry standards:

[0085] Migraine: A headache that meets both (a) and (b) below, lasts for 30 minutes or more, with or without aura: (a) Two or more of the following headache characteristics: Unilateral; ·Throbbing / pulsatile; Moderate to severe pain intensity; · Worsening with exercise / physical activity or causing avoidance of routine physical activity; (b) During the headache, one or more of the following associated symptoms: Nausea and / or vomiting; Photophobia and phonophobia.

[0069]

[0086] Probable migraine: A headache with or without aura lasting more than 30 minutes but lacking one of the characteristics of a migraine.

[0087] Migraine headache day (MHD): any calendar day on which a migraine headache or presumed migraine headache occurs.

[0070]

[0088] Episodic migraine = 4-14 MHD days / month; chronic migraine = 15 or more MHD days / month.

[0089] Example 1 Tricaprylin in migraine patients

[0090] This is a randomized, double-blind, placebo-controlled, parallel-group, multicenter study of tricaprylin as AC-SD-03 compared with placebo for migraine relief in participants with frequent migraines.

[0071]

[0091] Composition of tricaprylin oral powder for reconstitution, formulation AC-SD-03, oral powder for reconstitution

[0072] [Table 2]

[0073]

[0092] Alternatively, the following liquid formulations can be given and compared with placebo (90G: Phospholipon 90G; RH40: Kolliphor RH40):

[0074] [Table 3-1]

[0075] [Table 3-2]

[0076] [Table 3-3]

[0077]

[0093] Following up to 2 weeks of screening, the study duration will be 17 weeks, including a 4-week baseline measurement period (after which randomization will occur), a 12-week treatment period, and a 1-week safety follow-up period.

[0078]

[0094] The study will be completed in two parts. In Part 1, 54 participants will be randomized to receive tricaprylin as AC-SD-03 or placebo in a 1:1 ratio. Once 54 participants have been randomized, enrollment will be paused until the randomized participants complete the study. The decision to proceed to Part 2 (enroll additional participants) will be made based on an open-label analysis of all evaluable patient data from Part 1. The decision to continue into Part 2 will be based on the primary endpoint, ΔMD Mth3 The size of Part 2 will be determined by the Sponsor based on several factors, including the safety and tolerability profile observed during Part 1, the observed between-subject variability, and the one-sided p-value for the feasibility analysis. The size of Part 2 will be determined by the between-subject variability observed in Part 1 and will range from 80 to 180 participants.

[0079]

[0095] Number of Participants: Part 1: Approximately 135 participants will be screened to achieve 54 randomized participants and 46 evaluable participants (approximately 23 evaluable participants per treatment group). If a decision is made to proceed to Part 2, approximately 200-450 participants will be screened to achieve 78-180 randomized participants and 66-152 evaluable participants in Part 2. The sample size for Part 2 will be determined based on the standard deviation (SD) observed in Part 1.

[0080]

[0096] Investigational product: Formulation AC-SD-03 contains the active compound tricaprylin and excipients in a ratio of 1:1.5. Thus, 75 g of AC-SD-03 contains 30 g of tricaprylin and 45 g of excipients (carriers, emulsifiers and flavorings). Placebo formulation AC-SD-03P contains 30 g of safflower oil instead of the active compound tricaprylin and the same excipients as the active formulation.

[0081]

[0097] Treatment Groups and Duration: At the baseline visit, all participants will receive a sentinel dose of 12.5 g of AC-SD-03 (containing 5 g of tricaprylin). Participants who do not tolerate this sentinel dose will not be eligible to continue. Participants who tolerate the sentinel dose and meet other eligibility criteria will enter a 4-week baseline measurement period to determine participant eligibility for the study on migraine days and to establish baseline data for comparison of study-period endpoints.

[0082]

[0098] After a 4-week baseline measurement period, participants recording 4 to 24 migraine days per month will be randomized to AC-SD-03 or placebo (AC-SD-03P), titrated to 12.5 g twice daily to 75 g twice daily, over a 2-week period. Participants with fewer than 4 or more than 24 headache days per month in the baseline period will be discontinued from the study. Participants should not say how many migraine headache days their eligibility is based on, to avoid biased reporting.

[0083]

[0099] Once titration is complete, all participants will continue on their target dose for an additional 10-week maintenance period.

[0100] Upon completion of the 12-week, double-blind, placebo-controlled treatment phase, there will be a 1-week safety follow-up period.

[0084]

[0101] The primary endpoint was 3 months (ΔMD Mth3 ) Change from baseline in number of migraine headache days during the study.

[0102] Secondary endpoints were: From months 1 to 3, the first month of treatment (ΔMD Mth1 ) and month 2 (ΔMD Mth2 ) as well as the change from baseline in the number of migraine headache days during the overall period; · Change from baseline in duration of migraine headaches of moderate to severe intensity during treatment months 1, 2, and 3; · Change from baseline in migraine duration during treatment months 1, 2, and 3; · Proportion of participants with a 50% reduction from baseline in the number of migraine headache days in treatment months 1, 2, and 3; · Change from baseline in monthly acute migraine medication use during treatment months 1, 2, and 3; Time to first use of acute migraine medication; · Change from baseline Headache Impact Test (HIT-6) score at the end of months 1, 2, and 3; Incidence of adverse events; · Safety clinical laboratory testing; · Vital signs, ECG, C-SSRS;

[0103] The objectives of the examination are to: · Evaluation of the treatment of chronic versus episodic migraine headache attacks; · Change from baseline in the number of headache days (migraine and non-migraine headache) during treatment months 1, 2, and 3 (ΔHDMth1, ΔHDMth2, and ΔHDMth3); · Change from baseline in migraine severity during treatment months 1, 2, and 3; · Change from baseline in MIDAS scores at the end of months 1, 2, and 3; Plasma βHB and other pharmacokinetic parameters;

[0104] Test results

[0105] Three months after tricaprylin treatment, a significant reduction in the mean frequency of migraines (from an average of 4.1 attacks / month to 1.4 attacks / month, p<0.001) and duration (from 51.9 hours / month to 16.3 hours / month, p<0.001) is expected.

[0085]

[0106] Important selection criteria: 18-70 years old; Age at onset must be <50 years, frequent (recurrent or chronic) with or without aura for at least 1 year (per ICHD-3-beta) * Migraines; · Participants must have 4–24 migraine headache days per month as confirmed by the baseline measurement period; · Both episodic and chronic migraine were included (4–24 MHD); episodic migraine, 4–14 MHD / month; chronic migraine, 15 or more MHD / month; · Use of one acceptable migraine preventive medication will be permitted if the participant has been on a stable medication for at least 2 months prior to screening; · Must have failed preventive treatment for migraine headaches in categories 1–4 (no treatment response); ·Tolerating sentinel doses; -At least 80% compliance with the e-diary during the baseline period (28 days)

[0107] Important exclusion criteria: History of hemiplegic migraine, cluster headache, or other trigeminal-autonomic headaches; · Presence of a chronic pain syndrome (other than migraine), such as fibromyalgia; Use of barbiturates (and / or butalbital-containing sedatives) or opioids (and / or opioid-containing sedatives) for the acute treatment of migraine headaches on 4 or more days per month; · Advanced, severe, progressive or unstable disease of any kind that may interfere with efficacy: or the presence or history of any active GI condition not adequately controlled by medication, e.g., diverticulitis, Crohn's disease, severe GERD, peptic ulcer disease; · Use of CGRP medications, Botox injections, TENS, cranial nerve blocks, trigger point injections, acupuncture especially for migraines, and infusion therapy in the last 3 months; · Ketogenic diets, low-carb diets, and intermittent fasting (including the 5:2 diet);

[0108] Important protocol deviations: - Predictive symptom (number of migraine headache days between 4 and 24 days), subjects who did not have 5 days during the study; Note: These subjects were not excluded from the SAP-defined analyses.

[0086]

[0109] Primary endpoints and analysis sets: Primary endpoint - Change from baseline in number of migraine headache days during the 3-month period.

[0087] Note: ΔMHD at months 1 and 2 were calculated similarly, and data from months 1 and 2 were also used in the statistical model to assess the primary endpoint.

[0088] Analysis Set - Full Analysis Set (FAS): All randomized subjects who received at least one dose of IMP analyzed by primary treatment arm; o Safety Set (SAF): As above, but analyzed by treatment received; Efficacy Evaluable Set (EES): subset entry of the FAS with at least 14 / 28 diaries in any post-baseline month; Efficacy Evaluable Set for Intended Titration (EEITS): Per-protocol sensitivity analysis set for protocol amendment 3. A subset of EES who underwent 21-day titration and achieved a maximum daily dose of ≤40 g tricaprylin / placebo for 16-21 days.

[0089] *Note: Major protocol deviations were not excluded from the above analysis set.

[0110] Subjects were enrolled in the study as follows (see Figures 2-3 for baseline demographics, Figure 4 for baseline MMD, and Figure 1 for dosing and titration protocol scheme):

[0090] [Table 4]

[0091]

[0111] Results at 2 months showed a clinically relevant benefit of tricaprylin (one-sided p=0.066 vs. our target at p<0.2). At 3 months, EEITS showed a positive clinically relevant trend towards reaching the target at p<0.2 (p=0.269). (See Figures 5-7)

[0112] Sensitivity analyses in patients with MHD 4–24 at baseline in the EEITS show results consistent with the prespecified EEITS population (see Figure 6).

[0113] Subgroup analysis revealed a significant chronic / recurrent interaction (p=0.0076) (see Figures 8A-B).

[0114] Secondary endpoint analyses, including responder analyses, MHD50, MHD75, and MHD90, generally followed the trajectory of the primary endpoint, as illustrated in Figures 9-12.

[0092]

[0115] Example 2 Trigeminal autonomic headache responsive to tricaprylin

[0116] A 67-year-old man presented with a 10-year history of left-sided headaches that had waxed and waned. The man's medical history included bilateral hearing loss (right worse than left) and past episodes of dizziness leading to a possible diagnosis of Meniere's disease. He had hyperlipidemia that was controlled with statins. He was somewhat overweight (BMI 30.8), was vegetarian, and physically active.

[0093]

[0117] The headache, when present, was described as a dull, aching, non-throbbing pain that continued over the entire left side of the face and the left scalp. The pain was described as being centered around the eyes and felt like being poked in the eye. The pain also involved the left cheek and left scalp. He was unable to identify any specific trigger for the pain, but noted that it was accompanied by pain to touch on the left side of the head, including sensitivity to hair brushing. When pain was present, he noted it was present upon awakening in the morning and continued throughout the day.

[0094]

[0118] He had no other types of headaches, and had not experienced episodes of nasal congestion or pupil changes. He noted excessive tearing of the left eye at times. At one point, he was investigated for a possible "sinus disorder" and no sinus symptoms were diagnosed. Overall, the headaches were mild, did not interfere with activities of daily living, and were described as "annoying" rather than painful. He occasionally self-medicated with paracetamol, which provided moderate relief. He did not tolerate NSAIDs and did not undergo a trial of indomethacin.

[0095]

[0119] He had previously had a brain MRI which was normal and had been treated with amitriptyline 10 mg which partially reduced the level of discomfort but produced fatigue; the overall benefit-risk ratio was not felt to be positive and so was not continued.

[0096]

[0120] Family history included late-onset dementia (mother) and hearing loss in a maternal niece. Subject did not suffer from dementia or cognitive impairment.

[0121] The subject started a daily treatment regimen that included Axona®, a medical dietary supplement containing the active ingredient tricaprylin. Soon after starting daily treatment with Axona®, he noticed an improvement in his headaches, and after three months of intake, he noticed a complete cure of his discomfort. After discontinuing treatment, the discomfort recurred within one month.

[0097]

[0122] Consideration

[0123] Physical examination was unremarkable apart from hearing loss and mild overweight. ESR and other inflammatory markers as well as screening chemistry and hematology were normal.

[0098]

[0124] At the time of presentation, the headaches had recurred with an intensity of 4-6 / 10 and he was restarted on a course of Axona®, starting with 5 g tricaprylin daily and increasing over 2 weeks to 20 g daily.

[0099]

[0125] Within a month of starting Axona®, the maximum pain level had decreased to 3-4 / 10 and for many days the pain was absent, although the patient experienced a "numbness" sensation in the areas where the pain had previously occurred.

[0100]

[0126] Within two months of starting Axona®, all abnormal sensations, including scalp sensitivity, had resolved.

[0127] Axona® was discontinued after three months. Within six weeks, the pain returned. A third course of Axona® produced the same effect, with gradual reduction and healing of the pain.

Claims

1. 1. A composition comprising at least 95% pure tricaprylin for use in a method for treating or preventing headache in a subject in need thereof, comprising: The method comprises administering to the subject an effective amount of the composition. The composition.

2. The composition of claim 1, wherein the headache is a trigeminal autonomic headache.

3. The composition of claim 1 , wherein the headache is a migraine.

4. The composition described in claim 1, wherein the method is for the treatment or prevention of chronic migraine in a subject, and the subject experiences at least 15 migraine headaches over a consecutive 30-day period at baseline.

5. The composition described in claim 3, wherein the method results in a reduction in the number of migraine headache days by at least 2 days per month from baseline after at least 2 months of treatment.

6. 4. The composition of claim 3, wherein the method results in a reduction in migraine headache days of at least 4 days per month from baseline after at least 2 months of treatment.

7. The composition described in claim 4, wherein the method results in a reduction in the number of migraine headache days by at least 2 days per month from baseline after at least 2 months of treatment.

8. The composition described in claim 4, wherein the method results in a reduction in the number of migraine headache days by at least 4 days per month from baseline after at least 2 months of treatment.

9. The composition described in claim 4, wherein the method results in a reduction in the number of migraine headache days by at least 8 days per month from baseline after at least two months of treatment.

10. The composition described in claim 4, wherein the method results in a reduction in the number of migraine headache days by at least 10 days per month from baseline after at least two months of treatment.

11. The composition of claim 3, wherein the method provides improvement or remission of one or more symptoms of migraine selected from: change from baseline in duration of migraine headaches during treatment months 1, 2, or 3; change from baseline in duration of migraine headaches of moderate to severe intensity during treatment months 1, 2, or 3; proportion of participants with a 50% reduction from baseline in number of migraine headache days during treatment months 1, 2, or 3; proportion of participants with a 75% reduction from baseline in number of migraine headache days during treatment months 1, 2, or 3; proportion of participants with a 90% reduction from baseline in number of migraine headache days during treatment months 1, 2, or 3; change from baseline in use of monthly acute migraine medication during treatment months 1, 2, or 3; change from baseline to time to first use of acute migraine medication during treatment months 1, 2, or 3; change from baseline Headache Impact Test (HIT-6) score at the end of month 1, 2, or 3; occurrence of migraine-related adverse events including aura, nausea, and vomiting.

12. The composition of claim 4, wherein the method provides improvement or remission of one or more symptoms of migraine selected from: change from baseline in duration of migraine headaches during treatment months 1, 2, or 3; change from baseline in duration of migraine headaches of moderate to severe intensity during treatment months 1, 2, or 3; proportion of participants with a 50% reduction from baseline in number of migraine headache days during treatment months 1, 2, or 3; proportion of participants with a 75% reduction from baseline in number of migraine headache days during treatment months 1, 2, or 3; proportion of participants with a 90% reduction from baseline in number of migraine headache days during treatment months 1, 2, or 3; change from baseline in use of monthly acute migraine medication during treatment months 1, 2, or 3; change from baseline to time to first use of acute migraine medication during treatment months 1, 2, or 3; change from baseline Headache Impact Test (HIT-6) score at the end of month 1, 2, or 3; occurrence of migraine-related adverse events including aura, nausea, and vomiting.

13. 10. The composition of claim 1, wherein the tricaprylin is administered in an amount ranging from about 10 g / kg / day to about 60 g / kg / day of the compound in the composition.

14. 10. The composition of claim 1, administered orally in a single dose or in divided doses.

15. 10. The composition of claim 1, administered once, twice, or three times daily.

16. 10. The composition of claim 1, comprising at least about 30% by weight of the total composition of tricaprylin and one or more emulsion-forming excipients present in a concentration sufficient to form an emulsion that is stable under ambient conditions for at least one month.

17. 17. The composition of claim 16, wherein the one or more emulsion-forming excipients of the composition are selected from the group consisting of lecithin, hydrogenated castor oil, caprylic acid esters, sodium oleate, glycerol, citric acid esters of mono- and diglycerides, mono- and diglycerides of fatty acids including propylene glycol monocaprylate, and combinations thereof.

18. 17. The composition of claim 16, wherein the tricaprylin is present in the composition in an amount of about 30% to about 60% by weight of the total composition.

19. 17. The composition of claim 16, wherein the one or more emulsion-forming excipients are present in the composition in an amount from about 1% to about 10% by weight of the total composition.

20. 17. The composition of claim 16, wherein the stable emulsion exhibits an average particle size of less than 0.5 μm for at least one month at ambient conditions, preferably less than 0.3 μm for at least one month at ambient conditions, preferably less than 0.2 μm for at least one month at ambient conditions.

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