PRIORITY

This application claims priority to U.S. Provisional Application No. 63/116,891 filed November 22, 2020.

BACKGROUND

Cluster headache is a devastating, idiopathic pain syndrome, and the most severe type of the primary headache disorders. A cluster headache attack is characterized by unilateral orbital or periorbital pain, which is accompanied by ipsilateral autonomic features in the nose, eyes, and face. On average, a typical cluster headache attack lasts about 90 minutes, with some attacks lasting as few as fifteen minutes, while others can last up to three hours (May, 2005; IHS, 2018). The headache and facial pain that accompanies the attacks is so severe and excruciating that about 55% of cluster headache patients have reported having suicidal ideations (Rozen, 2012). The fact that over half of cluster headache patients have suicidal thoughts reflects the extent of the pain and its impact on daily life. Cluster headache was historically thought to be more prevalent among men than among women, occurring in a 3: 1 ratio of men to women (Rozen, 2012; Schurks, 2006). However, recent studies have reported ratios of 2: 1 of men to women, indicating a decreasing male predominance (Nunu Lund, 2017; Bahra 2002).

A cluster headache attack can occur from every other day up to eight times a day, and exhibits a remarkable circadian pattern, with attacks often occurring at the same time of the day with a tendency to occur in the evening. Furthermore, a predilection for a circadian pattern exists, with attack tendency increased in autumn and spring (Kudrow, 1987). Typically, attacks are accompanied by ipsilateral autonomic symptoms, such as ptosis, miosis, redness or flushing of the face, nasal congestion, rhinorrhea, peri -orbital swelling and/or restlessness or agitation.

There are two types of cluster headaches, classified as either chronic cluster headache (cCH), which accounts for about 15% of patients, or episodic cluster headache (eCH), which accounts for about 85% of patients. For cCH, remission periods are absent or last less than three months out of the year (IHS, 2018). For eCH, the attacks occur in ‘bouts’ (i.e. clusters) that last from weeks to months, and alternate with remission periods of months to years (IHS, 2013).

Cluster headache treatment entails fast-acting abortive treatment to effectively abort an ongoing attack, transitional treatment, and preventive treatment. Transitional treatment is also fast acting, but the effect usually lasts only a couple of weeks; it can bridge the gap between the start of prophylactic medication and adequate drug titration. The main goal in cluster headache treatment should always be to prevent all attacks. Unfortunately, attack freedom cannot always be achieved, especially in patients with cCH. For these patients, it is vital to have effective attack treatment options and to achieve the best effect/side effect ratio in close collaboration with the patient.

Current therapy mainly consists of pharmacotherapy, but neuromodulator treatment methods such as occipital nerve stimulation (de Coo I. F., 2017), (Miller, 2017), non-invasive vagal nerve stimulation (de Coo I. F., 2019), sphenopalatine ganglion stimulation (Fontaine, 2018) and blockade (Mojica, 2017), and local infdtration with anesthetics and corticosteroids have recently been tested.

The short duration and severity of cluster headache attacks calls for a fast-acting abortive treatment, but, to date, drugs that can effectively treat cluster attacks are limited. The most effective treatments have been 100% oxygen or subcutaneous sumatriptan (Becker, 2013).

Briefly inhaling pure oxygen through a mask provides dramatic relief for most who use it. The effects of this safe, inexpensive procedure can be felt within 15 minutes. Oxygen is generally safe and without side effects. The major drawback of oxygen is the need to carry an oxygen cylinder and regulator, which can make the treatment inconvenient and inaccessible at times. Small, portable units are available, but some people still find them impractical.

An injectable form of sumatriptan, known as Imitrex, which is commonly used to treat migraine, has been used for treatment of acute cluster headache. The first injection may be given while under medical observation. Some people may benefit from using sumatriptan in nasal spray form, but for most people this is not as effective as an injection and it may take longer to work. Sumatriptan is not recommended if one has uncontrolled high blood pressure or heart disease. Another triptan medication, zolmitriptan, known as Zomig, can be taken in nasal spray form for relief of cluster headache. This medication may be an option if one cannot tolerate other forms of fast-acting treatments.

SUMMARY

One general aspect of the invention includes a method of treating pain by administering an ergotamine and thymoquinone. In this embodiment, the ergotamine can be BOL-148, lysergic acid diethylamide (LSD), and lysergic acid amide (LSA). In a preferred embodiment, the ergotamine is BOL-148. In this embodiment, the thymoquinone can be Nigella sativa extract.

In an embodiment of the invention, the ergotamine and thymoquinone can be administered simultaneously or sequentially. In this embodiment, the ergotamine is administered within one hour of the thymoquinone.

In an embodiment of the invention, ergotamine and thymoquinone can be administered via oral administration, nasal administration, intravenous administration, intramuscular administration, parental administration, or topical administration. In a preferred embodiment, the administration is oral administration.

In an embodiment of the invention, the amount of ergotamine administered can be 0.01 to 10 mg, and the amount of thymoquinone administered can be 350-10,000 mg. In an embodiment of the invention, the method can further include administering melatonin, and in this embodiment the amount of melatonin administered can be 0.01-10 mg. In an embodiment of the invention, the method can also include administering a corticosteroid, an analgesic, or a triptan.

In an embodiment of the invention, the pain treated is a headache. In this embodiment, the headache is selected from tension headache, migraine headache, or cluster headache. In a preferred embodiment, the headache is cluster headache, and cluster headache can include both chronic cluster headache or episodic cluster headache.

Another general aspect of the invention includes a pharmaceutical composition including an ergotamine and thymoquinone. In this embodiment, the ergotamine can be BOL- 148, lysergic acid diethylamide (LSD), and lysergic acid amide (LSA). In a preferred embodiment, the ergotamine is BOL-148 (2-Bromolysergic acid diethylamide). In any embodiment, the thymoquinone can be Nigella sativa extract. The composition In some embodiments also includes melatonin, a corticosteroid, an analgesic, or a triptan. In a preferred embodiment, the composition further includes melatonin. In embodiments, the composition can further include one or more excipients.

DETAILED DESCRIPTION

The present invention teaches methods of treating pain and headaches, inclding but ot limited to tension headache, migraine headache, or cluster headache, by administration of i) an ergotamine and ii) thymoquinone (TQ). While non-hallucinogenic ergotamines are preferred, embodiments of the invention can include an ergotamine selected from the group consisting of BOL-148, lysergic acid diethylamide (LSD), and lysergic acid amide (LSA.) Methods according to the invention can further include administration of melatonin and/or various analgesics, corticosteroids, or triptans.

The present invention also teaches pharmaceutical compositions comprising i) an ergotamine, and ii) thymoquinone (TQ). Exemplary The ergotamine is selected from the group consisting of BOL-148, lysergic acid diethylamide (LSD), and lysergic acid amide (LSA). The thymoquinone can be provided as Nigella sativa extract, or as the isolated compound. The compositions can further include melatonin and/or various analgesics, corticosteroids, or triptans. The compositions can be formulated for oral, nasal, intravenous, intramuscular, parental, or topical administration, among others.

BOL-148

Recent evidence has indicated that psychedelics may be effective therapies for aborting acute cluster headache attacks than conventional treatments. Online interviews of cluster headache patients who had used either psilocybin or LSD to treat their condition found that 22 of 26 psilocybin users reported that psilocybin aborted attacks, and 25 of 48 psilocybin users and 7 of 8 LSD users reported cluster period termination. Extension of the remission period for attacks was reported by 18 of 19 psilocybin users and 4 of 5 LSD users (Sewell, 2006).

Despite cluster headaches being amenable to treatment with hallucinogenic drugs, such as LSD and psilocybin, because of the illegal status of these drugs and the kind of mental changes they induce, research into their medical use has been slow and therapeutic application limited to very specific circumstances under strict supervision. It had been thought that this specific therapeutic action against cluster headaches was limited to hallucinogenic drugs of this type, and therefore always presented a major barrier to their clinical use. However, a serendipitous discovery found that 2-bromo-LSD can treat cluster headaches.

2-Bromo-LSD, also known as BOL-148, is a derivative of lysergic acid invented by Albert Hofmann as part of the original research from which the closely related compound LSD was also derived. BOL-148 is inactive as a psychedelic and was barely studied for many years, although its behavior in the body is similar to LSD, making it useful for radiolabeling studies (Ginzel, 1956). BOL-148 was found to bind to many of the same receptors as LSD but acts as a neutral antagonist rather than an agonist.

Early reports examined the pharmacology of BOL-148 compared it with LSD, although not much conclusive evidence was found; however, it does appear that there likely is some overlap between the pharmacology of BOL-148 and LSD. For example, when 1 mg of BOL-148 was given three times a day for 5 days to 10 human volunteers, the effect of 1 pg/kg LSD was significantly attenuated (Isbell, 1959). If a single dose of 2-4 mg of BOL- 148 was given along with LSD, there was no effect on the LSD response. When 3 mg/d of BOL-148 was given for 2 days prior to LSD, a trend was observed but not a significant block of the LSD effect. Early in vitro studies showed that the “anti-serotonin” effect of BOL-148 was at least comparable to that of LSD (Cerletti, 1958), so downregulation of the 5-HT2A receptor by BOL-148 might be expected to block the effects of LSD. At the 5-HT2C receptor, however, BOL-148 is a silent antagonist and did not cause receptor downregulation at the choroid plexus 5-HT2C receptor, whereas the inverse agonist minanserin led to reduced 5-HT2C receptor density. However, BOL-148 generally has similar behavior to LSD in some respects that have been shown to be very useful in one specific area, the treatment of cluster headaches (Karst, 2010).

Three single oral doses of 30 pg/kg BOL-148 in five cluster headache sufferers could either break a cluster headache cycle or considerably decrease the frequency and intensity of attacks. The lack of psychedelic activity for BOL-148 clearly indicates that therapeutic efficacy in cluster headaches cannot be related to psychoactive effects, which presumably are manifested through the 5-HT2A receptor, but the mechanism of action remains unknown. It is likely that ergotamines, including BOL-148, LSD, dihydroergotamine, and methysergide, have positive treatment effects for headaches, including tension headache, migraine headache, and cluster headache through serotonin-receptor-mediated vasoconstriction.

Nigella sativa/Thymoquinone

Nigella sativa (NS), also known as black seed or black cumin, belonging to the Ranunculacea family, is an annual herb with many pharmacological properties (Ziaee, 2012). Nigella sativa has been used by healers in ancient civilizations as well as modern-day researchers, and has been established as a safe herbal product (Bamosa AO, 2010), (Bilal A, 2008), (Dehkordi FR, 2008), (Mohtashami R, 2015), (Bamosa, 2014). Traditionally, it has been used in different forms to treat many diseases including asthma, hypertension, diabetes, inflammation, cough, bronchitis, headache, eczema, fever, dizziness, and influenza. For example, soaking the seeds in the vinegar for one night and crushing them and smelling is a remedy for chronic headache (Beheshti et al., 2016). In Middle Eastern countries, Nigella sativa seed oil is used as an antiseptic, local analgesic, and for the treatment of asthma, bronchitis, rheumatism, and other inflammatory diseases (Y amell & Abascal, 2011).

Nigella sativa has been widely investigated for its biological activities and restorative potential, and has been demonstrated to have a wide range of activities such as diuretic, antihypertensive, anti-diabetic, anti-cancer, immune -modulatory, antimicrobial, anthelmintic, analgesics and calming, spasmolytic, bronchodilator, anti-inflammatory, anti-tussive, gastro- protective, hepato-protective, low density lipoprotein cholesterol decreasing, renal-protective and anti-oxidant properties (Abel-Salam, 2012; Keyhanmanesh et al., 2014a; Keyhanmanesh et al., 2014b; Kapoor, 2009; Hanafy & Hatem 1991; Abdel-Daim & Ghazy, 2015; Mousavi & Mohajeri, 2014; Pourbakhsh et al., 2014; Gholamnezhad et al., 2014; Dahri et al., 2005). Nigella sativa is also useful to treat a variety of diseases of the nervous system (Beheshi et al., 2016). Studies have shown that Nigella sativa hydro-alcoholic extracts have effects against neuronal damage and neurotoxicity (Hobbenaghi et al., 2014), (Al-Majed et al., 2006).

Numerous active compounds have been derived, distinguished, and reported in distinctive mixtures of Nigella sativa. Active compounds include thymoquinone (TQ) (30%- 48%), thymohydroquinone, dithymoquinone, p-cymene (7%-15%), carvacrol (6%-12%), 4- terpineol (2%-7%), t-anethole (l%-4%), the tricyclic sesquiterpene longifolene ( 1 %-8%), a- pinene, and thymol (R. M. Shrivastava, 2011). The seeds also contain various alkaloids, including the isoquinoline alkaloids nigellicimine and nigellicimine N-oxide, and pyrazole alkaloids or indazole ring bearing alkaloids which incorporate nigellidine and nigellicine (Khan MAU, 2003). Nigella sativa seeds additionally contain alpha-hederin, a water soluble pentacyclic triterpene, and saponin (Al-Jassir, 1992). Experimentally, it has been demonstrated that N. sativa extracts and the main constituent of their volatile oil, thymoquinone (TQ), possess antioxidant, anti-inflammatory and hepatoprotective properties (Khader & Eckl, 2014).

Neuron-protective effects have been studied in cultured hippocampal and cortical neurons treated simultaneously with thymoquinone and amyloid-P peptide (Api-42) for 72 h. TQ efficiently attenuated Api-42-induced neurotoxicity by improving cell viability. TQ has also been shown to inhibit mitochondrial membrane potential depolarization and the generation of reactive oxygen species caused by Api-42, and to restore synaptic vesicle recycling inhibition and to partially reverse the loss of spontaneous firing activity, and Api- 42 aggregation in vitro (Alhebshi et al., 2013).

Neither Nigella sativa nor thymoquinone have been used for the treatment of headaches, either alone or in combination with other actives.

Melatonin

Melatonin is produced by the pineal gland and plays a role in regulating circadian rhythms, including initiating and sustaining sleep. Secretion of melatonin is increased in darkness and suppressed by light; the process is regulated by the suprachiasmatic nucleus of the hypothalamus (Brzezinski, 1997). Circadian effects in cluster headache have been appreciated since at least the 1970s (Ferrari, 1979), and may suggest a therapeutic role for melatonin in the treatment thereof.

Melatonin has been used to treat a number of primary headache disorders (The International Classification of Headache Disorders, 3rd edition (beta version), 2013), including migraine, cluster headache, tension-type headache, hypnic headache, hemicrania continua, SUNCT/SUNA and primary stabbing headache. The level of evidence supporting melatonin’s efficacy in treating these disorders varies. For cluster headache and migraine there are randomized-placebo controlled trials. The mechanism of action of melatonin’s benefit in headache disorders is not known and may differ by headache disorder. Impact on the hypothalamus is one possibility, particularly in cluster headache and migraine where functional imaging studies have demonstrated the activation of the hypothalamus during attacks (Maniyar, 2014), (May, 1998); whereas for hypnic headache the occurrence of attacks exclusively out of sleep suggests chronobiological dysfunction and hypothalamic involvement. Notably there are melatonin receptors, MT1 and MT2, in the suprachiasmatic nucleus of the hypothalamus (Weaver, 1993), (Wu, 2013), so direct action of exogenous melatonin at the hypothalamus is possible.

During cluster periods, the timing and peak of endogenous melatonin release can become blunted or even absent (Nagtegaal, 1998), (Leone, 1992), (Leone, 1995), (Chazot, 1984), (Waldenlind, 1987). Exogenous melatonin supplementation may help by restoring these rhythms. However, there have been case reports of chronic cluster headache patients who have responded to melatonin — one responded within two days of initiation of melatonin at a dosage of 9 mg, and another found this dosage gave “immediate pain relief, with both daytime and nocturnal headaches completely abating” (Peres, 2001). One patient with delayed sleep phase syndrome and episodic cluster responded to melatonin at a dosage 5 mg nightly; although at one point the patient had to start taking it 2 hours earlier in order to phase shift his melatonin profde (Nagtegaal, 1998). Cluster headache is rare in children, however a case has been reported where a child responded to melatonin at a dosage of 3 mg twice daily (Arruda, 2011). These case reports suggest low dosage melatonin might be helpful in cluster headache.

Methods of Treatment

Methods of treatment of the present invention include treatment of pain by administration of an ergotamine selected from the group consisting of BOL-148, lysergic acid diethylamide (LSD), and lysergic acid amide (LSA), and ii) thymoquinone (TQ). The ergotamine and thymoquinone can be administered sequentially or simultaneously, and each can be administered 1, 2, 3, or 4 times per day. When administered sequentially, the ergotamine is preferably administered within an hour of the thymoquinone, or the thymoquinone is administered within an hour of the ergotamine. In exemplary embodiments, the ergotamine is BOL-148. The thymoquinone can be administered as the isolated compound, as Nigella sativa, or as a Nigella sativa extract. The methods can further include administration of melatonin, a corticosteroid, an analgesic, or a triptan. The melatonin, corticosteroid, analgesic, or triptan can be administered

1, 2, 3, or 4 times per day.

The amount of ergotamine, thymoquinone, and melatonin administered can be the same or different. The amounts may be delivered in a single dosage form or dosage forms with lesser amounts can be administered to achieve the dosage daily through multiple administrations. The dosages presented herein may be per dose or per day.

In an embodiment, the amount of ergotamine administered is 0.01-10,000 mg, 0.1- 10,000 mg, 1-10,000 mg, 0.01-1,000 mg, 1-1,000 mg, 0.01-500 mg, 1-500 mg, 0.01-100 mg, 1-100 mg, 0.01-50 mg, 1-50 mg, 0.01-30 mg, 1-30 mg, 0.01-10 mg, 1-10 mg, 0.01-5 mg, 1-5 mg, 0.01-3 mg, or 1-3 mg. In embodiments of the invention, the amount of ergotamine administered can be at least 0.01 mg, at least 0.1 mg, or at least 1 mg. In embodiments of the invention, the amount of ergotamine administered can be up to 10,000 mg, up to 1,000 mg, up to 500 mg, up to 100 mg, up to 50 mg, or up to 30 mg. The ergotamine can be administered 1, 2, 3, or 4 times per day.

In an embodiment, the amount of thymoquinone administered is 350-100,000 mg, 350-50,000 mg, 350-10,000 mg, 350-5,000 mg, 350-1,000 mg, or 350-500 mg. In embodiments of the invention, the amount of thymoquinone administered can be at least 350 mg. In embodiments of the invention, the amount of thymoquinone administered can be up to 100,000 mg, up to 50,000 mg, up to 10,000 mg, up to 5,000 mg, up to 1,000 mg, or up to 500 mg. The thymoquinone can be administered 1, 2, 3, or 4 times per day.

In an embodiment, the amount of melatonin administered is 0.01-10,000 mg, 0.1- 10,000 mg, 1-10,000 mg, 0.01-1,000 mg, 1-1,000 mg, 0.01-500 mg, 1-500 mg, 0.01-100 mg, 1-100 mg, 0.01-50 mg, 1-50 mg, 0.01-30 mg, 1-30 mg, 0.01-10 mg, 1-10 mg, 0.01-5 mg, 1-5 mg, 0.01-3 mg, or 1-3 mg. In embodiments of the invention, the amount of melatonin administered can be at least 0.01 mg, at least 0.1 mg, or at least 1 mg. In embodiments of the invention, the amount of melatonin administered can be up to 10,000 mg, up to 1,000 mg, up to 500 mg, up to 100 mg, up to 50 mg, or up to 30 mg. The melatonin can be administered 1,

2, 3, or 4 times per day.

Pain to be treated includes headaches. Headaches susceptible to treatment with the disclosed methods include, but are not limited to, tension headache, migraine headache, and cluster headache. Preferably, the headache to be treated is a cluster headache. Cluster headaches to be treated include both chronic cluster headache and episodic cluster headache.

The combination of the ergotamine’s serotonin receptor-mediated vasoconstriction together with thymoquinone’s modulation of calcitonin gene-related peptide (CGRP), and release in trigeminal ganglion neurons and brainstem, and stabilization of meningeal mast cells (MMCs), can deliver an enhanced effect in the treatment of pain, particularly headache pain, including tension headaches, migraines, and cluster headache. By combining the two modes of action of the ergotamine and thymoquinone, one can deliver a more effective treatment of headaches and pain associated with headaches.

Pharmaceutical Compositions

Pharmaceutical compositions according to the invention comprise i) an ergotamine selected from the group consisting of BOL-148, lysergic acid diethylamide (LSD), and lysergic acid amide (LSA), and ii) thymoquinone (TQ), or pharmaceutically acceptable salts thereof as an active ingredient together with one or more pharmaceutically acceptable carriers, excipients or diluents. In particular embodiments, the ergotamine is selected as BOL-148, due to its lack of psychedelic activity. The thymoquinone can be provided as Nigella sativa extract, or as the isolated compound. The compositions can further include melatonin, a corticosteroid, an analgesic, or a triptan. The amount of ergotamine, thymoquinone, and melatonin present in the compositions can be the same or different. The amounts may be delivered in a single dosage form or dosage forms with lesser amounts can be administered to achieve the dosage daily through multiple administrations. The dosages presented herein may be per dose or per day.

In an embodiment, the amount of ergotamine in the pharmaceutical composition is 0.01-10,000 mg, 0.1-10,000 mg, 1-10,000 mg, 0.01-1,000 mg, 1-1,000 mg, 0.01-500 mg, 1- 500 mg, 0.01-100 mg, 1-100 mg, 0.01-50 mg, 1-50 mg, 0.01-30 mg, 1-30 mg, 0.01-10 mg, 1- 10 mg, 0.01-5 mg, 1-5 mg, 0.01-3 mg, or 1-3 mg. In embodiments of the invention, the amount of ergotamine in the pharmaceutical composition can be at least 0.01 mg, at least 0. 1 mg, or at least 1 mg. In embodiments of the invention, the amount of ergotamine in the pharmaceutical composition can be up to 10,000 mg, up to 1,000 mg, up to 500 mg, up to 100 mg, up to 50 mg, or up to 30 mg. The dosage amount of ergotamine in the pharmaceutical composition can be adjusted to be administered 1, 2, 3, or 4 times per day. In an embodiment, the amount of thymoquinone in the pharmaceutical composition is 350-100,000 mg, 350-50,000 mg, 350-10,000 mg, 350-5,000 mg, 350-1,000 mg, or 350-500 mg. In embodiments of the invention, the amount of thymoquinone in the pharmaceutical composition can be at least 350 mg. In embodiments of the invention, the amount of thymoquinone in the pharmaceutical composition can be up to 100,000 mg, up to 50,000 mg, up to 10,000 mg, up to 5,000 mg, up to 1,000 mg, or up to 500 mg. The dosage amount of thymoquinone in the pharmaceutical composition can be adjusted to be administered 1, 2, 3, or 4 times per day.

In an embodiment, the amount of melatonin in the pharmaceutical composition is 0.01-10,000 mg, 0.1-10,000 mg, 1-10,000 mg, 0.01-1,000 mg, 1-1,000 mg, 0.01-500 mg, 1- 500 mg, 0.01-100 mg, 1-100 mg, 0.01-50 mg, 1-50 mg, 0.01-30 mg, 1-30 mg, 0.01-10 mg, 1- 10 mg, 0.01-5 mg, 1-5 mg, 0.01-3 mg, or 1-3 mg. In embodiments of the invention, the amount of melatonin in the pharmaceutical composition can be at least 0.01 mg, at least 0. 1 mg, or at least 1 mg. In embodiments of the invention, the amount of melatonin in the pharmaceutical composition can be up to 10,000 mg, up to 1,000 mg, up to 500 mg, up to 100 mg, up to 50 mg, or up to 30 mg. The dosage amount of melatonin in the pharmaceutical composition can be adjusted to be administered 1, 2, 3, or 4 times per day.

Preferably the composition is packaged for delivery in a unit dosage form comprising 0.01-10,000 mg of the ergotamine and 350-100,000 mg of thymoquinone. The unit dosage form can further preferably include 0.01-10,000 mg of melatonin. A unit dosage as defined herein is a maximum dose of medication that can be taken at any one time or within a specified dosage period, for example, 4 hours.

The pharmaceutical compositions can further include, in addition to or in place of melatonin, an analgesic known to be effective in the treatment of headaches, or a cluster headache drug. Analgesics include, but are not limited to, ibuprofen, aspirin, acetaminophen, naproxen, and ketoprofen. Other cluster headache drugs that can be administered with the present invention include, but are not limited to, analgesics, corticosteroids, and triptans. Triptans include, but are not limited to, sumatriptan and zolmitriptan.

Any conventional technique may be used for the preparation of pharmaceutical composition according to the invention. The active ingredient may be contained in a composition that provides quick release, sustained release, or delayed release after administration to the patient. Pharmaceutical compositions of the invention may be prepared, packaged, or sold in formulations suitable for oral, nasal, parenteral, and topical administration. The formulations of the pharmaceutical compositions described herein may be prepared by any method known or hereafter developed. In general, preparation includes bringing the active ingredient into association with a carrier or one or more other additional components, and then, if necessary or desirable, shaping or packaging the product into a desired single- or multi -dose unit.

As used herein, “additional components” include, but are not limited to, one or more of the following: excipients; surface active agents; dispersing agents; inert diluents; granulating and disintegrating agents; binding agents; lubricating agents; sweetening agents; flavoring agents; coloring agents; preservatives; physiologically degradable compositions such as gelatin; aqueous vehicles and solvents; oily vehicles and solvents; suspending agents; dispersing or wetting agents; emulsifying agents, demulcents; buffers; salts; thickening agents; fillers; emulsifying agents; antioxidants; stabilizing agents; pharmaceutically acceptable polymeric or hydrophobic materials as well as other components.

A formulation of a pharmaceutical composition of the invention suitable for oral administration may in the form of a discrete solid dosage unit. Solid dosage units include, for example, a tablet, a caplet, a hard or soft capsule, a cachet, a troche, or a lozenge. Each solid dosage unit contains a predetermined amount of the active ingredient, for example a unit dose or fraction thereof. Other formulations suitable for administration include, but are not limited to, a powdered or granular formulation, an aqueous or oily suspension, an aqueous or oily solution, or an emulsion. As used herein, an “oily” liquid is one which comprises a carbon or silicon-based liquid that is less polar than water.

A tablet comprising the active ingredients may be made, for example, by compressing or molding the active ingredients, optionally containing one or more additional components. Compressed tablets may be prepared by compressing, in a suitable device, the active ingredients in a free-flowing form such as a powder or granular preparation, optionally mixed with one or more of a binder, a lubricant, a glidant, an excipient, a surface active agent, and a dispersing agent. Molded tablets may be made by molding, in a suitable device, a mixture of the active ingredients, a pharmaceutically acceptable carrier, and at least sufficient liquid to moisten the mixture.

Tablets may be non-coated or they may be coated using methods known in the art or methods to be developed. Coated tablets may be formulated for delayed disintegration in the gastrointestinal tract of a subject, for example, by use of an enteric coating, thereby providing sustained release and absorption of the active ingredient. Tablets may further comprise a sweetening agent, a flavoring agent, a coloring agent, a preservative, or some combination of these in order to provide pharmaceutically elegant and palatable preparation.

Hard capsules comprising the active ingredients may be made using a physiologically degradable composition, such as gelatin. Such hard capsules comprise the active ingredients, and may further comprise additional components including, for example, an inert solid diluent. Soft gelatin capsules comprising the active ingredients may be made using a physiologically degradable composition, such as gelatin. Such soft capsules comprise the active ingredients, which may be mixed with water or an oil medium.

Liquid formulations of a pharmaceutical composition of the invention which are suitable for administration may be prepared, packaged, and sold either in liquid form or in the form of a dry product intended for reconstitution with water or another suitable vehicle prior to use. Liquid formulations may be prepared for oral, topical, nasal, or injectable administration. Injectable administration includes intravenous, intramuscular and peritoneal administration.

Liquid suspensions, in which the active ingredients are dispersed in an aqueous or oily vehicle, and liquid solutions, in which the active ingredients are dissolved in an aqueous or oily vehicle, may be prepared using conventional methods or methods to be developed. Liquid suspension of the active ingredients may be in an aqueous or oily vehicle and may further include one or more additional components such as, for example, suspending agents, dispersing or wetting agents, emulsifying agents, demulcents, preservatives, buffers, salts, flavorings, coloring agents, and sweetening agents. Oily suspensions may further comprise a thickening agent. Liquid solutions of the active ingredients may be in an aqueous or oily vehicle and may further include one or more additional components such as, for example, preservatives, buffers, salts, flavorings, coloring agents, and sweetening agents.

Powdered and granular formulations according to the invention may be prepared using known methods or methods to be developed. Such formulations may be administered directly to a subject, or used, for example, to form tablets, to fill capsules, or to prepare an aqueous or oily suspension or solution by addition of an aqueous or oily vehicle thereto. Powdered or granular formulations may further comprise one or more of a dispersing or wetting agent, a suspending agent, and a preservative. Additional excipients, such as fillers and sweetening, flavoring, or coloring agents, may also be included in these formulations.

A pharmaceutical composition of the invention may also be prepared, packaged, or sold in the form of oil-in-water emulsion or a water-in-oil emulsion. Such compositions may further comprise one or more emulsifying agents. These emulsions may also contain additional components including, for example, sweetening or flavoring agents.

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