WO2020053662A2 - Non-aqueous solutions for oral dosage - Google Patents

Abstract

Pharmaceutical compositions comprising a vehicle, a solubilizer, and a surfactant are disclosed to be used in conjunction with non-chemotherapeutic active pharmaceutical ingredients which are water soluble, or insoluble, or which are sensitive to water, but miscible in oil. Such non-chemotherapeutic active pharmaceutical ingredients may include topiramate, felodipine, fesoterodine, isradipine, nifedipine, nimodipine, nisoldipine, sodium valproate, omeprazole, Esomeprazole, Rabeprazole, Pentoprazole, methimazole, a derivative thereof, or a combination thereof. The pharmaceutical compositions may be administered as an oral solution. Other embodiments are directed towards methods of using and methods of making such formulations.

Description

NON-AQUEOUS SOLUTIONS FOR ORAL DOSAGE

Priority

[0001] This application claims priority to Indian Provisional Application No. IN201821034589 filed on September 13, 2018, titled“Non-aqueous Solutions for Oral Dosage” and is incorporated herein by reference.

Summary

[0002] Embodiments herein are directed to a pharmaceutical composition in the form of anon-aqueous liquid solution for active pharmaceutical ingredients. In some embodiments, the pharmaceutical composition comprises an active pharmaceutical ingredient, a vehicle, a surfactant, and a solubilizer. In some embodiments, the active pharmaceutical ingredient is water soluble, insoluble, sensitive to water, or miscible in oil. In some embodiments, the active pharmaceutical ingredient is a non-chemotherapeutic active pharmaceutical ingredient. In some embodiments, the active pharmaceutical ingredient may be selected from topiramate, felodipine, fesoterodine, isradipine, nifedipine, nimodipine, nisoldipine, sodium valproate, omeprazole, Esomeprazole, Rabeprazole, Pentoprazole, methimazole, a derivative thereof, or a combination thereof. In some embodiments, the pharmaceutical composition does not include a chemotherapeutic active pharmaceutical ingredient. In some embodiments, the pharmaceutical composition does not include a chemotherapeutic active pharmaceutical ingredient which is soluble in water, insoluble in water, or sensitive to water.

[0003] In some embodiments, the vehicle may be an oil. In some embodiments, the vehicle may be a medium chain fatty acid. In some embodiments, the medium chain fatty acid may be any fatty acid having from 6 to 12 carbon atoms. For example, the medium chain fatty acid may be selected from caproic acid (C6), caprylic acid (C8), capric acid (C10), or lauric acid (C12). In some embodiments, the vehicle is coconut oil, arachis oil, soya bean oil, castor oil, com oil, safflower oil, olive oil, apricot kernel oil, sesame oil, cotton seed oil, sunflower seed oil, palm oil, rapeseed oil, mineral oil, or a combination thereof. In some embodiments, the vehicle may be selected from caproic triglyceride, caprylic triglyceride, capric triglyceride, lauric triglyceride, or a combination thereof. In some embodiments, the vehicle is medium-chain triglycerides (MCTs), which comprise medium-chain (6 to 12 carbons) fatty acid esters of glycerol. Examples of MCTs which may be used in embodiments herein include MIGLYOL, made from various distillation fractions of coconut oil, palm kernel oil, camphor tree drupes, or combinations thereof. In some embodiments, the oil is Kollisolv MCT 70.

[0004] In some embodiments, the surfactant may be sorbitan esters (Span) of saturated or unsaturated fatty acids, polyethoxylated sorbitan esters (Tween) of saturated or unsaturated fatty acids, Caprylocaproyl macrogol-8 glycerides (Labrasol), Lauroyl macrogol- 32 glycerides (Gelucire 44/14), stearoyl macrogol- 32 glycerides (Gelucire 50/13), polyethoxylated and/or hydroginated castor oils such as PEG-40 hydrogenated castor oil (Cremophor RH 40®), PEG-60 hydrogenated castor oil (Cremophor RH 60®), PEG-35 castor oil, polyoxyl 35 castor oil (Cremophor EL), Macrogol (25) cetostearyl ether (Cremophor A25), polyethoxylated ethers from saturated or unsaturated fatty alcohols, polyethylene glycol such as PEG 200, poloxamer (Lutrol F 127), alpha tocopherol, polyoxyethylene lauryl ether (Biji 30, Brji 35), polyvinyl caprolactam-polyvinylacetate- polyethyleneglycol graft copolymer (e.g. Soluplus®), PEG-35 castor oil, or a combination thereof.

[0005] In some embodiments, the solubilizer is an alcohol. In some embodiments, the alcohol may be selected from ethanol, propylene glycol, polyhydric alcohols such as concentrated glycerol, glycerol, polyvinyl alcohol, propylene glycol, ethylene glycol, or a combination thereof.

[0006] In some embodiments, the pharmaceutical composition may further comprise an antioxidant, a sweetener, a flavoring agent, a buffering agent, a sweetness/flavor enhancing agent, a chelating agent, a preservative, or any combination thereof.

[0007] Some embodiments are directed to a methods of using the pharmaceutical composition disclosed herein for the treatment of diseases or disorders. In some embodiments, the disease or disorder comprises seizures, partial onset seizures, seizures associated with Lennox-Gastaut syndrome, generalized tonic-clonic seizures, migraine headaches, bipolar disorder, epilepsy, alcoholism, ***e and tobacco addiction, diabetes, neuropathic pain, diabetic neuropathic pain, obesity, sleep disorders, sleep-related eating disorders, post-traumatic stress disorder, depression, cluster headaches, or a combination thereof. In some embodiments, the pharmaceutical composition comprises topiramate.

[0008] In some embodiments, a method of treating a seizure in a subject in need thereof comprises administering to the subject the pharmaceutical composition disclosed herein. In some embodiments, the pharmaceutical composition comprises topiramate.

[0009] In some embodiments, a method of preventing a migraine headache in a subject in need thereof comprises administering to the subject the pharmaceutical composition disclosed herein. In some embodiments, the pharmaceutical composition comprises topiramate.

[0010] In some embodiments, the pharmaceutical composition comprises about 1 wt% to about 30 wt% active pharmaceutical ingredient, about 1 wt% to about 20 wt% surfactant, about 0.1 wt% to about 40 wt% solubilizer, and about 0.1 wt% to about 99 wt% of a vehicle.

Detailed Description

[0011] Before the present compositions and methods are described, it is to be understood that this invention is not limited to the particular processes, formulations, compositions, or methodologies described, as these may vary. It is also to be understood that the terminology used in the description is for the purpose of describing the particular versions or embodiments only, and is not intended to limit the scope of embodiments herein which will be limited only by the appended claims. Unless defined otherwise, all technical and scientific terms used herein have the same meanings as commonly understood by one of ordinary skill in the art. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of embodiments disclosed herein, the preferred methods, devices, and materials are now described. All publications mentioned herein are incorporated by reference in their entirety. Nothing herein is to be construed as an admission that embodiments herein is not entitled to antedate such disclosure by virtue of prior invention.

[0012] It must also be noted that as used herein and in the appended claims, the singular forms“a,”“an,” and“the” include plural reference unless the context clearly dictates otherwise. Thus, for example, reference to a“surfactant” is a reference to one or more surfactants and equivalents thereof known to those skilled in the art, and so forth.

[0013] As used herein, the term “about” means plus or minus 10% of the numerical value of the number with which it is being used. Therefore, about 50% means in the range of 45%-55%.

[0014] “Administering” when used in conjunction with a therapeutic means to administer a therapeutic directly into or onto a target tissue or to administer a therapeutic to a patient whereby the therapeutic positively impacts the tissue to which it is targeted. Thus, as used herein, the term “administering”, when used in conjunction with an active pharmaceutical ingredient, can include, but is not limited to, providing the active pharmaceutical ingredient into or onto the target tissue; or providing the active pharmaceutical ingredient systemically to a patient by, e.g., intravenous injection whereby the therapeutic reaches the target tissue;. “Administering” a composition may be accomplished by injection, topical administration, orally, or by either method in combination with other known techniques. In some embodiments, administering is through an oral route of administration.

[0015] The term“subject” as used herein includes, but is not limited to, humans and non-human vertebrates such as wild, domestic, and farm animals. In certain embodiments, the subject described herein is an animal. In certain embodiments, the subject is a mammal. In certain embodiments, the subject is a human. In certain embodiments, the subject is a non-human animal. In certain embodiments, the subject is a non-human mammal. In certain embodiments, the subject is a domesticated animal, such as a dog, cat, cow, pig, horse, sheep, or goat. In certain embodiments, the subject is a companion animal such as a dog or cat. In certain embodiments, the subject is a livestock animal such as a cow, pig, horse, sheep, or goat. In certain embodiments, the subject is a zoo animal. In another embodiment, the subject is a research animal such as a rodent, dog, or non-human primate. In certain embodiments, the subject is a non-human transgenic animal such as a transgenic mouse or transgenic pig.

[0016] The term“improve” is used to convey that the compounds of embodiments herein change either the appearance, form, characteristics and/or the physical attributes of the tissue to which it is being provided, applied or administered.

[0017] The term “inhibit” includes the administration of a compound of embodiments herein to prevent the onset of the symptoms, alleviating the symptoms, or eliminating the disease, condition or disorder.

[0018] By "pharmaceutically acceptable", it is meant the carrier, diluent or excipient must be compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.

[0019] As used herein, the term“therapeutic” means an agent utilized to treat, combat, inhibit, ameliorate, prevent or improve an unwanted condition or disease of a patient.

[0020] A “therapeutically effective amount” or “effective amount” of a composition is a predetermined amount calculated to achieve the desired effect. The activity contemplated by the present methods includes both medical therapeutic and/or prophylactic treatment, as appropriate. The specific dose of a compound administered according to this invention to obtain therapeutic and/or prophylactic effects will, of course, be determined by the particular circumstances surrounding the case, including, for example, the compound administered, the route of administration, concomitant therapies and the condition being treated. However, it will be understood that the effective amount administered will be determined by the physician in the light of the relevant circumstances including the condition to be treated, the choice of compound to be administered, and the chosen route of administration, and therefore the above dosage ranges are not intended to limit the scope of embodiments herein in any way. A therapeutically effective amount of a compound of this disclosure is typically an amount such that when it is administered in a physiologically tolerable excipient composition, it is sufficient to achieve an effective systemic concentration or local concentration in the tissue.

[0021] The terms "treat," "treated," or "treating," as used herein, refers to both therapeutic treatment and prophylactic or preventative measures, wherein the object is to inhibit, prevent or slow down (lessen) an undesired physiological condition, disorder or disease, or to improve, inhibit, or otherwise obtain beneficial or desired clinical results. For the purposes of this invention, beneficial or desired clinical results include, but are not limited to, improvement or alleviation of symptoms; diminishment of the extent of the condition, disorder or disease; stabilization (z.e., not worsening) of the state of the condition, disorder or disease; delay in onset or slowing of the progression of the condition, disorder or disease; amelioration of the condition, disorder or disease state; and remission (whether partial or total), whether detectable or undetectable, or enhancement or improvement of the condition, disorder or disease. Treatment includes eliciting a clinically significant response without excessive levels of side effects. Treatment also includes prolonging survival as compared to expected survival if not receiving treatment.

[0022] As used herein, the term“a derivative thereof’ refers to a salt thereof, a pharmaceutically acceptable salt thereof, an ester thereof, a free acid form thereof, a free base form thereof, a solvate thereof, a deuterated derivative thereof, a hydrate thereof, an N-oxide thereof, a clathrate thereof, a prodrug thereof, a polymorph thereof, a stereoisomer thereof, a geometric isomer thereof, a tautomer thereof, a mixture of tautomers thereof, an enantiomer thereof, a diastereomer thereof, a racemate thereof, a mixture of stereoisomers thereof, an isotope thereof (e.g., tritium, deuterium), or a combination thereof. In some embodiments, the active pharmaceutical ingredient may be administered as a derivative thereof.

[0023] The transitional term “comprising,” which is synonymous with “including,”“containing,” or“characterized by,” is inclusive or open-ended and does not exclude additional, unrecited elements or method steps. By contrast, the transitional phrase “consisting of’ excludes any element, step, or ingredient not specified in the claim. The transitional phrase“consisting essentially of’ limits the scope of a claim to the specified materials or steps “and those that do not materially affect the basic and novel characteristic(s)” of the claimed invention.

[0024] In embodiments or claims where the term“comprising” is used as the transition phrase, such embodiments can also be envisioned with replacement of the term “comprising” with the terms“consisting of’ or“consisting essentially of.”

[0025] As used herein, the term“consists of’ or“consisting of’ means that the composition, formulation or the method includes only the elements, steps, or ingredients specifically recited in the particular claimed embodiment or claim.

[0026] As used herein, the term“consisting essentially of’ or“consists essentially of’ means that the composition, formulation or the method includes only the elements, steps or ingredients specifically recited in the particular claimed embodiment or claim and may optionally include additional elements, steps or ingredients that do not materially affect the basic and novel characteristics of the particular embodiment or claim. For example, the only active pharmaceutical ingredient(s) in the formulation or method that treats the specified condition (e.g. seizures) is the specifically recited therapeutic(s) in the particular embodiment or claim.

[0027] The weight percentages disclosed herein may be weight-to-weight, weight- to-volume, or volume-to-volume percentages, as appropriate.

[0028] Topiramate is used to prevent both partial onset and generalized seizures and is approved to treat simple partial seizures, complex partial seizures, and generalized tonic-clonic seizures in both children and adults. It is also indicated for treatment of Lennox - Gastaut syndrome (a disorder that causes seizures and developmental delays) in children.

[0029] There are three classifications of partial seizures: simple, complex, and secondarily generalized. A simple partial seizure usually manifests as jerking or shaking in one area of the body, which may progress to other areas. Simple partial seizures may also manifest with somatosensory, visual, auditory, olfactory, autonomic (sweating, pupillary dilation, epigastric rising), or psychiatric symptoms. In the case of complex partial seizures, the patient's consciousness may also be impaired. Patients experiencing a complex partial seizure will often exhibit a blank stare followed by automatism, which may include lip smacking, chewing, picking at clothing, or purposeless walking. Secondarily generalized seizures can evolve directly from simple partial or complex partial seizures, or progress from simple partial to complex partial to generalized. [0030] Generalized seizures involve a loss of consciousness and may or may not be convulsive. Absence seizures (formerly called“petit mal”) may be typical or atypical. The symptoms of typical absence seizures include a blank stare, eye blinking, and in some instances automatisms, and the patient may experience increased or decreased tone. These brief seizures tend to occur in groups and can occur 50 to 100 times in a day. Atypical absence seizures begin and end less abruptly than the typical absence seizures, but last longer and result in more pronounced changes in tone.

[0031] Myoclonic seizures manifest with quick, involuntary muscle jerks, which may be isolated to one part of the body or involve the entire body. Myoclonic seizures may accompany other generalized seizures and are common to specific epilepsy syndromes. Tonic seizures are generally associated with other epileptic syndromes and typically last less than a minute. Tonic seizures involve violent spasm or stiffening, and in many instances the lower extremities are extended and the upper extremities are flexed. In addition, the patient may turn the head or eyes to one side. Clonic seizures, most common in neonates and children, also exhibit repetitive muscular jerks but at a slower rate, and while clonic seizures can last as long as several minutes, brief episodes are more common.

[0032] Generalized tonic-clonic seizures (also called“grand mal”) can occur at any age but are rare in very young infants. The seizures start with a sudden-onset tonic phase, typically lasting less than a minute, with all of the skeletal muscles contracting at once causing the patient to fall stiffly. In addition, the patient's diaphragm and chest muscles contract, forcing out air in a sigh or“epileptic cry.” During the clonic phase, the patient may clench the jaws, biting the inside of the cheek or side of the tongue with the molars, and consciousness may not return for 10 to 15 minutes. The episode may result in feeling confusion, fatigue, and headache, which can last several hours to several days.

[0033] Atonic seizures result in a sudden loss of postural tone, causing the patient to fall. After a few seconds, the patient regains full consciousness. Atonic seizures are commonly associated with other seizure types and are common in Lennox-Gastaut syndrome.

[0034] Other epileptic conditions include juvenile myoclonic epilepsy and Lennox-Gastaut syndrome. Juvenile myoclonic epilepsy is a generalized, idiopathic epileptic syndrome, often exhibiting three seizure types: myoclonic, absence, and generalized tonic- clonic. Lennox-Gastaut syndrome may be symptomatic (brain lesion identified) or cryptogenic (brain lesion assumed), and the generalized syndrome may include atypical absence, tonic, atonic, and tonic-clonic seizures. Patients suffering from Lennox-Gastaut syndrome also have varying degrees of psychomotor retardation. [0035] Memory impairment, mental slowing and attention deficits are the most frequently reported cognitive disorders in people with epilepsy and sometimes patients can find these cognitive consequences more debilitating than the actual seizures. Cognitive deficits in epilepsy are likely to be attributed to three key factors: the syndrome itself, the seizures, and the effect of the anti epileptic drug used for seizure control. The cognitive side effects of anti-epileptic drugs are particularly important in cognitively vulnerable populations such as children and elderly subjects. For example, side effects that manifest as minor cognitive impairments when observed in adults can cause extensive learning and cognition difficulties in children.

[0036] In addition to its use as an anticonvulsant, topiramate is most frequently prescribed for migraine prophylaxis. Migraine is a severe form of recurrent headache typically accompanied by dizziness, nausea, vomiting or extreme sensitivity to light and sound. The classic migraine type may begin with aura, which consists of episodes of well- defined, transient focal neurological dysfunction that develops over the course of minutes and may last up to an hour.

[0037] Migraine treatment has progressed greatly over the last decade but unfortunately, prophylactic treatment of migraine has lagged behind acute care treatment. Beta-adrenergic blockers, calcium channel antagonists, antidepressant medications, and antiepileptic drugs (AEDs) have primary indications for other medical conditions but are commonly used for the prophylactic pharmacotherapy of migraine. For migraine prophylaxis preventive medications are typically selected by efficacy, adverse reactions, patient preference, co-occurrence of illness, and cost. The overall goals of prophylactic migraine therapy are to reduce the frequency and severity of migraine attacks, to make acute migraine attacks more responsive to abortive therapy and to improve the quality of life for patients. Many classes of drugs have been used but the prophylactic pharmacotherapy of migraine is less than satisfactory, because of poor efficacy, associated unacceptable side effects, tachyphylaxis and drug interactions.

[0038] Topiramate has been approved by FDA for migraine prophylaxis. Topiramate has numerous effects on the central nervous system, including neuronal excitability blockade and on excitatory amino acids, which are considered to be involved in the pathophysiology of migraine. Due to these effects, topiramate has been used for preventive management of chronic and intractable migraine.

[0039] Topiramate has been used by psychiatrists to treat bipolar disorder, although it is not FDA approved for this purpose. Because it is also one of only three AEDs that have a statistically proven propensity to induce weight loss, the drug has been investigated for use in treatment of obesity, especially to aid in the reduction of binge eating. Topiramate is useful for neuropathic pain relief. In some groups of patients, diabetics for example, the potential of weight loss is desirable and may therefore be a major reason for using this medication for the treatment of diabetic neuropathic pain.

[0040] Other investigational uses of topiramate include treating alcoholism, ***e and tobacco addiction, sleep disorders, sleep-related eating disorders, post-traumatic stress disorder, depression, and cluster headache.

[0041] For the treatment of epilepsy, the recommended dosage of Topamax® is 400 mg/day typically taken in two divided doses (Physicians' Desk Reference, Thompson Healthcare, 56th Ed., pp. 2590-2595 (2002)). Lower doses than 400 mg/day (50-200 mg/day) are typically used for treating cluster headache and migraine prevention in non-epileptic subjects. Topiramate pharmacokinetics are linear, producing a dose-proportional increase in blood plasma concentration levels with increased dosing. Further, topiramate treatment has shown no evidence of patients developing drug tolerance with prolonged treatment over time. Following oral administration of an immediate release dosage form, topiramate is rapidly absorbed with peak plasma drug concentrations noted in approximately 2 hours. The mean elimination half-life is about 21 hours. Topiramate pharmacokinetics are also not significantly affected by food.

[0042] The currently marketed immediate release topiramate formulation (Topamax®) is not ideal as it is associated with poor patient compliance as well as treatment- emergent side effects that lead to poor patient tolerance. The pharmacokinetics of the Topamax lead to high Cmax-related adverse effects including paresthesia, drowsiness, nausea, and vomiting, weight loss, ataxia, taste perversion and renal calculi. The most frequently reported adverse effects include behavioral and cognitive difficulties with an incidence of almost 50% in one retrospective review of 174 patients ((Kellet et al. J. Neurol. Neurosurg and Psych. 1999; 66:759-763). Similar results were also observed in various other studies (Thompson et al. J. Neurol. Neurosurg and Psych. 2000; 69:634-641 and Meador et al. Neurology 2005; 64: 2108-2114). Decline in verbal frequency, attention, processing speed and working memory were seen for Topamax in another adjunctive study of patients with epilepsy (Lee et al. Epilepsia 2003; 44: 339-347). The negative cognition effects of Topamax are especially important to those who require maximal cognitive efficiency in their jobs and daily activities. [0043] The time it takes for topiramate to reach peak plasma levels (i.e., about two hours) also limits its effective use in the treatment of some conditions, such as neuropathic pain. Therefore, improved dosage forms of topiramate are needed in order to increase the safety, effectiveness, and utility of the compound.

[0044] Embodiments herein are directed to a pharmaceutical composition in the form of non-aqueous liquid solution for active pharmaceutical ingredients. In some embodiments, the pharmaceutical composition comprises an active pharmaceutical ingredient, a vehicle, a surfactant, and a solubilizer. In some embodiments, the active pharmaceutical ingredient is water soluble, insoluble, sensitive to water, or miscible in oil. In some embodiments, the pharmaceutical composition disclosed herein does not include a chemotherapeutic active pharmaceutical ingredient. In some embodiments, the active pharmaceutical ingredient is a non-chemotherapeutic pharmaceutical ingredient.

[0045] In some embodiments, the active pharmaceutical ingredient may be selected from topiramate, felodipine, fesoterodine, isradipine, nifedipine, nimodipine, nisoldipine, sodium valproate, omeprazole, Esomeprazole, Rabeprazole, Pentoprazole, methimazole, a derivative thereof, or a combination thereof. Other non-limiting anti convulsants (APIs) that may be present in the compositions include divaprex, phenobarbital, methlyphenobarbital, metharbital, barbexaclone, stiripentol, clobazam, clonazepam, clorazepate, diazepam, midazolam, lorazepam, nitrazepam, temazepam, nimetazepam, potassium bromide, felbamate, carbamazepine, oxcarbazepine, progabide, tiagabine, gabapentin, pregabalin, ethotoin, phenytoin, mephenytoin, fosphenytoin, paramethadione, trimethadione, ethadione, beclaminde, primidone, brivaracetam, levetiracetam, seletracetam, ethsuximide, phesuximide, mesuximide, acetazol amide, sulthiame, methazolamide, zonisamide, lamotrigine, pheneturide, phenacemide, valpromide, valnoctamide, or a pharmaceutically acceptable salt.

[0046] In some embodiments, the active pharmaceutical ingredient is water soluble, insoluble, or sensitive to water. The definition of solubility is as per the ETnited States Pharmacopoeia as shown below in Table 1 :

TABLE 1 : SOLUBILITY

[0047] Alternatively, according to the Biopharmaceutics Classification System (BCS), a drug is considered to be poorly water-soluble if its highest dose strength is not soluble in 250 mL or less of aqueous media over the pH range of 1 to 7.5. In some embodiments, the pharmaceutical composition may be used with any BCS Class 2 or Class 4 non-chemotherapeutic agent. In some embodiments, the pharmaceutical composition may be used with any Biopharmaceutics Drug Disposition Classification System (BDDCS) Class 2 or Class 4 non-chemotherapeutic agent. Currently, 90% of orally administered drugs in clinical development are categorized as BCS/BDDCS II or IV and 40% fail because of insufficient biopharmaceutical properties such as poor drug solubility and sensitivity. This underlines the need for improved pharmaceutical formulations to deliver these therapeutics.

[0048] In some embodiments, the active pharmaceutical ingredient is present in the pharmaceutical composition in an effective amount of about 0.1 mg/mL, about 0.5 mg/mL, about 1 mg/mL, about 1.5 mg/mL, about 2 mg/mL, about 2.5 mg/mL, about 3 mg/mL, about 3.5 mg/mL, about 4 mg/mL, about 4.5 mg/mL, about 5 mg/mL, about 5.5 mg/mL, about 6 mg/mL, about 7 mg/mL, about 8 mg/mL, about 9 mg/mL, about 10 mg/mL, about 12 mg/mL, about 14 mg/mL, about 16 mg/mL, about 18 mg/mL, about 20 mg/mL, about 22 mg/mL, about 25 mg/mL, about 27 mg/mL, about 30 mg/mL, about 40 mg/mL, about 50 mg/mL, about 60 mg/mL, about 70 mg/mL, about 80 mg/mL, about 90 mg/mL, about 100 mg/mL, about 150 mg/mL, about 200 mg/mL, about 250 mg/mL, about 300 mg/mL, about 350 mg/mL, or a range of any two of these values.

[0049] In some embodiments, the active pharmaceutical ingredient is present in the pharmaceutical composition in an effective amount from about 1 mg/mL to about 350 mg/mL, about 1 mg/mL to about 300 mg/mL, about 1 mg/mL to about 250 mg/mL, about 1 mg/mL to about 200 mg/mL, about 1 mg/mL to about 150 mg/mL, about 1 mg/mL to about 100 mg/mL, about 1 mg/mL to about 50 mg/mL, about 1 mg/mL to about 25 mg/mL, about 1 mg/mL to about 20 mg/mL, about 1 mg/mL to about 15 mg/mL, about 1 mg/mL to about 10 mg/mL, or about 1 mg/mL to about 5 mg/mL, and values in-between any of these ranges.

[0050] In some embodiments, the active pharmaceutical ingredient is present in the pharmaceutical composition in an effective amount of about 0.01 wt%, 0.05 wt%, 0.1 wt%, 0.2 wt%, 0.3 wt%, 0.4 wt%, 0.5 wt%, 0.6 wt%, 0.7 wt%, 0.8 wt%, 0.9 wt%, about 1 wt%, about 2 wt%, about 3 wt%, about 5 wt%, about 10 wt%, about 15 wt%, about 20 wt%, about 25 wt%, about 30 wt%, about 35 wt%, about 40 wt%, about 45 wt%, about 50 wt%, about 55 wt%, or a range of any two of these values. In some embodiments, the active pharmaceutical ingredient is in an effective amount from about 0.01 wt% to about 50 wt%. In some embodiments, the active pharmaceutical ingredient is in an effective amount from about 0.01 wt% to about 40 wt%. In some embodiments, the active pharmaceutical ingredient is in an effective amount from about 0.01 wt% to about 35 wt%. In some embodiments, the active pharmaceutical ingredient is in an effective amount from about 0.01 wt% to about 30 wt%. In other embodiments, the active pharmaceutical ingredient is present in an effective amount from about 0.01 wt% to about 20 wt% of the total composition, about 0.01 wt% to about 15 wt% of the total composition, about 0.01 wt% to about 10 wt% of the total composition, about 0.01 wt% to about 4.5 wt% of the total composition, about 0.01 wt% to about 2 wt% of the total composition, or about 0.01 wt% to about 1 wt% of the total composition, and any individual amount or any ranges between any two of these values. In some embodiments, the weight percentages disclosed herein may be weight-to-volume percentages.

[0051] In some embodiments, the active pharmaceutical ingredient is topiramate. In some embodiments, the topiramate is selected from the group consisting of a crystalline phase, an amorphous phase, a semi-crystalline phase, a semi-amorphous phase, and mixtures thereof. In some embodiments, topiramate disclosed herein is salt of topiramate, or a polymorph, solvate, hydrate, dehydrate, co-crystal, anhydrous, or amorphous form thereof. In some embodiments, the topiramate is in the form of nanoparticles.

[0052] In some embodiments, the pharmaceutical composition comprises one or more vehicles. Vehicles disclosed herein are the liquid bases which carry drug and other excipients in dissolved or dispersed state and may be selected from non-aqueous vehicles. Examples of suitable non-aqueous vehicles are but not limited to vegetable oils, mineral oils, organic oily bases or emulsified bases and triglycerides. In some embodiments, the vehicle is an oil. In some embodiments, the vehicle is a medium chain triglyceride (e.g. that sold under the trade name Kollisolv® MCT 70). In some embodiments, the oil is a vehicle and is added to the formulation at a quantum sufficit.

[0053] In some embodiments, the vehicle may be a medium chain fatty acid. In some embodiments, the medium chain fatty acid may be any fatty acid having from 6 to 12 carbon atoms. For example, the medium chain fatty acid may be selected from caproic acid (C6), caprylic acid (C8), capric acid (C10), and lauric acid (C12). In some embodiments, the vehicle is coconut oil, arachis oil, soya bean oil, castor oil, com oil, safflower oil, olive oil, apricot kernel oil, sesame oil, cotton seed oil, sunflower seed oil, palm oil, rapeseed oil, mineral oil, or a combination thereof. In some embodiments, the vehicle may be selected from caproic triglyceride, caprylic triglyceride, capric triglyceride, lauric triglyceride, or a combination thereof. In some embodiments, the vehicle is medium-chain triglycerides (MCTs), which comprise medium-chain (6 to 12 carbons) fatty acid esters of glycerol. Examples of MCTs which may be used in embodiments herein include MIGLYOL, made from various distillation fractions of coconut oil, Kollisolv, palm kernel oil, camphor tree drupes, or combinations thereof. Without intending to be limiting, it is believed that medium chain triglycerides exhibit excellent stabilization capability for alkylating agents which are sensitive to hydrolysis (e.g. topiramate).

[0054] In some embodiments, the vehicle may be present in the composition in an amount of about 0.1 wt%, about 1 wt%, about 3 wt%, about 5 wt%, about 10 wt%, about 15 wt%, about 20 wt%, about 25 wt%, about 30 wt%, about 35 wt%, about 40 wt%, about 45 wt%, about 50 wt%, about 55 wt%, about 60 wt%, about 65 wt%, about 70 wt%, about 75 wt%, about 80 wt%, about 85 wt%, about 90 wt%, about 95 wt%, about 99 wt%, or a range of any two of these values. In some embodiments, the vehicle may be in an amount from about 0.1 wt% to about 99.9 wt%. from about 1 wt% to about 99 wt% of the total composition, about 1 wt% to about 90 wt% of the total composition, about 1 wt% to about 80 wt% of the total composition, about 1 wt% to about 70 wt% of the total composition, about 1 wt% to about 60 wt% of the total composition, about 1 wt% to about 50 wt% of the total composition, about 1 wt% to about 40 wt% of the total composition, about 1 wt% to about 30 wt% of the total composition, about 80 wt% to about 99.9 wt% of the total composition, about 85 wt% to about 99.9 wt% of the total composition, about 90 wt% to about 99.9 wt% of the total composition, or about 95 wt% to about 99.9 wt% of the total composition. In some embodiments, the weight percentages disclosed herein may be volume-to-volume or weight-to-volume percentages.

[0055] In some embodiments, the pharmaceutical composition comprises one or more surfactants selected from sorbitan esters (Span) of saturated or unsaturated fatty acids, polyethoxylated sorbitan esters (Tween) of saturated or unsaturated fatty acids, Caprylocaproyl macrogol-8 glycerides (Labrasol), Lauroyl macrogol-32 glycerides (Gelucire 44/14), stearoyl macrogol- 32 glycerides (Gelucire 50/13), polyethoxylated and/or hydroginated castor oils such as PEG-40 hydrogenated castor oil (Cremophor RH 40®), PEG-60 hydrogenated castor oil (Cremophor RH 60®), PEG-35 castor oil, polyoxyl 35 castor oil (Cremophor EL), Macrogol (25) cetostearyl ether (Cremophor A25), polyethoxylated ethers of saturated or unsaturated fatty alcohols, polyethylene glycol such as PEG 200, poloxamer (Lutrol F 127), alpha tocopherol, polyoxyethylene lauryl ether (Brji 30, Brji 35), polyvinyl caprolactam-polyvinylacetate- polyethyleneglycol graft copolymer (e.g. Soluplus®), PEG-35 castor oil, or a combination thereof.

[0056] In some embodiments, the surfactant is in the pharmaceutical composition in an amount of about 0.5 mg/mL, about 1 mg/mL, about 5 mg/mL, about 10 mg/mL, about 15 mg/mL, about 20 mg/mL, about 25 mg/mL, about 30 mg/mL, about 35 mg/mL, about 40 mg/mL, about 45 mg/mL, about 50 mg/mL, about 100 mg/mL, about 150 mg/mL, about 200 mg/mL, about 250 mg/mL, about 300 mg/mL, about 350 mg/mL, about 400 mg/mL, about 450 mg/mL, about 500 mg/mL, about 550 mg/mL, about 600 mg/mL, about 650 mg/mL, about 700 mg/mL, about 750 mg/mL, or a range of any two of these values. In some embodiments, the surfactant is in the pharmaceutical composition in an amount of about 0.5 mg/mL to about 660 mg/mL. In some embodiments, the surfactant is in the pharmaceutical composition in an amount of about 1 mg/mL to about 660 mg/mL. In some embodiments, the surfactant is in the pharmaceutical composition in an amount of about 5 mg/mL to about 660 mg/mL. In some embodiments, the surfactant is in the pharmaceutical composition in an amount of about 10 mg/mL to about 650 mg/mL. In some embodiments, the surfactant is in the pharmaceutical composition in an amount of about 30 mg/mL to about 650 mg/mL. In some embodiments, the surfactant is in the pharmaceutical composition in an amount of about 30 mg/mL to about 520 mg/mL.

[0057] In some embodiments, the surfactant is in the pharmaceutical composition in an amount of about 0.01 wt%, about 0.1 wt%, about 0.5 wt%, about 1 wt%, about 2 wt%, about 3 wt%, about 4 wt%, about 5 wt%, about 6 wt%, about 7 wt%, about 8 wt%, about 9 wt%, about 10 wt%, , or a range of any two of these values. In some embodiments, the surfactant may be in an amount from about 0.01 wt% to about 10 wt% of the total composition, about 0.01 wt% to about 9 wt% of the total composition, about 0.01 wt% to about 8 wt% of the total composition, about 0.01 wt% to about 7 wt% of the total composition, about 0.01 wt% to about 6 wt% of the total composition, about 0.01 wt% to about 5 wt% of the total composition, about 0.01 wt% to about 4 wt% of the total composition, about 0.01 wt% to about 3 wt% of the total composition. In some embodiments, the surfactant in the composition does not exceed more than about 10 wt% in the composition, more than about 9 wt% in the composition, more than about 8 wt% in the composition, more than about 7 wt% in the composition, more than about 6 wt% in the composition, more than about 5 wt% in the composition, more than about 4 wt% in the composition, more than about 3 wt% in the composition, or more than about 2 wt% in the composition. In some embodiments, the weight percentages disclosed herein may be volume- to-volume or weight-to-volume percentages.

[0058] In some embodiments, the pharmaceutical composition comprises one or more solubilizers. Solubilizers are organic solvents used in liquid drug formulations to increase the solubility of poorly soluble substances and enhance the chemical stability of a drug. In some embodiments, the solubilizer may be a non-aqueous solvent, for example monoalcohols, such as alkanols having 1 to 8 carbon atoms (like ethanol, isopropanol, benzyl alcohol and phenylethyl alcohol), polyalcohols, such as alkylene glycols (like glycerine, ethylene glycol and propylene glycol), and glycol ethers, such as mono-, di-, and tri-ethylene glycol monoalkyl ethers, for example, ethylene glycol monomethyl ether and diethylene glycol monomethyl ether, and combinations thereof. In some embodiments, the solubilizer is an alcohol. In some embodiments, the alcohol may be selected from ethanol, propylene glycol, and polyhydric alcohols such as concentrated glycerol, glycerol, polyvinyl alcohol, propylene glycol, ethylene glycol, or a combination thereof. In some embodiments, the solubilizer is ethanol. In some embodiments, the solubilizer is propylene glycol.

[0059] In some embodiments, the solubilizer may be present in the composition in an amount of about 0.1% v/v, about 1% v/v, about 2% v/v, about 3% v/v, about 4% v/v, about 5% v/v, about 6% v/v, about 7% v/v, about 8% v/v, about 9% v/v, about 10% v/v, about 15% v/v, about 20% v/v, about 25% v/v, about 30% v/v, about 35% v/v, about 40% v/v, about 45% v/v, about 50% v/v, about 55% v/v, or a range of any two of these values.

[0060] In some embodiments, the solubilizer may be present in the composition in an amount of about 0.1% w/w, about 1% w/w, about 3% w/w, about 5% w/w, about 10% w/w, about 15% w/w, about 20% w/w, about 25% w/w, about 30% w/w, about 35% w/w, about 40% w/w, about 45% w/w, about 50% w/w, about 55% w/w, or a range of any two of these values. In some embodiments, the solubilizer may be in an amount of about 0.1% w/w to about 55% w/w.

[0061] In some embodiments, the solubilizer is present in the composition from about 0.1 wt% to about 55 wt% of the total composition, about 0.1 wt% to about 50 wt% of the total composition, about 0.1 wt% to about 40 wt% of the total composition, about 0.1 wt% to about 30 wt% of the total composition, about 0.1 wt% to about 10 wt% of the total composition, or about 0.1 wt% to about 5 wt% of the total composition, and any individual amount or any ranges between any two of these values. In some embodiments, the solubilizer in the composition does not exceed more than about 20 wt% in the composition, more than about 15 wt% in the composition, more than about 10 wt% in the composition, more than about 7 wt% in the composition, more than about 6 wt% in the composition, more than about 5 wt% in the composition, more than about 4 wt% in the composition, or more than about 3 wt% in the composition. In some embodiments, the weight percentages disclosed herein may be volume-to-volume or weight-to-volume percentages.

[0062] In some embodiments, the ratio of the surfactant to the solubilizer in the composition is about 1 : 1 to about 1 : 5, about 1 : 1 to about 1 : 4, about 1 : 1 to about 1 : 3, about 1 : 1 to about 1 : 2, or about 1 : 1 to about 1 : 1.5 weight percentages. Specific examples include about 1 : 1, about 1 : 1.5, about 1 :2, about 1 :2.5, about 1 :3, about 1 :3.5, about 1 : 4, about 1 :4.5, about 1 :5, about 2:2.5, about 2:3, about 2:3.5, about 2: 4, about 2:4.5, about 2:5, about 3:3.5, about 3:4, about 3:4.5, or about 3:5 weight percentages. The weight percentages may be weight-to-weight or weight-to-volume percentages.

[0063] In some embodiments, the ratio of the surfactant to the vehicle in the composition is about 1 : 10 to about 1 :90, 1 : 10 to about 1 :80, 1 : 10 to about 1 :70, 1 : 10 to about 1 :60, 1 : 10 to about 1 :50, 1 : 10 to about 1 :40, 1 : 10 to about 1 :30, or 1 : 10 to about 1 :20 weight percentages. Specific examples include about 1 :90, about 1 :85, about 1 :80, about 1 :70, about 1 :60, about 1 :50, about 1 :40, about 1 :30, about 1 :20, about 1 : 10 weight percentages. The weight percentages may be weight-to-weight or weight-to-volume percentages.

[0064] In some embodiments, the pharmaceutical composition is a non-aqueous solution and comprises about 0.01 wt% to about 30 wt% active pharmaceutical ingredient, about 1 wt% to about 10 wt% surfactant, about 0.1 wt% to about 40 wt% solubilizer, and about 0.1 wt% to about 99 wt% vehicle.

[0065] In some embodiments, the pharmaceutical composition is a non-aqueous solution and comprises about 0.01 wt% to about 2 wt% active pharmaceutical ingredient, about 1 wt% to about 5 wt% surfactant, about 0.1 wt% to about 5 wt% solubilizer, and about 0.1 wt% to about 90 wt% vehicle.

[0066] In some embodiments, the pharmaceutical composition is a non-aqueous solution and comprises about about 2 wt% topiramate, about 3 wt% surfactant, about 5 wt% solubilizer, and about 90 wt% vehicle.

[0067] In some embodiments, the pharmaceutical composition is a non-aqueous solution and comprises about 2 wt% topiramate, about 3 wt% caprylocaproyl macrogol-8 glycerides, about 5 wt% ethanol, and about 89.8 wt% medium chain triglyceride. [0068] In some embodiments, the pharmaceutical composition is a non-aqueous solution comprises about 2 wt% topiramate, about 3 wt% caprylocaproyl macrogol-8 glycerides, about 5 wt% ethanol, and about 89.8 wt% Kollisolv MCT 70.

[0069] In some embodiments, the pharmaceutical composition is a non-aqueous solution and consisting essentially of about 2 wt% topiramate, about 3 wt% caprylocaproyl macrogol-8 glycerides, about 5 wt% ethanol, and about 89.8 wt% medium chain triglyceride.

[0070] In some embodiments, the pharmaceutical composition is a non-aqueous solution consisting of about 2 wt% topiramate, about 3 wt% caprylocaproyl macrogol-8 glycerides, about 5 wt% ethanol, about 0.2 wt% flavoring agent, about 0.03 wt% sweetening agent, and a medium chain triglyceride added q.s.

[0071] In some embodiments, the pharmaceutical composition further includes one or more pharmaceutically acceptable excipients selected from the group comprising of one or more preservatives, one or more antioxidants, one or more buffering agents, one or more chelating agents, one or more sweetening agents, one or more flavoring agents, one or more sweetness/flavor enhancing agents, or combination thereof. In some embodiments, the pharmaceutically acceptable excipient is in an amount of about 0.1 wt%, about 0.5 wt%, about 1 wt%, about 2 wt%, about 3 wt%, about 4 wt%, about 5 wt%, about 6 wt%, about 7 wt%, about 8 wt%, about 9 wt%, about 10 wt%, or a range of any two of these values.

[0072] Preservatives are compounds which are included in pharmaceutical dosage form to prevent the growth of microorganisms during the product's manufacture and shelf life. Examples of the suitable preservatives are, but not limited to, benzyl alcohol, chloro- butanol, chloro-cresol, alkyl esters of parabens, phenol, phenyl ethanol, benzoic acid, potassium sorbate, sodium benzoate and antimicrobial solvents like propylene glycol, chloroform, or a combination thereof.

[0073] Antioxidants are substances capable of inhibiting oxidation and that may be added to pharmaceutical products to prevent deterioration by oxidative processes. Examples of suitable antioxidants are but not limited to Butyl atedhy dr oxyani sole (BHA), Butyl atedhydroxy toluene (BHT), Sodium metabi sulfite, Ascorbic acid, Alphatocopherol, Sodium edetate, or any combination thereof. In some embodiments, the antioxidants are BHA and BHT.

[0074] Buffering agents are compounds which provide stability and pH control to the pharmaceutical formulations. Examples of suitable buffering agents are but not limited to sodium acetate, tris(hydroxymethyl)aminom ethane (TRIS), triethanolamine, sodium citrate, ammonium sulfate, sodium phosphate, di sodium hydrogen phosphate, potassium citrate, citric acid monohydrate, trisodium citrate dehydrate, or a combination thereof.

[0075] Chelating agents are compounds which are used for drug stabilization, to maintain potency of active pharmaceutical ingredients and to stabilize colors and flavors. Examples of suitable chelating agents are but not limited to citric acid monohydrate, disodium edetate, dipotassium edetate, edetic acid, fumaric acid, malic acid, phosphoric acid, sodium edetate, tartaric acid, trisodium edetate, or a combination thereof.

[0076] Sweetening agents are compounds that impart sweetness and improve patient compliance through taste masking. Examples of the suitable sweetening agents are but not limited to sucralose, sucrose, acesulfame potassium, liquid glucose, glycerine, sorbitol, liquid maltitol, saccharin sodium, aspartame, or a combination thereof. In some embodiments, the sweetening agent is sucralose. Sweetening agents may be present from about 0.01 wt% to about 5 wt% of the total composition, about 0.01 wt% to about 4 wt% of the total composition, about 0.01 wt% to about 3 wt% of the total composition, about 0.01 wt% to about 2 wt% of the total composition, or about 0.01 wt% to about 1 wt% of the total composition.

[0077] Flavoring agents are the compounds which are added to increase patient acceptance of the drug by masking the specific taste sensations. Examples of suitable flavoring agent are, but not limited to, essential oils including peppermint oil, orange oil or lemon oil, fruit flavor, peppermint flavor, strawberry flavor, tutti-fruity flavor, mint flavor, or a combination thereof. In some embodiments, the flavoring agent is a tutti-fruity flavor. Flavoring agents may be present from about 0.01 wt% to about 5 wt% of the total composition, about 0.01 wt% to about 4 wt% of the total composition, about 0.01 wt% to about 3 wt% of the total composition, about 0.01 wt% to about 2 wt% of the total composition, or about 0.01 wt% to about 1 wt% of the total composition.

[0078] In some embodiments, the pharmaceutical composition disclosed herein is a non-aqueous liquid or a non-aqueous solution. In some embodiments, the non-aqueous liquid solution is suitable for oral administration. In some embodiments, the pharmaceutical compositions may also be in the form of non-aqueous syrups, non-aqueous suspensions and non-aqueous emulsions.

[0079] In some embodiments, the pharmaceutical compositions disclosed herein does not contain an aqueous solvent. In some embodiments, the pharmaceutical compositions disclosed herein contains substantially no aqueous solvents. In some embodiments, the pharmaceutical compositions disclosed herein contain less than 1% of aqueous solvent in the total composition. In some embodiments, the pharmaceutical compositions disclosed herein contain less than 0.5% of aqueous solvent in the total composition. In some embodiments, the pharmaceutical compositions disclosed herein contain less than 0.1% of aqueous solvent in the total composition.

[0080] In some embodiments, topiramate in the compositions disclosed herein is stable for extended periods of time. For example, in some embodiments, topiramate in the compositions is stable at temperature ranges from about 4 °C to about 50 °C for a period of 12-36 months. In some embodiments, topiramate in the compositions is stable at temperature ranges from about 4 °C to about 45 °C for a period of 12-36 months. In some embodiments, topiramate in the compositions is stable at temperature ranges from about 4 °C to about 40 °C for a period of 12-36 months. In some embodiments, topiramate in the compositions is stable at temperature ranges from about 4 °C to about 35 °C for a period of 12-36 months. In some embodiments, topiramate in the compositions is stable at temperature ranges from about 4 °C to about 30 °C for a period of 12-36 months.

[0081] In some embodiments, the pharmaceutical composition disclosed herein is useful for the manufacture of a medicament. In one of the further embodiments, the pharmaceutical composition disclosed herein is useful as a medicament.

[0082] In some embodiments, the active pharmaceutical ingredient may be administered in combination with one or more additional active pharmaceutical ingredients. In some embodiments, the pharmaceutical compositions disclosed herein may include an additional active pharmaceutical ingredient. In some embodiments, the pharmaceutical compositions disclosed herein may be administered in conjunction with, either concurrently or sequentially, with the additional active pharmaceutical ingredient.

Methods of Treatment

[0083] Some embodiments are directed to a methods of using the pharmaceutical composition disclosed herein for the treatment of diseases or disorders. In some embodiments, a method of treating a disease or a disorder in a subject in need thereof comprises administering to the subject the pharmaceutical composition disclosed herein. In some embodiments, the disease or disorder comprises seizures, partial onset seizures, seizures associated with Lennox-Gastaut syndrome, generalized tonic-clonic seizures, migraine headaches, bipolar disorder, epilepsy, alcoholism, ***e and tobacco addiction, diabetes, neuropathic pain, diabetic neuropathic pain, obesity, sleep disorders, sleep-related eating disorders, post-traumatic stress disorder, depression, cluster headaches, or a combination thereof. In some embodiments, pharmaceutical composition comprises topiramate.

[0084] In some embodiments, a method of treating a seizure in a subject in need thereof comprises administering to the subject the pharmaceutical composition disclosed herein, wherein the active pharmaceutical ingredient present in the composition is topiramate.

[0085] In some embodiments, a method of preventing a migraine headache in a subject in need thereof comprises administering to the subject the pharmaceutical composition disclosed herein, wherein the active pharmaceutical ingredient present in the composition is topiramate.

[0086] In some embodiments, the pharmaceutical compositions disclosed herein comprising topiramate are suited to improve the duration and/or frequency of seizures associated with Lennox-Gastaut syndrome. In some embodiments, the pharmaceutical compositions disclosed herein comprising topiramate are suited to inhibit the onset of migraine headaches.

[0087] In other embodiments, methods of administration may include, but are not limited to, intravascular injection, intravenous injection, intraarterial injection, intratumoral injection, intraperitoneal injection, subcutaneous injection, intramuscular injection, transmucosal administration, oral administration, topical administration, local administration, or regional administration.

[0088] In some embodiments, the compositions disclosed herein may be administered once, as needed, once daily, twice daily, three times a day, once a week, twice a week, every other week, every other day, or the like for one or more dosing cycles. A dosing cycle may include administration for about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks, about 9 weeks, or about 10 weeks. After this cycle, a subsequent cycle may begin approximately 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 weeks later. The treatment regime may include 1, 2, 3, 4, 5, or 6 cycles, each cycle being spaced apart by approximately 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 weeks.

[0089] The pharmaceutical compositions of embodiments disclosed herein may have unexpectedly dramatic dissolution profiles. Rapid dissolution of an administered active pharmaceutical ingredient is preferable, as faster dissolution generally leads to greater bioavailability and faster onset of action. To improve the dissolution profile and bioavailability of an active pharmaceutical ingredient, it would be useful to increase dissolution of the active pharmaceutical ingredient used so that it could attain a level close to 100% dissolution of the drug substance. [0090] The pharmaceutical compositions disclosed herein comprising the active pharmaceutical ingredient or derivative thereof, exhibit improved or comparable pharmacokinetic profiles when compared to marketed or known compositions of the same active pharmaceutical ingredient or derivative thereof. For example, the Cmax and/or AUC of the pharmaceutical compositions of disclosed herein can be greater than or substantially equal to the Cmax and/or AUC for known or marketed compositions, e.g. solid formulations, administered at the same dose. In addition, the Tmax of the pharmaceutical compositions disclosed herein can be lower than or substantially equal to that obtained for a known or marketed composition, administered at the same dose. In addition, combinations of an improved or comparable Cmax, AUC and Tmax profile can be exhibited by the pharmaceutical compositions disclosed herein, as compared to known or marketed compositions. In further aspects, the pharmaceutical compositions disclosed herein may result in minimal different absorption levels when administered under fed as compared to fasting conditions.

[0091] In some embodiments, the pharmaceutical compositions disclosed herein may exhibit a Tmax not greater than about 90%, not greater than about 80%, not greater than about 70%, not greater than about 60%, not greater than about 50%, not greater than about 30%, not greater than about 25%, not greater than about 20%, not greater than about 15%, not greater than about 10%, or not greater than about 5% of the Tmax exhibited by a marketed or known formulation, when administered at a same dose.

[0092] In some embodiments, the pharmaceutical compositions disclosed herein may exhibit a Cmax which is at least about 50%, at least about 100%, at least about 200%, at least about 300%, at least about 400%, at least about 500%, at least about 600%, at least about 700%, at least about 800%, at least about 900%, at least about 1000%, at least about 1100%, at least about 1200%, at least about 1300%, at least about 1400%, at least about 1500%, at least about 1600%, at least about 1700%, at least about 1800%, or at least about 1900% greater than the Cmax exhibited by a marketed or known formulation, when administered at a same dose.

[0093] In some embodiments, the pharmaceutical compositions disclosed herein may exhibit an AUC which is at least about 25%, at least about 50%, at least about 75%, at least about 100%, at least about 125%, at least about 150%, at least about 175%, at least about 200%, at least about 225%, at least about 250%, at least about 275%, at least about 300%, at least about 350%, at least about 400%, at least about 450%, at least about 500%, at least about 550%, at least about 600%, at least 5 about 750%, at least about 700%, at least about 750%, at least about 800%, at least about 850%, at least about 900%, at least about 950%, at least about 1000%, at least about 1050%, at least about 1100%, at least about 1150%, or at least about 1200% greater than the AUC exhibited by a marketed or known formulation, when administered at a same dose.

[0094] In some embodiments, the Tmax of the active pharmaceutical ingredient or salt thereof used for the preparation of the pharmaceutical composition disclosed herein, when assayed in the plasma of the mammalian subject, is less than about 6 to about 8 hours. In other embodiments, the Tmax of the active pharmaceutical ingredient or salt thereof is less than about 6 hours, less than about 5 hours, less than about 4 hours, less than about 3 hours, less than about 2 hours, less than about 1 hour, or less than about 30 minutes after administration.

[0095] In some aspects, the pharmaceutical compositions disclosed herein exhibit improved or comparable bioavailability as compared to known or marketed compositions.

Methods of preparing formulation

[0096] A general process for the preparation of the liquid oral pharmaceutical compositions of embodiments above may be as follows:

(a) Mix one or more surfactants and one or more solubilizers under stirring;

(b) Dissolve active pharmaceutical ingredient in the mixture obtained in Step

(a);

(c) Add one or more antioxidants, sweeteners, or preservatives in the mixture obtained in Step (b).

(d) Dilute the obtained mixture in Step (c) up to the desired volume with the filler/vehicle;

(e) Add one or more flavoring agents in the final composition obtained in Step (d).

[0097] The embodiments illustrating the method and materials used may be further understood by reference to the following non-limiting examples. EXAMPLES

Example 1 : A liquid oral pharmaceutical composition comprising Topiramate

TABLE 2: TOPIRAMATE FORMULATION

[0098] Method of preparation is as below:

(a) Mix caprylocaproyl polyoxylglyceride and ethanol under stirring;

(b) Dissolve topiramate in the mixture obtained in step (a);

(c) Add the mixture of step (b) in to a medium chain triglyceride;

(d) Add one or more flavoring agents or sweetener or anti-oxidant into the mixture of step (c) and mix till dissolved; and

(e) Make up a volume up to final batch size with vehicle under stirring.

[0099] Those who are skilled in the art can also understand that some variations in the herein described processes for the preparation of liquid compositions of the present invention can be adopted which are well within the skills of the skilled artisan. One can change sequences of the steps in the above mentioned process for the purposes of suitability and convenience without affecting the quality and characteristics of the resulting product.

[0100] Those who are reasonably skilled in the art can easily understand that similar liquid formulations using other active non-chemotherapeutic agents, including without limitation those mentioned in the above paragraphs with other suitable excipients, may be prepared in the above mentioned formulas using above mentioned processes for preparation. Such other examples of compositions and processes of preparation thereof are also within the ambit of the invention disclosed and claimed in the present application.

EXAMPLE 2: Stability Study Results of Topiramate Liquid Composition [0101] The oral liquid pharmaceutical composition prepared according to Example 1 exhibits unexpected stability profile when tested after three (3) and six (6) months under the conditions 40°C/25 RH and 25°C/40 RH. The liquid composition according to the present disclosure possesses low amounts of impurities and highest degree of purity. The results of the stability tests conducted are summarized in the table below:

TABLE 3 : STABILITY

EXAMPLE 3 : Stability of topiramate in aqueous solutions

TABLE 4

[0102] Based on observations at 25C and 40C, it was concluded that topiramate is not compatible in aqueous vehicle-based product.

EXAMPLE 4: Solubility studies

TABLE 5

[0103] Based on above data, it was concluded that topiramate is soluble in ethanol, labrasol and medium chain triglycerides but it is not compatible with ethanol at a high concentration (formulation A), while stable at lower concentration (15 ml per 300 ml).

EXAMPLE 5: Optimization of solubilizer

TABLE 6

[0104] From the above table, trials with ethanol 2.5% 3.0% and 3.5% were found with particles. Trials with 4% (TOPL1013) and 5 % ethanol (TOPL1018) were found clear. From above data, ethanol with 5% concentration was finalized for further trials.

EXAMPLE 6: Optimization of surfactant

TABLE 7

TABLE 8

[0105] From the above studies, it was concluded that trial with 3 % of labrasol released topiramate more than 85% within 15 minutes and dispersed well in dissolution media, while trial without labrasol did not disperse in water and float on the surface of dissolution media. It also released 36.6 % topiramate within 15 minutes and did not recover more than 90% of topiramate after stirring at 200 RPM for 30 min. Further, due to lack of dispersibility, very high % O.D. was observed with TOPL1018 formulation. From above data, batch with 3% Labrasol provided promising dissolution profile. EXAMPLE 7: Optimization of sucralose concentration

[0106] Different concentrations of sucralose were used to check clarity of solution of the formulation, formula presented in below table:

TABLE 9

[0107] From the above studies it was observed that batch with sucralose 1.0 mg/ml (TOPL1031) and batch with sucralose 2.0 mg/ml (TOPL1027) were hazy. Batch with sucralose 0.2 mg/ml (TOPL1050) was clear but not palatable. Batch with sucralose 0.3 mg/ml (TOPL1052) was clear and palatable, and therefore sucralose 0.3 mg/ml was preferred.

EXAMPLE 8:

[0108] An exemplary topiramate solution is described below:

TABLE 10

EXAMPLE 9: Topiramate dissolution profile

[0109] Topiramate oral solution 20 mg/mL was evaluated for dissolution profiles in purified water, 0.1 N HC1, 4.5 pH acetate buffer media, and 6.8 pH phosphate buffer, and compared with innovator drug product Topomax. Dissolution profiles are shown below.

[0110] Volume : 900 ml

[0111] Apparatus : ETSP apparatus Type 2 (paddle type) RPM : 50 RPM

TABLE 11 : Comparative dissolution profile of Topiramate solution 20 mg/ml & Topamax 100 mg tablets in Purified water (deaerated)

TABLE 12: Comparative dissolution profile of Topiramate solution 20 mg/ml & Topamax 100 mg tablets in 0.1 N HCL

TABLE 13: Comparative dissolution profile of Topiramate solution 20 mg/ml &

Topamax 100 mg tablets in 4.5 pH acetate buffer

TABLE 14: Comparative dissolution profile of Topiramate solution 20 mg/ml & Topamax 100 mg tablets in 6.8 pH Phosphate buffer

[0112] From the results it was concluded that Topiramate solution 20 mg/ml shows comparable dissolution profile to that of US Reference product (i.e. Topamax 100 mg tablets) in all four dissolution media. Both formulations show more than 85% average drug release in all the dissolution media (purified water, pH 1.2, 4.5 and 6.8).

[0113] Although embodiments herein has been described in considerable detail with reference to certain preferred embodiments thereof, other versions are possible. Therefore, the spirit and scope of the appended claims should not be limited to the description and the preferred versions contained within this specification.

Claims

1. A pharmaceutical composition comprising an active pharmaceutical ingredient, a solubilizer, a surfactant, and a vehicle, wherein

the active pharmaceutical ingredient is present at about 0.01 wt% to about 30 wt% of the composition;

the surfactant is present from about 1 wt% to about 10 wt% of the composition;

the solubilizer is present from about 0.1 wt% to about 40 wt% of the composition;

the vehicle is present from about 0. 1 wt% to about 99 wt % of the composition; and wherein the composition is a non-aqueous solution.

2. The pharmaceutical composition of claim 1, wherein the active pharmaceutical ingredient is selected from topiramate, felodipine, fesoterodine, isradipine, nifedipine, nimodipine, nisoldipine, sodium valproate, omeprazole, Esomeprazole, Rabeprazole, Pentoprazole, methimazole, a derivative thereof, and a combination thereof.

3. The pharmaceutical composition of claim 1, wherein the active pharmaceutical ingredient is topiramate.

4. The pharmaceutical composition of claim 1, wherein the solubilizer is an alcohol.

5. The pharmaceutical composition of claim 1, wherein the solubilizer is selected from ethanol, propylene glycol, glycerol, polyvinyl alcohol, propylene glycol, ethylene glycol, and a combination thereof

6. The pharmaceutical composition of claim 1, wherein the surfactant is selected from sorbitan esters, polyethoxylated sorbitan esters, Caprylocaproyl macrogol-8 glycerides, Lauroyl macrogol-32 glycerides, stearoyl macrogol- 32 glycerides, polyethoxylated castor oil, hydroginated castor oil, PEG-40 hydrogenated castor oil, PEG-60 hydrogenated castor oil, PEG-35 castor oil, polyoxyl 35 castor oil, Macrogol (25) cetostearyl ether, polyethoxylated ethers, polyethylene glycol, poloxamer, alpha tocopherol, polyoxyethylene lauryl ether, polyvinyl caprolactam-polyvinylacetate- polyethyleneglycol graft copolymer, PEG-35 castor oil, polyoxyl 35 castor oil, and a combination thereof.

7. The pharmaceutical composition of claim 1, wherein the vehicle is selected from caproic acid (C6), caprylic acid (C8), capric acid (C10), lauric acid (C12), coconut oil, arachis oil, soya bean oil, castor oil, com oil, safflower oil, olive oil, apricot kernel oil, sesame oil, cotton seed oil, sunflower seed oil, palm oil, rapeseed oil, mineral oil, vegetable oil, caproic triglyceride, caprylic triglyceride, capric triglyceride, lauric triglyceride, medium-chain (6 to 12 carbons) fatty acid esters of glycerol, coconut oil, Kollisolv, palm kernel oil, camphor tree drupes, or a combination thereof.

8. The pharmaceutical composition of claim 1, wherein the composition comprises the active pharmaceutical ingredient in a therapeutically effective amount.

9. The pharmaceutical composition of claim 1, wherein the composition comprises the active pharmaceutical ingredient in an amount of about 1 mg/mL to about 50 mg/mL.

10. The pharmaceutical composition of claim 1, wherein the composition comprises the solubilizer in an amount of about 0.1 wt% to about 10 wt% of the composition.

11. The pharmaceutical composition of claim 1, wherein the composition comprises the surfactant in an amount of about 1 wt% to about 5 wt% of the composition.

12. The pharmaceutical composition of claim 1, wherein the active pharmaceutical ingredient is topiramate, the solubilizer is ethanol, the surfactant is polyethoxylated glyceride, and the vehicle is a medium chain triglyceride.

13. The pharmaceutical composition of claim 1, wherein the composition comprises about 0.01 wt% to about 2 wt% of the active pharmaceutical ingredient, about 1 wt% to about 5 wt% of the surfactant, about 0.1 wt% to about 5 wt% of the solubilizer, and about 0.1 wt% to about 90 wt% of the vehicle.

14. The pharmaceutical composition of claim 1, wherein the composition comprises about 2 wt% topiramate, about 3 wt% caprylocaproyl macrogol-8 glyceride, about 5 wt% ethanol, about 89.8 wt% medium chain triglyceride, and further comprises about 0.03 wt% sucralose, and 0.2 wt% flavoring agent.

15. A method of treating a disease or disorder in a subject in need thereof, the method comprising administering a pharmaceutical composition in the form of a liquid oral solution comprising topiramate, a solubilizer, a surfactant, and a vehicle.

16. The method of claim 15, wherein the disease or disorder is selected from the group consisting of seizures, partial onset seizures, seizures associated with Lennox-Gastaut syndrome, generalized tonic-clonic seizures, migraine headaches, bipolar disorder, epilepsy, alcoholism, ***e and tobacco addiction, diabetes, neuropathic pain, diabetic neuropathic pain, obesity, sleep disorders, sleep-related eating disorders, post-traumatic stress disorder, depression, cluster headaches, and a combination thereof.