Use of improved release huperzine formulations in higher doses

Abstract

The name of the invention is the use of improved release huperzine formulations in higher doses. Pharmaceutical compositions and methods of treating neurological disorders and seizure disorders with high dose modified release compositions of huperzine are disclosed. The pharmaceutical compositions and methods described herein allow for higher dose administration of huperzine while avoiding fast peak plasma levels, thereby avoiding dose-limiting adverse events associated with immediate release formulations.

Description

[0001] This application is a divisional application of a Chinese national stage patent application with the application number 201980066576.9, which entered the Chinese national stage on April 8, 2021, of a PCT application with the international application number PCT / US2019 / 062241, the international filing date of November 19, 2019, and the invention title "Use of a Modified Release Huperzine Preparation at Higher Doses". SUMMARY OF THE INVENTION

[0002] Huperzine A is a naturally occurring sesquiterpene alkaloid compound found in firmoss Huperzia serrata. It is a potent inhibitor of acetylcholinesterase. In several countries, huperzine A is sold as a dietary supplement for memory support. In China, huperzine A is approved by the China Food and Drug Administration (CFDA) for the treatment of dementia.

[0003] Huperzine A has been administered to healthy volunteers and patients in many trials (many in China), demonstrating acceptable safety, tolerability, and efficacy in Alzheimer's disease, benign senescent forgetfulness, vascular dementia, myasthenia gravis, schizophrenia, and cocaine dependence. The doses used in these trials were between 0.01 mg / day and 0.8 mg / day via oral administration or intramuscular injection. Although these studies have shown favorable safety profiles, in some studies, transient dose-related nausea occurred at higher dose levels.

[0004] The applicant conducted a dose-escalation study in patients with drug-resistant epilepsy to investigate the safety and tolerability of an immediate-release preparation of huperzine A. In this study, patients experienced dose-limiting adverse events (nausea and vomiting), many of which occurred within the first 31 hours, most likely due to the rapid plasma exposure of the immediate-release preparation (see below).

[0005] Although huperzine A may potentially provide additional beneficial effects in the fields of neurological disorders, seizure disorders, memory, and language impairment, the immediate-release preparations of huperzine A are insufficient to treat conditions that require a higher therapeutic threshold due to dose-related adverse events, especially in patients with chronic conditions. Immediate-release preparations also have the additional disadvantage of requiring administration 4 to 6 times per day due to the short half-life (t 1 / 2 ) associated with these preparations. In many patient populations, such as those with memory loss or seizures, administration 4 to 6 times per day is unacceptable because compliance becomes a major issue for these patients. Non-clinical studies have shown that higher doses (such as up to 6.4 mg / day) may be safe if delivered with a preparation that reduces the fluctuations in peak-to-trough plasma levels compared to those previously used.

[0006] Zhou et al. have reported sustained-release pills containing huperzine in Chinese Patent Application CN101081217. However, compared to immediate-release formulations, these formulations do not significantly reduce peak plasma concentration and also do not prolong the time to reach maximum plasma concentration (T max ). As a result, these formulations will not overcome the serious adverse events associated with high peak plasma concentrations and will require administration 4 - 6 times a day, thus having little advantage over immediate-release formulations.

[0007] Compared to the lower doses used previously, the present invention allows for the use of higher doses of huperzine, thereby providing improved efficacy while maintaining a desirable safety profile not achievable with previously known formulations.

[0008] Embodiments of the present invention relate to modified-release pharmaceutical compositions for oral delivery of huperzine, which can be used to treat various neurological disorders and diseases, such as pain, Alzheimer's disease, and seizure disorders. The compositions provide modified-release formulations that allow for the optimal efficacy of huperzine without the dose-limiting adverse events associated with immediate-release formulations.

[0009] Embodiments of the present invention relate to a pharmaceutical composition for oral delivery, the pharmaceutical composition comprising: (a) a sugar sphere core of about 74 wt% to 86 wt%, wherein the sugar sphere core has a particle size of about 500 - 710 μm; (b) a huperzine layer coating the sugar sphere, wherein the huperzine layer comprises about 0.95 wt% to about 1 wt% of huperzine or a pharmaceutically acceptable salt of huperzine equivalent to about 0.95 wt% to about 1 wt% of huperzine and one or more excipients, wherein the total amount of excipients is about 5 wt% to about 9 wt%; and (c) a plasticized ethylcellulose polymer layer of about 7 wt% to 16 wt% coating the huperzine layer, wherein the huperzine layer contains a therapeutically effective amount of huperzine. In some embodiments, the huperzine is huperzine A or a pharmaceutically acceptable salt thereof.

[0010] Some embodiments of the present invention relate to a pharmaceutical composition, the pharmaceutical composition comprising: (a) a sugar sphere core of about 80 wt% to about 83 wt%, wherein the sugar sphere core has a particle size of about 500 - 710 μm; (b) a huperzine A layer coating the sugar sphere, wherein the huperzine A layer comprises about 0.95 wt% to about 1 wt% of huperzine A or a pharmaceutically acceptable salt of huperzine A equivalent to about 0.95 wt% to about 1 wt% of huperzine A, about 5 wt% to about 6 wt% of hydroxypropyl methylcellulose, and about 0.95 wt% to about 1 wt% of polyvinylpyrrolidone; and (c) a plasticized ethylcellulose polymer layer of about 8 wt% to about 12 wt% coating the huperzine A layer, wherein the huperzine A layer contains a therapeutically effective amount of huperzine A.

[0011] Some embodiments of the present invention relate to a pharmaceutical composition, characterized in that after oral administration of a therapeutically effective dose of the composition to a human subject, the maximum plasma concentration (C max ) of huperzine A in plasma is from about 4 ng / mL to about 8 ng / mL, T max is from about 4 hours to about 8 hours and t 1 / 2 is from about 8 hours to about 12 hours. In one embodiment, C max is from about 4 ng / mL to about 6 ng / mL, T max is from about 4 hours to about 8 hours, and t 1 / 2 is from about 10 hours to about 12 hours. In one embodiment, C max is about 6 ng / mL, T max is about 4 hours, and t 1 / 2 is about 8.3 hours.

[0012] Some embodiments of the present invention relate to a pharmaceutical composition comprising a therapeutically effective amount of huperzine A, characterized in that T max is from about 4 - 8 hours and C max is reduced by about 25% to about 75% when compared to C max of an immediate release huperzine preparation administered at an equivalent dose. In some embodiments, C max is reduced by 50%.

[0013] Some embodiments of the present invention relate to a pharmaceutical composition which, when tested at 37 °C in 50 mM phosphate (pH 6.8) according to USP Type 1 dissolution apparatus at 50 revolutions per minute, exhibits the following dissolution profile: about 36% to about 46% of huperzine is released after 2 hours, about 61% to about 77% of huperzine is released after 4 hours, about 84% to about 97% of huperzine is released after 8 hours, and not less than about 89% of huperzine is released after 12 hours.

[0014] Some embodiments of the present invention describe a method of treating a neurological disorder or a seizure disorder, the method comprising administering a pharmaceutical composition according to any of the embodiments described herein. In some embodiments, the composition is administered twice daily. In some embodiments, the seizure disorder is epilepsy, i.e., recurrent seizures - such as focal impaired awareness seizures (FIAS) - with or without loss of consciousness, formerly known as complex partial seizures (CPS).

[0015] Some embodiments of the present invention describe a method of treating a disorder in a patient in need selected from the group consisting of a neurological disorder and a seizure disorder, wherein the patient has a favorable side effect profile, the method comprising administering one or more titrating doses of huperzine A, and then administering a maintenance dose of huperzine A; wherein the huperzine A is administered in a modified release formulation of huperzine. In some embodiments, the modified release formulation of huperzine is a pharmaceutical composition according to any of the embodiments described herein.

[0016] Some embodiments of the present invention describe a method of reducing the frequency of seizures in a patient in need, the method comprising administering to the patient one or more titrating doses of the pharmaceutical composition, and then administering a maintenance dose of the pharmaceutical composition, wherein the titrating dose comprises from about 0.5 mg to about 2.5 mg BID administered twice daily (BID); and wherein the maintenance dose comprises from about 3.0 mg BID to about 4.0 mg BID. In some embodiments, the frequency of seizures in the patient is reduced by greater than about 75%.

[0017] Some embodiments of the present invention describe a method of reducing the frequency of seizures in a patient in need, the method comprising administering to the patient a pharmaceutical composition comprising a therapeutically effective amount of huperzine. In some embodiments, the therapeutically effective amount of huperzine is from about 3.0 mg to about 4.0 mg BID.

[0018] Some embodiments of the present invention describe a method of treating a neurological disorder and a seizure disorder in a patient in need, wherein the patient has a favorable side effect profile and / or a reduced seizure frequency, the method comprising administering a dosing regimen comprising from about 0.25 mg to about 0.75 mg BID from day 1 to day 16; from about 0.75 mg to about 1.75 mg BID from day 17 to day 40; from about 1.75 mg to about 2.5 mg BID from day 41 to day 90; and from about 2.5 mg to about 3.0 mg BID from day 91 to day 180.

[0019] Some embodiments of the present invention describe a method for treating a patient in need of treatment for a neurological disorder and a seizure disorder, wherein the patient has a favorable side effect profile and / or a reduced seizure frequency, the method comprising administering to the patient a dosing regimen comprising from about 0.25 mg to about 0.75 mg BID from day 1 to day 16; from about 0.75 mg to about 1.75 mg BID from day 17 to day 40; from about 1.75 mg to about 2.5 mg BID from day 41 to day 90; from about 2.5 mg to about 3.0 mg BID from day 91 to day 180; and from about 3.0 mg to about 4.0 mg BID from day 181 to day 270.

[0020] Some embodiments of the present invention describe a method for treating a patient in need of treatment for a neurological disorder and a seizure disorder, wherein the patient has a favorable side effect profile and / or a reduced seizure frequency, the method comprising administering to the patient one or more titration doses of the pharmaceutical composition, followed by administering a maintenance dose of the pharmaceutical composition, wherein the titration dose comprises from about 0.5 mg BID to about 2.5 mg BID administered twice daily (BID); and wherein the maintenance dose comprises from about 3.0 mg BID to about 4.0 mg BID.

[0021] Some embodiments of the present invention describe a method for treating a patient in need of treatment for a neurological disorder and a seizure disorder, wherein the patient has a favorable side effect profile, the method comprising administering a first dosing regimen selected from at least one of a. to i. (further described below) and a second dosing regimen selected from at least one of j. to o. (further described below), provided that the second dosing regimen is incremented from the first dosing regimen, and further provided that the last dosing regimen is a maintenance dose and will thus be administered for as long as the patient requires its treatment:

[0022] a. Optionally administer a dose of about 0.25 mg of huperzine A every about 12 hours for at least two days and at most two weeks;

[0023] b. Optionally administer a dose of about 0.5 mg of huperzine A every about 12 hours for at least two days and at most two weeks;

[0024] c. Optionally administer a dose of about 0.75 mg of huperzine A every about 12 hours for at least two days and at most two weeks;

[0025] d. Optionally administer a dose of about 1 mg of huperzine A every about 12 hours for at least two days and at most two weeks;

[0026] e. Optionally administer a dose of about 1.25 mg of huperzine A, once every about 12 hours for at least two days and at most two weeks;

[0027] f. Optionally administer a dose of about 1.5 mg of huperzine A, once every about 12 hours for at least two days and at most two weeks;

[0028] g. Optionally administer a dose of about 1.75 mg of huperzine A, once every about 12 hours for at least two days and at most two weeks;

[0029] h. Optionally administer a dose of about 2 mg of huperzine A, once every about 12 hours for at least two days;

[0030] i. Optionally administer a dose of about 2.5 mg of huperzine A, once every about 12 hours for at least two days;

[0031] j. Optionally administer a dose of about 2.75 mg of huperzine A, once every about 12 hours for at least two days;

[0032] k. Optionally administer a dose of about 3.0 mg of huperzine A, once every about 12 hours for at least two days;

[0033] l. Optionally administer a dose of about 3.25 mg of huperzine A, once every about 12 hours for at least two days;

[0034] m. Optionally administer a dose of about 3.5 mg of huperzine A, once every about 12 hours for at least two days;

[0035] n. Optionally administer a dose of about 3.75 mg of huperzine A, once every about 12 hours for at least two days;

[0036] o. Optionally administer a dose of about 4.0 mg of huperzine A, once every about 12 hours for at least two days;

[0037] wherein the huperzine A in a.-o. is administered in the form of a modified release formulation of huperzine A. In some embodiments, the modified release formulation of huperzine A is a pharmaceutical composition according to any of the embodiments described herein.

[0038] Some embodiments describe a method of treating a disorder in a patient in need thereof selected from the group consisting of a neurological disorder and a seizure disorder, wherein the patient has a favorable side effect profile, the method comprising administering a modified release formulation of huperzine A, wherein the modified release agent of huperzine A is characterized in healthy subjects by the steady-state average plasma concentration (C ss)selected from the group consisting of: about 0.52 to about 0.82 ng / mL at a dose of 0.25 mg; about 1.91 to about 2.99 ng / mL at a dose of 0.50 mg; about 3.56 to about 5.55 ng / mL at a dose of 0.75 mg; about 5.58 to about 8.72 ng / mL at a dose of 1 mg; about 8.22 to about 12.84 ng / mL at a dose of 1.25 mg; about 9.02 to about 14.09 ng / mL at a dose of 1.5 mg; about 10.04 to about 15.69 ng / mL at a dose of 1.75 mg; about 16 to about 25 ng / mL at a dose of 2.0 mg; and about 18.48 to about 28.88 ng / mL at a dose of 2.5 mg; about 25.2 ng / ml at a dose of 2.75 mg; about 27.8 ng / mL at a dose of 3.0 mg; about 30.3 ng / mL at a dose of 3.25 mg; about 32.9 ng / mL at a dose of 3.50 mg; about 35.5 ng / mL at a dose of 3.75 mg and about 38.0 ng / mL at a dose of 4.0 mg.

[0039] Some embodiments describe a method of treating a disorder in a patient in need thereof selected from the group consisting of a neurological disorder and a seizure disorder, wherein the patient has a favorable side effect profile and / or reduced seizure frequency, the method comprising administering a modified release formulation of huperzine A, wherein the modified release formulation of huperzine A is characterized in that when administered at a therapeutically effective dose, the C of huperzine A in plasma ss is at least 8 ng / mL. BRIEF DESCRIPTION OF THE DRAWINGS

[0040] Figure 1 Shows simulated plasma levels of huperzine A after immediate release dosing on an exemplary titration schedule of 2 mg BID.

[0041] Figure 2 Shows simulated plasma levels of the modified release formulation 4A of huperzine A based on a titration schedule of 0.5 mg huperzine A twice daily for 1 - 2 days; 1 mg huperzine A twice daily for 3 - 4 days; 1.5 mg huperzine A twice daily for 5 - 6 days and 2 mg twice daily for 7 - 11 days.

[0042] Figure 3 Shows in vivo plasma concentrations over time in healthy subjects obtained during dose titration of the pharmaceutical composition 4D from 0.25 mg to 2.5 mg.

[0043] Figure 4 Shows in vivo plasma concentrations (C ss ) in healthy humans at various doses of the pharmaceutical composition 4D.

[0044] Figure 5 Shows the mean in vivo plasma concentrations of three human patients obtained during dose titration with Formulations 4F1 / 4F2 at doses of 0.5 mg, 0.75 mg, 1.25 - 1.75 mg, and 2.5 mg BID.

[0045] Figure 6A and 6B Shows a graph of plasma levels versus seizure counts for three human patients.

[0046] Figure 7 Is a schematic diagram of the composition of the present invention. Detailed Description

[0047] Definition

[0048] The present invention is not limited to the specific methods, compositions, or processes described, as these may vary. The terms used in this specification are for the purpose of describing particular forms or embodiments only and are not intended to limit the scope of the present invention. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. All publications mentioned herein are incorporated by reference in their entirety. Nothing herein should be construed as an admission that the present invention is not entitled to antedate such disclosure by virtue of prior invention.

[0049] It must also be noted that, unless the context clearly dictates otherwise, as used herein and in the appended claims, the singular forms "a / an" and "the" include plural referents. Thus, for example, reference to "a symptom" refers to one or more symptoms and their equivalents known to those skilled in the art, and so forth.

[0050] As used herein, the term "about" means plus or minus 10% of the numerical value of the number with which it is used. Thus, about 50 mL means in the range of 45 mL - 55 mL.

[0051] The terms "administering" or "administration", etc. refer to providing the composition of the present invention (e.g., a composition according to any of the embodiments described herein) to a subject in need of treatment. Preferably, the subject is a mammal, more preferably a human. The present invention includes administering a composition according to any of the embodiments described herein alone or in combination with another therapeutic agent. When a composition according to any of the embodiments described herein is administered in combination with another therapeutic agent, the composition and the other therapeutic agent may be administered simultaneously or at different times.

[0052] As used herein, "adverse event" refers to any adverse medical event in a patient or clinical study participant who has received a pharmaceutical product and is not necessarily causally related to such treatment. For example, an adverse event can cause discomfort to a subject and (a) disrupt the subject's daily activities, (b) cause a substantial interference with the subject's daily activities and may be disabling or life-threatening, (c) endanger the subject's life, (d) result in dose-limiting toxicity, or (e) require additional medication to counter the adverse event, or a combination thereof. For example, if a subject experiences nausea, vomiting, and / or diarrhea after administration of a huperzine preparation such that an antiemetic needs to be administered in order to continue taking the huperzine preparation, then the subject has a dose-limiting adverse event. If a subject experiences a life-threatening event, requires hospitalization, has a medically significant event, has an event that results in persistent or severe disability or incapacity, or an event that results in death, then the subject has a serious adverse event.

[0053] As used herein, "amyloid-related disease" includes diseases associated with the accumulation of amyloid, which can be limited to one organ, "localized amyloidosis"; or spread to several organs, "systemic amyloidosis". Secondary amyloidosis may be associated with chronic infections (such as tuberculosis) or chronic inflammation (such as rheumatoid arthritis), including a familial form of secondary amyloidosis, which is also seen in familial Mediterranean fever (FMF) and another type of systemic amyloidosis found in patients on long-term hemodialysis. Localized forms of amyloidosis include, but are not limited to, type II diabetes and any related diseases, neurodegenerative diseases such as scrapie, bovine spongiform encephalopathy, Creutzfeldt-Jakob disease, Alzheimer's disease, senile systemic amyloidosis (SSA), cerebral amyloid angiopathy, Parkinson's disease, and prion protein-related disorders (such as prion-related encephalopathies) and rheumatoid arthritis.

[0054] The phrase "better side effect profile" means that, compared to an immediate-release formulation of huperzine, one or more side effects experienced by a patient or group of patients after treatment with a modified-release formulation of huperzine (1) have a lower incidence, (2) have a shorter duration, or (3) have a lower severity, or a combination thereof.

[0055] The term "C max " is the peak plasma concentration of a drug after administration to a subject.

[0056] As used herein, the term "dose" refers to the amount of an active compound, such as huperzine or huperzine A without any inactive ingredients or salts.

[0057] As used herein, the term "effective amount" refers to the amount of a drug or agent, or combination of drugs or agents, that will elicit a biological or medical response in a tissue, system, animal, or human, such as that sought by a researcher or clinician.

[0058] As used herein, the term "epilepsy" refers to a brain disorder characterized by a persistent predisposition to epileptic seizures, as well as the neurobiological, cognitive, psychological, and social consequences of this disorder. An epileptic seizure is a transient occurrence of signs and / or symptoms due to abnormal, excessive, or synchronous neuronal activity in the brain.

[0059] Those skilled in the art will understand that the term "plasticized ethylcellulose" is also known by non-proprietary names, for example, "plasticized ethylcellulose"; synonyms and several brand names, such as

[0060] Those skilled in the art will understand that the term "hydroxyproylmethylcellulose" is also known by many non-proprietary names, for example, "HPMC", "hydroxypropylmethylcellulose", "hypromellosum", and "hypromellose"; synonyms; and several brand names, such as Methocel TM 。

[0061] Unless otherwise defined in a particular embodiment, the term "huperzine" refers to huperzine A, huperzine B, or huperzine C, or a pharmaceutically acceptable salt or solvate thereof. Huperzine A is (1R,9S,13E)-1-amino-13-ethylidene-11-methyl-6-azatricyclo[7.3.1.02,7]trideca-2(7),3,10-triene-5-one. Huperzine B is (4aR,5R,10bR)-2,3,4,4a,5,6-hexahydro-12-methyl-1H-5,10b-propano-1,7-phenanthrolin-8(7H)-one. Huperzine C is (1R,9S,13R)-1-amino-13-vinyl-11-methyl-6-azatricyclo[7.3.1.02,7]trideca-2(7),3,10-triene-5-one.

[0062]

[0063] Preferably, in any of the embodiments described herein, the huperzine is huperzine A.

[0064] As used herein, the term "maintenance dose" refers to the dose of huperzine administered to maintain the desired level of the drug in the blood. In some embodiments, the maintenance dose is a therapeutically effective amount.

[0065] The term "modified release formulation of huperzine" refers to any oral huperzine formulation in which the release characteristics of huperzine, including time, duration, and / or location, are selected to achieve a therapeutic or convenience objective not provided by immediate release of huperzine.

[0066] The term "neurological disorder" includes, but is not limited to, amyloid-related disorders such as Alzheimer's disease and amyloid disorders as described herein, psychiatric disorders such as Tourette syndrome, post-traumatic stress disorder (PTSD), panic disorder, and anxiety disorders, obsessive-compulsive disorder, and schizophrenia, developmental disorders such as fragile X syndrome and autism, pain, drug addiction such as alcoholism, neurodegenerative diseases such as Parkinson's disease and Huntington's disease, and stroke and ischemic brain injury, amyotrophic lateral sclerosis, and epilepsy. "Neurological disorder" also includes any disorder, symptom, or effect associated with or related to exposure to neurotoxins, including but not limited to neurotoxins such as chemical warfare agents.

[0067] The terms "patient" or "subject" are used throughout the specification in context to describe an animal, typically a mammal and preferably a human, being treated with a pharmaceutical composition according to any of the embodiments described herein, including prophylactic treatment (prevention). For the treatment of those infections, afflictions, or disease states specific to a particular animal such as a human patient, the term patient refers to the particular animal.

[0068] "Pharmaceutically acceptable" means that the carrier, diluent, or excipient must be compatible with the other ingredients of the formulation and not harmful to its recipient.

[0069] The term "pharmaceutically acceptable huperzine salt equivalent to about 1% by weight of huperzine" refers to a pharmaceutically acceptable huperzine salt that, if converted to huperzine, would provide about 1% by weight of huperzine A free base. Similarly, the terms "pharmaceutically acceptable huperzine salt equivalent to about 0.5% to about 1.5% by weight", "pharmaceutically acceptable huperzine salt equivalent to about 0.9% to about 1% by weight", "pharmaceutically acceptable huperzine salt equivalent to about 0.95% to about 1% by weight", etc., refer to pharmaceutically acceptable huperzine salts that, if converted to huperzine, would provide about 0.5% to about 1.5%, about 0.9% to about 1%, about 0.95% to about 1% huperzine free base, respectively. For example, 6 grams of huperzine A are required to provide 1% by weight of a 600-gram pharmaceutical formulation, but 6.89 g of the HCl salt of huperzine A are required to provide 1% by weight of huperzine A.

[0070] Those skilled in the art will understand that the term "polyvinylpyrrolidone" is also known by several non-proprietary names, e.g., "PVP", "polyvinyl pyrrolidone", "povidone", and "polyvidone". It should also be understood that polyvinylpyrrolidone is referred to by its K value, which indicates the average molecular weight of polyvinylpyrrolidone. Examples of polyvinylpyrrolidone include, but are not limited to, polyvinylpyrrolidone K30, polyvinylpyrrolidone K10, polyvinylpyrrolidone K360, polyvinylpyrrolidone K40.

[0071] As used herein, the term "seizure disorder" refers to any disorder in which one or more seizures are symptomatic. As used herein, seizures may be due to abnormal electrical activity in the brain or may be non-epileptic seizures, which are not accompanied by abnormal electrical activity in the brain. Seizures can be caused by (e.g., but not limited to) psychological problems, psychological stress, trauma, hypoglycemia, hyponatremia, fever, alcohol use or drug use, or unknown causes. Types of seizures and seizure disorders include, but are not limited to, epilepsy (including intractable epilepsy), generalized seizures, primary generalized seizures, absence seizures, myoclonic seizures, partial seizures, complex partial seizures with or without generalization (e.g., focal impaired awareness seizures (FIAS)), Lennox-Gastaut Syndrome, Dravet Syndrome, and generalized epilepsy with febrile seizure plus (GEFS+). In some embodiments, the seizure disorder is epilepsy.

[0072] As used herein, the term "therapeutic agent" refers to an agent that is utilized to treat, combat, ameliorate, prevent, or improve an unwanted disorder or disease in a patient. In part, embodiments of the present invention relate to the treatment of neurodegenerative diseases, including seizure disorders such as epilepsy.

[0073] The term "therapeutically effective amount" refers to any amount that results in an improvement in a disease, disorder, or side effect, such that the treatment, cure, prevention, or amelioration occurs, or the rate of progression of the disease or disorder is reduced. The term also includes within its scope an amount that effectively enhances normal physiological function.

[0074] The term "t 1 / 2 " is the time it takes for the plasma concentration to reach half of its original value after the formulation is administered to a subject.

[0075] "t max " refers to the time it takes to reach C after the formulation is administered to a subjectmax Time.

[0076] As used herein, the terms "treat", "treated" or "treating" refer to therapeutic treatment and prophylactic or preventive measures, wherein the goal is to prevent or slow down (mitigate) an undesired physiological disorder, condition or disease, or to obtain a beneficial or desired clinical outcome. For the purposes of the present invention, beneficial or desired clinical outcomes include, but are not limited to: alleviation of symptoms; reduction in the degree of a disorder, condition or disease; stabilization (i.e., no worsening) of the state of a disorder, condition or disease; delay in the onset of a disorder, condition or disease or slowing of the progression of a disorder, condition or disease; amelioration of the state of a disorder, condition or disease; and remission (whether partial or complete) (whether detectable or undetectable) or enhancement or improvement of a disorder, condition or disease. Treatment includes eliciting a clinically significant response without an excessive level of side effects. Treatment also includes an extension of survival as compared to the expected survival in the absence of treatment.

[0077] In some embodiments, the compounds and methods disclosed herein can be used with or for a subject in need of such treatment, which subject may also be referred to as "in need". As used herein, the phrase "in need" means that the subject has been identified as having a need for a particular method or treatment and has been administered such treatment for that particular purpose.

[0078] Generally, the term "tissue" refers to any aggregate of similar specialized cells united in the performance of a particular function.

[0079] The embodiments set forth herein are described with "comprising", however any embodiment described herein can also be described with "consists of" or "consisting of", which means that the formulation or method includes only the elements, steps or ingredients specifically recited in the particular claimed embodiment or claim and in each embodiment described herein, or can be described with "consisting essentially of" or "consists essentially of", which means that the formulation or method includes only the specified materials or steps and those materials or steps that do not materially affect the basic and novel features of the claimed invention.

[0080] The term "VEM" refers to video electroencephalogram monitoring.

[0081] Pharmaceutical composition

[0082] Embodiments of the present invention relate to modified release oral pharmaceutical compositions of huperzine and, more particularly, to huperzine A. The Applicant has discovered a modified release formulation of huperzine that provides therapeutically effective plasma concentrations of huperzine even at high doses administered twice daily and overcomes the rapid peak plasma levels associated with the dose-limiting side effects of huperzine. Exemplary formulations are disclosed in U.S. Application No. 15 / 985,390, filed May 21, 2018, the disclosure of which is incorporated herein by reference in its entirety.

[0083] Dose escalation studies (not published) conducted by the Applicant have shown that peak plasma levels greater than about 5 ng / mL are highly likely to cause nausea and vomiting, especially within the first 31 hours. In the study, 7 out of 8 subjects experienced nausea and / or vomiting within the first 31 hours. The mean initial nausea time for these subjects was 17.7 hours and they exhibited a mean huperzine plasma level of 4.8 ng / mL. The one subject who did not experience nausea did not reach plasma levels above 5 ng / mL until 42 hours after the initial dose. These findings would suggest the existence of a time-concentration relationship where plasma exposure between 4 - 5 ng / mL achieved within the first 31 hours may lead to drug-related adverse events. Prior to the Applicant's immediate release dose escalation studies, it was not known at what plasma concentration threshold to keep below in order to obtain a better side effect profile and / or reduced seizure frequency.

[0084] Thus, twice-daily administration of about 2 mg of immediate release huperzine A is expected to cause early high plasma peaks associated with nausea and vomiting. Additionally, peak-to-trough plasma exposure is expected to fluctuate below the therapeutic threshold. Further, a single missed dose of huperzine is expected to not only place the subject below the therapeutic threshold, but upon resuming the immediate release dose, expose the subject to rapid peak plasma concentrations, potentially resulting in nausea and vomiting with each missed dose ( Figure 1 ). This makes the immediate release formulation an unfavorable and potentially dangerous treatment option. In contrast, the modified release formulation developed by the Applicant and administered as described herein achieves the therapeutic threshold and, unlike immediate release pharmaceutical formulations, initially keeps the plasma exposure level below the 5 ng / mL threshold, thus avoiding the adverse nausea and vomiting associated with the immediate release formulation. Further, if a subject misses a dose after achieving the therapeutic level, the plasma concentration will not drop so low as to result in a serious adverse event ( Figure 2)。The Applicant has described modified release formulations of huperzine at up to 5 mg / day and up to 2.5 mg BID doses in U.S. Patent Application No. 15 / 985,390; said patent application is incorporated herein by reference in its entirety. However, higher doses of huperzine are considered disadvantageous due to dose-limiting adverse effects such as increased nausea, vomiting, and / or diarrhea.

[0085] The Applicant has now found that higher dose modified release oral formulations of huperzine have unexpectedly unpredictable properties compared to other dose oral formulations of huperzine. These formulations and dosing regimens allow for attainment of a higher therapeutic threshold without side effects associated with peak plasma levels and also allow for twice-daily dosing.

[0086] To illustrate the advantages of the modified release formulation of huperzine A in treating, for example, seizure disorders, the Applicant used non-clinical animal data. The Applicant generated pharmacokinetic data in dogs (see below), allometric scaling, and modeling to determine the C of huperzine A in plasma of about 16 ng / mL (2.5 mg BID dose) to about 28 ng / mL (4 mg BID dose) compared to 0.5 mg to 2.0 mg BID doses. max A significant improvement in efficacy is expected to be achieved in treating subjects suffering from seizure disorders.

[0087] The modified release oral pharmaceutical formulation of huperzine of the present invention comprises a soluble core; a huperzine layer coating the soluble core; a polymer coating the huperzine layer; and an optional curable topcoat comprising HPMC or Opadry; wherein the huperzine layer comprises a therapeutically effective amount of huperzine.

[0088] In some embodiments of the present invention, the soluble core is a completely soluble core. In other embodiments, the core is a sugar sphere. In some aspects, the sugar sphere comprises sucrose and starch. In some embodiments, the sucrose is at least 62 wt% sucrose. In other embodiments, the sugar sphere is Sugar spheres. In some aspects, the sugar spheres have a particle size of from about 250 μm to about 1700 μm. In some embodiments, the sugar spheres are selected from particle sizes of from about 250 μm to about 355 μm, from about 500 μm to about 600 μm, from about 600 μm to about 710 μm, from about 710 μm to about 850 μm, from about 850 μm to about 1000 μm, from about 850 μm to about 1180 μm, from about 1000 μm to about 1180 μm, from about 1000 μm to about 1400 μm, from about 1400 μm to about 1700 μm, and combinations thereof. In other embodiments, the sugar spheres are selected from particle sizes of from about 500 μm to about 600 μm or from about 600 μm to about 710 μm. In some embodiments, the sugar spheres are selected from particle sizes of from about 500 μm to about 710 μm. In some embodiments, the sugar spheres are PF006.

[0089] In other embodiments, the sugar spheres account for from about 74 wt% to about 86 wt% of the pharmaceutical composition. In some embodiments, the sugar spheres account for from about 79 wt% to about 84 wt% of the pharmaceutical composition. In some embodiments, the sugar spheres account for from about 80 wt% to about 86 wt% of the pharmaceutical composition. In some embodiments, the sugar spheres account for from about 80 wt% to about 83 wt% of the pharmaceutical composition. In some embodiments, the sugar spheres account for from about 81 wt% to about 83 wt% of the pharmaceutical composition. In some embodiments, the sugar spheres account for from about 81 wt% to about 82.8 wt% of the pharmaceutical composition. In some embodiments, the sugar spheres account for from 81.5 wt% to 83.0 wt%. In some embodiments, the sugar spheres account for from about 79.1 wt% to about 80 wt% of the pharmaceutical composition. In some embodiments, the sugar spheres account for from about 80 wt% to about 81 wt% of the pharmaceutical composition. In some embodiments, the sugar spheres account for from about 81 wt% to about 82 wt% of the pharmaceutical composition. In some embodiments, the sugar spheres account for from about 81 wt% to about 81.9 wt% of the pharmaceutical composition. In some embodiments, the sugar spheres account for from about 81.9 wt% to about 82.8 wt% of the pharmaceutical composition. In some embodiments, the sugar spheres account for from about 82 wt% to about 83 wt% of the pharmaceutical composition. In some embodiments, the sugar spheres account for from about 82.8 wt% to about 83.7 wt% of the pharmaceutical composition.

[0090] In some embodiments, the weight percentage of the sugar spheres in the pharmaceutical composition is between a lower limit of about 74 wt%, about 75 wt%, about 76 wt%, about 77 wt%, about 78 wt%, about 79 wt%, about 80 wt%, about 81 wt%, about 82 wt%, about 83 wt%, about 84 wt%, about 85 wt% and about 86 wt% and an upper limit of about 86 wt%, about 85 wt%, about 84 wt%, 83 wt%, 82 wt%, 81 wt%, 80 wt%, 79 wt%, 78 wt%, 77 wt%, 76 wt%, 75 wt% and 74 wt%.

[0091] In some embodiments, the weight percentage of the sugar spheres in the pharmaceutical composition is about 74 wt%, about 75 wt%, about 76 wt%, about 77 wt%, about 78 wt%, about 79 wt%, about 80 wt%, about 81 wt%, about 82 wt%, about 83 wt%, about 84 wt%, about 85 wt% or about 86 wt%.

[0092] In some embodiments of the present invention, the huperzine layer comprises huperzine A or a pharmaceutically acceptable salt thereof. In some embodiments, huperzine A is an extract of Huperzia serrata. In some embodiments, the extract of Huperzia serrata is 99% huperzine A.

[0093] In some aspects, the weight percentage of huperzine in the pharmaceutical composition comprises from about 0.4 wt% to about 1.5 wt% of huperzine or a pharmaceutically acceptable salt of huperzine equivalent to from 0.4 wt% to about 1.5 wt% of huperzine. In some embodiments, the weight percentage of huperzine in the pharmaceutical composition comprises from about 0.9 wt% to about 1 wt% of huperzine or a pharmaceutically acceptable salt of huperzine equivalent to from 0.9 wt% to about 1 wt% of huperzine. In some embodiments, the weight percentage of huperzine in the pharmaceutical composition comprises from about 0.95 wt% to about 1 wt% of huperzine or a pharmaceutically acceptable salt of huperzine equivalent to from 0.95 wt% to about 1 wt% of huperzine. In some embodiments, the weight percentage of huperzine in the pharmaceutical composition comprises about 1 wt% of huperzine or a pharmaceutically acceptable salt of huperzine equivalent to about 1 wt%. In some embodiments, the weight percentage of huperzine in the pharmaceutical composition comprises between the lower limits of about 0.4 wt%, 0.5 wt%, about 0.6 wt%, about 0.7 wt%, about 0.8 wt%, about 0.9 wt%, about 1 wt%, about 1.1 wt%, about 1.2 wt%, about 1.3 wt%, about 1.4 wt% and about 1.5 wt% and the upper limits of about 1.5 wt%, about 1.4 wt%, about 1.3 wt%, 1.2 wt%, 1.1 wt%, 1 wt%, 0.9 wt%, 0.8 wt%, 0.7 wt%, 0.6 wt%, 0.5 wt% and 0.4 wt% of huperzine, or a pharmaceutically acceptable salt of huperzine equivalent to the lower limits of about 0.5 wt%, about 0.6 wt%, about 0.7 wt%, about 0.8 wt%, about 0.9 wt%, about 1 wt%, about 1.1 wt%, about 1.2 wt%, about 1.3 wt%, about 1.4 wt% and about 1.5 wt% and the upper limits of about 1.5 wt%, about 1.4 wt%, about 1.3 wt%, 1.2 wt%, 1.1 wt%, 1 wt%, 0.9 wt%, 0.8 wt%, 0.7 wt%, 0.6 wt%, 0.5 wt% and 0.4 wt% of huperzine. In some embodiments, the weight percentage of huperzine in the pharmaceutical composition comprises 0.4 wt%, 0.5 wt%, about 0.6 wt%, about 0.7 wt%, about 0.8 wt%, about 0.9 wt%, about 1 wt%, about 1.1 wt%, about 1.2 wt%, about 1.3 wt%, about 1.4 wt% and about 1.5 wt%, or a pharmaceutically acceptable salt of huperzine equivalent to 0.4 wt%, 0.5 wt%, about 0.6 wt%, about 0.7 wt%, about 0.8 wt%, about 0.9 wt%, about 1 wt%, about 1.1 wt%, about 1.2 wt%, about 1.3 wt%, about 1.4 wt% and about 1.5 wt% of huperzine. In other embodiments, the huperzine layer comprises a therapeutically effective amount of huperzine.

[0094] In some embodiments, according to any of the embodiments described herein, huperzine or a pharmaceutically acceptable salt thereof is huperzine A or a pharmaceutically acceptable salt thereof.

[0095] In some aspects, the huperzine layer further comprises one or more excipients. In some embodiments, the total amount of the excipient is from about 5 wt% to about 10 wt% of the pharmaceutical composition. In some embodiments, the total amount of the excipient is from about 5 wt% to about 9 wt% of the pharmaceutical composition. In some embodiments, the total amount of the excipient is from about 5 wt% to about 7 wt% of the pharmaceutical composition. In some embodiments, the total amount of the excipient in the huperzine layer is selected from about 5 wt%, about 6 wt%, about 7 wt%, about 8 wt%, about 9 wt% or about 10 wt% of the pharmaceutical composition. In some embodiments, the excipient is selected from hydroxypropyl methylcellulose or polyvinylpyrrolidone and combinations thereof.

[0096] In some embodiments, the hydroxypropyl methylcellulose is a low-viscosity or very low-viscosity hydroxypropyl methylcellulose, such as Methocel TM . In other embodiments, the hydroxypropyl methylcellulose is Methocel VLV, etc. In some aspects, the amount of hydroxypropyl methylcellulose in the huperzine layer is from about 6 wt% to about 7 wt% of the composition. In some aspects, the amount of hydroxypropyl methylcellulose in the huperzine layer is from about 5 wt% to about 6 wt% of the composition. In some embodiments, the amount of hydroxypropyl methylcellulose in the huperzine layer is about 6 wt%. In some embodiments, the amount of hydroxypropyl methylcellulose in the huperzine layer is about 5 wt%. In other embodiments, the hydroxypropyl methylcellulose is Methocel VLV, and the amount of Methocel VLV in the huperzine layer is about 6.1 wt% of the composition.

[0097] In some embodiments of the present invention, the polyvinylpyrrolidone is any polyvinylpyrrolidone suitable for use in oral formulations. In other embodiments, the polyvinylpyrrolidone is polyvinylpyrrolidone K30. In some aspects, the amount of polyvinylpyrrolidone in the huperzine layer is from about 0.5 wt% to about 1.5 wt% of the composition. In some embodiments, the polyvinylpyrrolidone in the huperzine layer is from about 0.95 wt% to about 1 wt% of the composition. In some embodiments, the polyvinylpyrrolidone in the huperzine layer is from about 0.90 wt% to about 1 wt% of the composition. In some embodiments, the polyvinylpyrrolidone in the huperzine layer is about 1 wt% of the composition. In other embodiments, the polyvinylpyrrolidone is polyvinylpyrrolidone K30, and the amount of polyvinylpyrrolidone K30 in the huperzine layer is about 1 wt% of the composition.

[0098] In some embodiments, one or more excipients in the huperzine layer are a combination of hydroxypropyl methylcellulose and polyvinylpyrrolidone. In some embodiments, one or more excipients in the huperzine layer are from about 5 wt% to about 7 wt% hydroxypropyl methylcellulose and from about 0.5 wt% to about 1.5 wt% polyvinylpyrrolidone. In some embodiments, one or more excipients in the huperzine layer are about 6 wt% hydroxypropyl methylcellulose and about 1 wt% polyvinylpyrrolidone.

[0099] In some embodiments of the present invention, the polymer coating is a polyacrylamide polymer or ethylcellulose polymer layer coating the huperzine layer. In some embodiments, the polymer coating is a non-polyacrylamide polymer coating coating the huperzine layer. In some embodiments, the polymer coating is a plasticized ethylcellulose polymer layer coating the huperzine layer. In other embodiments, the plasticized ethylcellulose is In some aspects, the plasticized ethylcellulose is NF type B.

[0100] In some embodiments, the plasticized ethylcellulose polymer accounts for from about 7 wt% to about 16 wt% of the composition. In some embodiments, the plasticized ethylcellulose polymer accounts for from about 8 wt% to about 13 wt% of the composition. In some embodiments, the plasticized ethylcellulose polymer accounts for from about 7 wt% to about 12 wt% of the composition. In some embodiments, the plasticized ethylcellulose polymer accounts for from about 8 wt% to about 12 wt% of the composition. In some embodiments, the plasticized ethylcellulose polymer accounts for from about 9 wt% to about 11 wt% of the composition. In some embodiments, the plasticized ethylcellulose polymer accounts for from about 9 wt% to about 10 wt% of the composition. In some embodiments, the plasticized ethylcellulose polymer accounts for from about 8.3 wt% to about 9.2 wt% of the pharmaceutical composition. In some embodiments, the plasticized ethylcellulose polymer accounts for from about 9.2 wt% to about 10.1 wt% of the pharmaceutical composition. In some embodiments, the plasticized ethylcellulose polymer accounts for from about 10.1 wt% to about 11 wt% of the pharmaceutical composition. In some embodiments, the plasticized ethylcellulose polymer accounts for from about 11 wt% to about 12 wt% of the pharmaceutical composition. In some embodiments, the plasticized ethylcellulose polymer accounts for from about 12 wt% to about 12.9 wt% of the pharmaceutical composition. In some embodiments, the plasticized ethylcellulose polymer accounts for from about 15 wt% to about 16 wt% of the pharmaceutical composition.

[0101] In some embodiments, the weight percentage of the plasticized ethylcellulose polymer in the composition is between a lower limit of 7 wt%, 8 wt%, 9 wt%, 10 wt%, 11 wt%, 12 wt%, 13 wt%, 14 wt%, 15 wt% and 16 wt% and an upper limit of 16 wt%, 15 wt%, 14 wt%, 13 wt%, 12 wt%, 11 wt%, 10 wt%, 9 wt%, 8 wt% and 7 wt%.

[0102] In some embodiments, a pharmaceutical composition for oral delivery comprises:

[0103] a) a soluble core according to any of the embodiments herein described for soluble cores;

[0104] b) a huperzine layer coating the soluble core, the huperzine layer according to any of the embodiments herein described for huperzine layers, huperzine or pharmaceutically acceptable salts of huperzine, the huperzine layer comprising huperzine or a pharmaceutically acceptable salt of huperzine; and

[0105] c) a polymer coating coating the huperzine layer according to any of the embodiments herein described; and

[0106] d) an optional curable topcoat coating the polymer layer and comprising HPMC or an Opadry sealing coating.

[0107] In some aspects of the invention, a pharmaceutical composition for oral delivery comprises: (a) from about 74 wt% to about 86 wt% of a sugar sphere core, wherein the sugar sphere core has a particle size of about 500 - 710 μm; (b) a huperzine layer coating the sugar sphere, wherein the huperzine layer comprises from about 0.95 wt% to about 1 wt% of huperzine or a pharmaceutically acceptable salt of huperzine equivalent to from about 0.95 wt% to about 1 wt% of huperzine and one or more excipients, wherein the total amount of excipients is from about 5 wt% to about 9 wt%; (c) a plasticized ethylcellulose polymer layer from about 7 wt% to about 16 wt% coating the huperzine layer, wherein the huperzine layer comprises a therapeutically effective amount of huperzine. In other aspects, the huperzine is huperzine A. In other embodiments, the one or more excipients are a combination of hydroxypropylmethylcellulose and polyvinylpyrrolidone. In other embodiments, the one or more excipients are a combination of about 6 wt% hydroxypropylmethylcellulose and about 1 wt% polyvinylpyrrolidone. In some embodiments, the hydroxypropylmethylcellulose is low viscosity hydroxypropylmethylcellulose, the polyvinylpyrrolidone is polyvinylpyrrolidone K30, and the plasticized ethylcellulose is NF type B.

[0108] In some aspects of the present invention, a pharmaceutical composition for oral delivery comprises: (a) from about 79 wt% to about 84 wt% of a sugar sphere core, wherein the sugar sphere core has a particle size of about 500 - 710 μm; (b) a huperzine layer coating the sugar sphere, wherein the huperzine layer comprises from about 0.95 wt% to about 1 wt% of huperzine or a pharmaceutically acceptable salt of huperzine equivalent to from about 0.95 wt% to about 1 wt% of huperzine, about 6 wt% of hydroxypropyl methylcellulose, and from 0.95 wt% to about 1 wt% of polyvinylpyrrolidone; and (c) a plasticized ethylcellulose polymer layer from about 8 wt% to about 13 wt% coating the huperzine layer, wherein the huperzine layer comprises a therapeutically effective amount of huperzine. In other aspects, the huperzine is huperzine A. In other aspects, the huperzine is huperzine A, the hydroxypropyl methylcellulose is low viscosity hydroxypropyl methylcellulose, the polyvinylpyrrolidone is polyvinylpyrrolidone K30, and the plasticized ethylcellulose is NF type B, the hydroxypropyl methylcellulose is low viscosity hydroxypropyl methylcellulose, the polyvinylpyrrolidone is polyvinylpyrrolidone K30, and the plasticized ethylcellulose is NF type B.

[0109] In some aspects of the present invention, a pharmaceutical composition for oral delivery comprises: (a) from about 80 wt% to about 83 wt% of a sugar sphere core, wherein the sugar sphere core has a particle size of about 500 - 710 μm; (b) a huperzine layer coating the sugar sphere, wherein the huperzine layer comprises from about 0.95 wt% to about 1 wt% of huperzine or a pharmaceutically acceptable salt of huperzine equivalent to from about 0.95 wt% to about 1 wt% of huperzine, from about 5 wt% to about 6 wt% of hydroxypropyl methylcellulose, and from 0.95 wt% to about 1 wt% of polyvinylpyrrolidone; and (c) a plasticized ethylcellulose polymer layer from about 8 wt% to about 12 wt% coating the huperzine layer, wherein the huperzine layer comprises a therapeutically effective amount of huperzine. In other aspects, the huperzine is huperzine A, the hydroxypropyl methylcellulose is low viscosity hydroxypropyl methylcellulose, the polyvinylpyrrolidone is polyvinylpyrrolidone K30, and the plasticized ethylcellulose is NF type B.

[0110] In some aspects of the present invention, a pharmaceutical composition for oral delivery comprises: (a) about 81 wt% to about 82 wt% of a sugar sphere core, wherein the sugar sphere core has a particle size of about 500 - 710 μm; (b) a huperzine layer coating the sugar spheres, wherein the huperzine layer comprises about 0.95 wt% to about 1 wt% of huperzine or a pharmaceutically acceptable salt of huperzine equivalent to about 0.95 wt% to about 1 wt% of huperzine, about 5 wt% to about 6 wt% of hydroxypropyl methylcellulose, and about 0.95 wt% to about 1 wt% of polyvinylpyrrolidone; and (c) a plasticized ethylcellulose polymer layer of about 10 wt% to about 11 wt% coating the huperzine layer, wherein the huperzine layer comprises a therapeutically effective amount of huperzine. In other aspects, the huperzine is huperzine A, the hydroxypropyl methylcellulose is low viscosity hydroxypropyl methylcellulose, the polyvinylpyrrolidone is polyvinylpyrrolidone K30, and the plasticized ethylcellulose is NF type B.

[0111] In some aspects of the present invention, a pharmaceutical composition for oral delivery comprises: (a) about 81.5 wt% of a sugar sphere core, wherein the sugar sphere core has a particle size of about 500 - 710 μm; (b) a huperzine layer covering the sugar spheres, wherein the huperzine layer comprises about 1 wt% of huperzine or a pharmaceutically acceptable salt of huperzine equivalent to 1 wt% of huperzine, about 5.9 wt% of hydroxypropyl methylcellulose, and about 1 wt% of polyvinylpyrrolidone; and (c) a plasticized ethylcellulose polymer layer of about 10.7 wt% covering the huperzine layer, wherein the huperzine layer comprises a therapeutically effective amount of huperzine. In other aspects, the huperzine is huperzine A, the hydroxypropyl methylcellulose is low viscosity hydroxypropyl methylcellulose, the polyvinylpyrrolidone is polyvinylpyrrolidone K30, and the plasticized ethylcellulose is NF type B.

[0112] In some aspects of the present invention, a pharmaceutical composition for oral delivery comprises: (a) from about 82 wt% to about 83 wt% of a sugar sphere core, wherein the sugar sphere core has a particle size of about 500 - 710 μm; (b) a huperzine layer coating the sugar spheres, wherein the huperzine layer comprises from about 0.95 wt% to about 1 wt% of huperzine or a pharmaceutically acceptable salt of huperzine equivalent to from about 0.95 wt% to about 1 wt% of huperzine, from about 5 wt% to about 6 wt% of hydroxypropyl methylcellulose, and from about 0.95 wt% to about 1 wt% of polyvinylpyrrolidone; and (c) a plasticized ethylcellulose polymer layer of from about 9 wt% to about 10 wt% coating the huperzine layer, wherein the huperzine layer comprises a therapeutically effective amount of huperzine. In other aspects, the huperzine is huperzine A, the hydroxypropyl methylcellulose is low viscosity hydroxypropyl methylcellulose, the polyvinylpyrrolidone is polyvinylpyrrolidone K30, and the plasticized ethylcellulose is NF type B.

[0113] In some aspects of the present invention, a pharmaceutical composition for oral delivery comprises: (a) about 83 wt% of a sugar sphere core, wherein the sugar sphere core has a particle size of about 500 - 710 μm; (b) a huperzine layer covering the sugar spheres, wherein the huperzine layer comprises about 1 wt% of huperzine or a pharmaceutically acceptable salt of huperzine equivalent to 1 wt% of huperzine, about 6 wt% of hydroxypropyl methylcellulose, and about 1 wt% of polyvinylpyrrolidone; and (c) a plasticized ethylcellulose polymer layer of about 9 wt% covering the huperzine layer, wherein the huperzine layer comprises a therapeutically effective amount of huperzine. In other aspects, the huperzine is huperzine A, the hydroxypropyl methylcellulose is low viscosity hydroxypropyl methylcellulose, the polyvinylpyrrolidone is polyvinylpyrrolidone K30, and the plasticized ethylcellulose is NF type B.

[0114] In some aspects of the present invention, a pharmaceutical composition for oral delivery according to any of the embodiments described herein further comprises a sealing coating between the huperzine layer and the plasticized ethylcellulose layer.

[0115] In some aspects of the present invention, a pharmaceutical composition for oral delivery according to any of the embodiments described herein further comprises a top coating above the sealing coating. In some embodiments, the top coating may comprise a curable composition comprising HPMC, Surelease, or Opadry.

[0116] In some aspects of the present invention, a pharmaceutical composition for oral delivery comprises: (a) from about 75 wt% to about 76 wt% of a sugar sphere core, wherein the sugar sphere core has a particle size of about 500 - 710 μm; (b) a huperzine layer coating the sugar sphere, wherein the huperzine layer comprises from about 0.9 wt% to about 1 wt% of huperzine or a pharmaceutically acceptable salt of huperzine equivalent to from about 0.9 wt% to about 1 wt% of huperzine, from about 5 wt% to about 6 wt% of hypromellose, and from about 0.9 wt% to about 1 wt% of polyvinylpyrrolidone; (c) a sealing coating coating the huperzine layer, the sealing coating comprising from about 1 wt% to about 2 wt% of hypromellose; and (d) a plasticized ethylcellulose polymer layer of from about 15 wt% to about 16 wt% coating the huperzine layer, wherein the huperzine layer contains a therapeutically effective amount of huperzine. In other aspects, the huperzine is huperzine A, the hypromellose is low viscosity hypromellose, the polyvinylpyrrolidone is polyvinylpyrrolidone K30, and the plasticized ethylcellulose is NF type B.

[0117] Some embodiments describe a pharmaceutical composition according to any of the embodiments described herein, which, when tested at 37 °C in 50 mM phosphate buffer (pH 6.8) using a USP Type 1 dissolution apparatus at 50 revolutions per minute, exhibits the following dissolution profile: about 36% of huperzine is released after 2 hours, about 63% of huperzine is released after 4 hours, about 84% of huperzine is released after 8 hours, and not less than about 89% of huperzine is released after 12 hours. In some embodiments, the huperzine is huperzine A.

[0118] Some embodiments describe a pharmaceutical composition according to any of the embodiments described herein, which, when tested at 37 °C in 50 mM phosphate buffer (pH 6.8) using a USP Type 1 dissolution apparatus at 50 revolutions per minute, exhibits the following dissolution profile: about 46% of huperzine is released after 2 hours, about 77% of huperzine is released after 4 hours, about 97% of huperzine is released after 8 hours, and not less than about 99% of huperzine is released after 12 hours. In some embodiments, the huperzine is huperzine A.

[0119] The pharmaceutical composition of the present invention is formulated for oral administration and can be in the form of, for example, tablets, sprays, capsules, and pills. In one aspect, the pharmaceutical composition according to any of the embodiments described herein is formulated for oral administration in the form of capsules. In some aspects, the pharmaceutical composition according to any of the embodiments described herein is formulated for oral administration in the form of tablets. The compositions of the present invention may contain additional non-toxic pharmaceutically acceptable carriers and / or diluents and / or adjuvants and / or excipients. The use of such media and agents for pharmaceutical active substances is well known in the art and includes tablet binders, lubricants, flavoring agents, preservatives, wetting agents, emulsifying agents, and dispersing agents.

[0120] As described below and in the following examples, the applicant has shown that the compositions and methods described in any of the embodiments herein have surprising and unpredictable properties. For example, the applicant surprisingly and unexpectedly found that patients administered a dose of about 3.0 mg BID to about 4.0 mg BID of the huperzine composition described herein showed abnormally improved seizure control. In some cases, starting from a dose of 2.5 mg BID, patients showed increased seizure reduction without any side effects or dose-limiting side effects. In some cases, patients showed a seizure reduction improvement of about 90% or more, about 92% or more, about 95% or more, and even complete elimination of seizures.

[0121] For the study, the applicant used a composition comprising an inert core layer, a huperzine layer coating the core layer, and a polymer layer coating the huperzine layer as shown in Table 1.

[0122] Table 1

[0123]

[0124] *MCC = microcrystalline cellulose spheres

[0125] **HPMC = hydroxypropyl methylcellulose; PVP = polyvinylpyrrolidone

[0126] Treatment method

[0127] The pharmaceutical compositions according to any of the embodiments described herein can be used to treat a neurological disorder in a patient in need thereof, including a seizure disorder. They can be therapeutically administered to treat, prevent or slow the rate of onset of neurological dysfunction. Some embodiments describe methods of treating neurological disorders and seizure disorders. Some embodiments describe methods of treating a neurological disorder with a pharmaceutical composition according to any of the embodiments described herein, the neurological disorder being selected from amyloid-related disorders such as Alzheimer's disease and the amyloid disorders described herein, psychiatric disorders such as Tourette syndrome, post-traumatic stress disorder (PTSD), panic and anxiety disorders, obsessive-compulsive disorder and schizophrenia, developmental disorders such as fragile X syndrome and autism, pain, drug addiction such as alcoholism, neurodegenerative diseases such as Parkinson's disease and Huntington's disease, and stroke and ischemic brain injury, amyotrophic lateral sclerosis, epilepsy, and any disorder, symptom or effect associated with or related to exposure to a neurotoxin (including but not limited to a neurotoxin such as a chemical warfare agent).

[0128] In some aspects, the present invention provides a method of treating a seizure or seizure disorder, the seizure or seizure disorder being selected from epilepsy (including intractable epilepsy), generalized seizures, primary generalized seizures, absence seizures, myoclonic seizures, partial seizures, complex partial seizures with or without generalization (e.g., focal impaired awareness seizures (FIAS)), Lennox-Gastaut syndrome, Dravet syndrome, and generalized epilepsy with febrile seizure plus (GEFS+). In some embodiments, the seizure is epilepsy.

[0129] The pharmaceutical compositions according to any of the embodiments described herein can be therapeutically administered to treat, prevent or slow the rate of onset of neuronal dysfunction such as epilepsy and seizures; or prophylactically administered to protect against further seizures associated with epilepsy or to avoid or prevent the onset of seizures associated with other disorders. For example, the pharmaceutical compositions according to any of the embodiments described herein can be prophylactically administered to slow or stop the progression of seizures and epilepsy in a patient who has had a stroke and is at risk of developing seizures due to the stroke.

[0130] Other embodiments describe methods of treating epilepsy, intractable epilepsy and FIAS, the methods comprising administering to a patient in need thereof a pharmaceutical composition according to any of the embodiments described herein.

[0131] In some embodiments, the pharmaceutical compositions of the invention are administered at a dose that reduces the frequency of seizures by at least 10%, with few side effects. Preferably, the reduction is greater than about 70%, 75%, 80%, 85%, 90%, 95%, or seizures are eliminated. For example, the pharmaceutical compositions and methods according to any of the embodiments described herein prevent the development of seizures or completely eliminate seizures.

[0132] In other aspects, the invention provides methods for treating any condition, symptom, or effect associated with or related to exposure to a neurotoxin (including but not limited to neurotoxins such as chemical warfare agents), the method comprising administering to a patient in need thereof a pharmaceutical composition according to any of the embodiments described herein.

[0133] In some embodiments, the dose of the pharmaceutical composition of the invention is preferably no more than 15 mg / day. In some embodiments, the dose of the pharmaceutical composition of the invention is preferably no more than 20 mg / day. In some embodiments, the daily dose according to any of the embodiments described herein is administered twice a day. In some embodiments, the dose is from about 1.5 mg twice a day to about 5.0 mg twice a day. In some embodiments, the dose is from about 3.0 mg twice a day to about 4.0 mg twice a day. In some embodiments, the dose is about 2.75 mg twice a day, about 3.0 mg twice a day, about 3.25 mg twice a day, about 3.50 mg twice a day, about 3.75 mg twice a day, 4.0 mg twice a day, 4.5 mg twice a day, 4.75 mg twice a day, or 5.0 mg twice a day. In other embodiments, the dose is 5.5, 6.0, 6.5, 7.0, 7.5, 8.0, 8.5, 9.0, 9.5, or 10 mg twice a day.

[0134] In some embodiments, for example, to treat symptoms or effects associated with or related to exposure to a neurotoxin (including but not limited to neurotoxins such as chemical warfare agents), a dose of from about 2.75 mg twice a day to about 5.0 mg twice a day, from about 3.0 mg twice a day to about 4.75 mg twice a day, from about 3.25 mg twice a day to about 4.5 mg twice a day, from about 3.5 mg twice a day to about 4.25 mg twice a day, from about 3.75 mg twice a day to about 4.0 mg twice a day, or from about 3 mg twice a day to about 4 mg twice a day may also be used.

[0135] In some embodiments, the present disclosure provides a method of treating a neurological disorder or a seizure disorder, the method comprising administering to a patient in need thereof one or more titrating doses of a modified release formulation of huperzine, followed by an oral modified release formulation of a maintenance dose of huperzine, wherein the patient has a better side effect profile and / or a reduced seizure frequency. In some embodiments, the titrating dose comprises from about 0.5 mg BID to about 2.5 mg BID. In some embodiments, the titrating dose comprises from about 0.25 mg twice daily to about 2.5 mg twice daily, from about 0.5 mg twice daily to about 2.5 mg twice daily, from about 0.5 mg twice daily to about 2.0 mg twice daily, from about 0.75 mg twice daily to about 1.75 mg twice daily, or from about 1.0 mg twice daily to about 1.5 mg twice daily, and ranges between any two of these values or less than any one of these values. In some embodiments, the maintenance dose comprises from about 3.0 mg BID to about 4.0 mg BID. In some embodiments, the maintenance dose can comprise from about 2.75 mg twice daily to about 5.0 mg twice daily, from about 3.0 mg twice daily to about 4.75 mg twice daily, from about 3.25 mg twice daily to about 4.5 mg twice daily, from about 3.5 mg twice daily to about 4.25 mg twice daily, from about 3.75 mg twice daily to about 4.0 mg twice daily, or from about 3 mg twice daily to about 4 mg twice daily, and ranges between any two of these values or less than any one of these values. In some embodiments, the titrating dose can comprise one or more of the following: about 0.5 mg twice daily, about 0.75 mg twice daily, about 1.75 mg twice daily, about 2.5 mg twice daily, and the maintenance dose can comprise one or more of the following: about 2.5 mg twice daily, about 2.75 mg twice daily, about 3.0 mg twice daily, about 3.25 mg twice daily, about 3.5 mg twice daily, about 3.75 mg twice daily, and about 4.0 mg twice daily, and ranges between any two of these values or less than any one of these values.

[0136] In some embodiments, the present disclosure provides a method of treating a neurological disorder or a seizure disorder, the method comprising administering to a patient in need thereof a therapeutically effective amount of a modified release formulation of huperzine. In some embodiments, the therapeutically effective amount of huperzine comprises a twice-daily dose of from about 3.0 mg to about 4.0 mg. This includes about 2.75 mg twice daily, about 3.0 mg twice daily, about 3.25 mg twice daily, about 3.5 mg twice daily, about 3.75 mg twice daily, and about 4.0 mg twice daily, and ranges between any two of these values or less than or greater than any one of these values.

[0137] In some embodiments, the present disclosure provides a method of treating a disorder selected from the group consisting of a neurological disorder or a seizure disorder, the method comprising administering to a patient in need thereof a pharmaceutical composition for oral delivery, the pharmaceutical composition comprising: from about 74 wt% to about 86 wt% of a sugar sphere core, wherein the sugar sphere core has a particle size of about 500 - 710 μm; a huperzine layer coating the sugar sphere, wherein the huperzine layer comprises from about 0.95 wt% to about 1 wt% of huperzine or a pharmaceutically acceptable salt of huperzine equivalent to from about 0.95 wt% to about 1 wt% of huperzine and one or more excipients, wherein the total amount of excipients is from about 5 wt% to about 9 wt%; a plasticized ethylcellulose polymer layer from about 7 wt% to about 16 wt% coating the huperzine layer, wherein the huperzine layer contains a therapeutically effective amount of huperzine. In some embodiments, the therapeutically effective amount of huperzine comprises a twice-daily dose of from about 3.0 mg to about 4.0 mg. This includes about 2.75 mg BID, about 3.0 mg BID, about 3.25 mg BID, about 3.5 mg BID, about 3.75 mg BID, and about 4.0 mg BID, as well as any value between any two of these values or less than or greater than any one of these values.

[0138] In some embodiments of the methods described herein, the seizure disorder is selected from epilepsy and focal impaired awareness seizures. In some embodiments, the seizure disorder is focal impaired awareness seizures (FIAS).

[0139] In some embodiments, the present disclosure provides a method of treating a neurological disorder or a seizure disorder, the method comprising administering to a patient in need thereof one or more titration doses of a modified-release formulation of huperzine, followed by an oral modified-release formulation of a maintenance dose of huperzine, wherein the patient has a better side effect profile and / or a reduced seizure frequency. In some embodiments, the modified-release formulation of huperzine administered at the titration dose is the same modified-release formulation of huperzine administered at the maintenance dose. In other embodiments, the modified-release formulation of huperzine administered at the titration dose is different from the modified-release formulation of huperzine administered at the maintenance dose. In other embodiments, the huperzine is huperzine A. In some embodiments, the modified-release formulation of huperzine is as Figure 7as shown, and comprising a soluble core; an active huperzine A layer coating the soluble core; a polymer coating coating the huperzine A layer; and an optional curable top coating comprising HPMC or Opadry. In other embodiments, the modified release huperzine preparation is a pharmaceutical composition according to any of the embodiments described herein. In some embodiments, the modified release preparation of huperzine is a pharmaceutical composition according to any of the embodiments described herein and is the same pharmaceutical composition for the titration dose and the maintenance dose. In some embodiments, the oral modified release preparation of huperzine is a pharmaceutical composition comprising huperzine A according to any of the embodiments described herein and is the same pharmaceutical composition comprising huperzine A for the titration dose and the maintenance dose. In some embodiments, the dose is titrated from a low dose to a high dose over several days to several weeks until the maintenance dose is reached.

[0140] Some embodiments describe a method of treating a patient in need of treatment for a neurological disorder or a seizure disorder, wherein the patient has a better side effect profile and / or a reduced seizure frequency, the method comprising administering a first dosing regimen selected from a. to i. (described further below) and a second dosing regimen selected from j. to o. (described further below), provided that the second dosing regimen is incremented from the first dosing regimen, and further provided that the last dosing regimen is a maintenance dose and thus the administration is continued for as long as the patient requires treatment:

[0141] a. Optionally administer a dose of about 0.25 mg of huperzine A, about once every 12 hours for at least two days and at most two weeks;

[0142] b. Optionally administer a dose of about 0.5 mg of huperzine A, about once every 12 hours for at least two days and at most two weeks;

[0143] c. Optionally administer a dose of about 0.75 mg of huperzine A, about once every 12 hours for at least two days and at most two weeks;

[0144] d. Optionally administer a dose of about 1 mg of huperzine A, about once every 12 hours for at least two days and at most two weeks;

[0145] e. Optionally administer a dose of about 1.25 mg of huperzine A, about once every 12 hours for at least two days and at most two weeks;

[0146] f. Optionally administer a dose of about 1.5 mg of huperzine A, about once every 12 hours for at least two days and at most two weeks;

[0147] g. Optionally administer a dose of about 1.75 mg of huperzine A, about once every 12 hours for at least two days and at most two weeks;

[0148] h. Optionally administer a dose of about 2 mg of huperzine A, once every about 12 hours for at least two days and at most two weeks;

[0149] i. Optionally administer a dose of about 2.5 mg of huperzine A, once every about 12 hours for at least two days;

[0150] j. Optionally administer a dose of about 2.75 mg of huperzine A, once every about 12 hours for at least two days;

[0151] k. Optionally administer a dose of about 3.0 mg of huperzine A, once every about 12 hours for at least two days;

[0152] l. Optionally administer a dose of about 3.25 mg of huperzine A, once every about 12 hours for at least two days;

[0153] m. Optionally administer a dose of about 3.5 mg of huperzine A, once every about 12 hours for at least two days;

[0154] n. Optionally administer a dose of about 3.75 mg of huperzine A, once every about 12 hours for at least two days;

[0155] o. Optionally administer a dose of about 4.0 mg of huperzine A, once every about 12 hours for at least two days;

[0156] wherein the huperzine in a.-o. is administered in the form of a modified release formulation.

[0157] In other embodiments, the modified release formulation is a pharmaceutical composition according to any of the embodiments described herein. In other embodiments, the huperzine is huperzine A. In other embodiments, each dose before the maintenance dose is administered for 2 days to two weeks. It should be understood that any combination of at least one dosing regimen selected from a. to i. and at least one dosing regimen selected from j. to o. allows any combination of dosing regimens, and thus describes at least two dosing regimens (1 initial dose lower than the maintenance dose and 1 maintenance dose) and at most 14 dosing regimens (the increasing dosing regimens of a. to i. and the maintenance doses of j. to n).

[0158] In some embodiments, the method comprises administering any of the following dosing regimens (wherein the last-specified dose is the maintenance dose):

[0159]

[0160] In some embodiments, the method comprises:

[0161] a. Administer about 0.5 mg of huperzine A, once every about 12 hours for at least 2 days. b. Administer about 0.75 mg of huperzine A, once every about 12 hours for at least 2 days. c. Administer about 1.75 mg of huperzine A, once every about 12 hours for at least 2 days.

[0162] d. Administer about 3.0 mg of huperzine A, once every about 12 hours for at least two days.

[0163] In some embodiments, step d. is administered for the duration of the patient's need for treatment.

[0164] In some embodiments, the method further comprises, after step d.:

[0165] e. Administer about 3.25 mg of huperzine A, once every about 12 hours for the duration the patient needs.

[0166] In some embodiments, the method further comprises, after step d.:

[0167] e. Administer about 3.25 mg of huperzine A, once every about 12 hours for at least 2 days;

[0168] f. Administer about 3.5 mg of huperzine A, once every about 12 hours for at least 2 days;

[0169] In some embodiments, the method further comprises, after step d.:

[0170] e. Administer about 3.25 mg of huperzine A, once every about 12 hours for at least 2 days;

[0171] f. Administer about 3.5 mg of huperzine A, once every about 12 hours for at least 2 days;

[0172] g. Administer about 3.75 mg of huperzine A, once every about 12 hours for the duration the patient needs.

[0173] In some embodiments, the method further comprises, after step d.:

[0174] e. Administer about 3.25 mg of huperzine A, once every about 12 hours for at least 2 days;

[0175] f. Administer about 3.5 mg of huperzine A, once every about 12 hours for at least 2 days;

[0176] g. Administer about 3.75 mg of huperzine A, once every about 12 hours for at least 2 days;

[0177] h. Administer about 4.0 mg of huperzine A, about once every 12 hours for the time required by the patient.

[0178] Some embodiments of the present disclosure relate to a method of treating a neurological disorder or a seizure disorder in a patient in need thereof, wherein the patient has a better side effect profile and / or a reduced seizure frequency, the method comprising administering a modified release formulation (4F1 / 4F2) of huperzine A, wherein the modified release formulation of huperzine A is characterized by a C ss characterized by:

[0179] Dose (mg) Css (ng / mL) 2.5 About 7.43 to about 9.08 2.75 About 8.19 to about 10.0 3.0 About 9.0 to about 11.0 3.25 About 9.8 to about 12.0 3.5 About 10.7 to about 13.1 3.75 About 11.6 to about 14.2 4.0 About 12.5 to about 15.3

[0180] In other embodiments, the modified release formulation is a pharmaceutical composition according to any of the embodiments described herein.

[0181] Some embodiments describe a method of treating a neurological disorder or a seizure disorder in a patient in need thereof, wherein the patient has a better side effect profile, the method comprising administering a modified release formulation of huperzine A, wherein the modified release formulation of huperzine is characterized in that the Css of huperzine in plasma is about 0.6 ng / mL to about 12 ng / mL when administered at a therapeutically effective dose. In some embodiments, when administered at a therapeutically effective dose, the Css of huperzine in plasma is about 2 ng / mL to about 12 ng / mL. In some embodiments, when administered at a therapeutically effective dose, the Css of huperzine in plasma is about 4 ng / mL to about 12 ng / mL. In some embodiments, when administered at a therapeutically effective dose, the Css of huperzine in plasma is about 6 ng / mL to about 12 ng / mL. In some embodiments, when administered at a therapeutically effective dose, the Css of huperzine in plasma is about 4 ng / mL to about 10 ng / mL. In some embodiments, when administered at a therapeutically effective dose, the Css of huperzine in plasma is about 4 ng / mL to about 8 ng / mL. In some embodiments, when administered at a therapeutically effective dose, the Css of huperzine in plasma is about 6.4 ng / mL to about 10 ng / mL. In some embodiments, when administered at a therapeutically effective dose, the Css of huperzine in plasma is about 8 ng / mL. In some embodiments, when administered at a therapeutically effective dose, the Css of huperzine in plasma is at least 8 ng / mL. In other embodiments, the huperzine is huperzine A. In other embodiments, the modified release formulation is a pharmaceutical composition according to any of the embodiments described herein.

[0182] Some embodiments of the present disclosure relate to a method of treating a neurological disorder or a seizure disorder, the method comprising administering to a patient in need thereof a modified release formulation of huperzine. In some embodiments, the huperzine is huperzine A. In some embodiments, the modified release formulation of huperzine is a pharmaceutical composition according to any of the embodiments described herein. In some embodiments, the modified huperzine formulation is Formulation 4F1 / 4F2.

[0183] The pharmaceutical compositions of the invention can be administered in combination with one or more other therapeutic agents. The choice of therapeutic agent to be co-administered with the compositions of the invention will depend in part on the disorder being treated. For example, the compounds of the invention can be used in combination with other agents for treating other symptoms and side effects commonly associated with epilepsy or seizures, such as fainting, fatigue, muscle spasms, auras, amnesia, anxiety, depression, headache, drowsiness or stupor, such other agents as acetaminophen, ibuprofen, naproxen, carisoprodol, chlorzoxazone, cyclobenzaprine, methocarbamol, methocarbamol, meclizine, tizanidine, baclofen, dantrolene, diazepam, citalopram, escitalopram, fluoxetine, paroxetine, sertraline, duloxetine, venlafaxine, imipramine, hydroxyzine, propranolol, gabapentin, pregabalin, alprazolam, clonazepam, chlordiazepoxide, lorazepam, buspirone, modafinil, armodafinil, ethosuximide, valproic acid, levetiracetam, lacosamide, eslicarbazepine, carbamazepine, oxcarbazepine, phenytoin, fosphenytoin, topiramate, CGRP inhibitors, flunarizine, cannabinoids, and / or lamotrigine.

[0184] Such other therapeutic agents can be administered before, simultaneously with, or after the administration of the huperzine pharmaceutical composition according to any of the embodiments described herein.

[0185] Examples

[0186] Although the invention has been described in considerable detail with reference to certain preferred embodiments thereof, other forms are possible. Therefore, the spirit and scope of the appended claims should not be limited to the description and preferred forms included within this specification. Aspects of the invention will be illustrated by reference to the following non-limiting examples. The following examples are for illustrative purposes only and should not be construed as limiting the invention in any way.

[0187] Example 1: Evaluation of the bioavailability, safety and tolerability of modified-release huperzine A after multiple-dose administration in healthy subjects

[0188] A single-center, on-site / outpatient dose-escalation study was conducted using the oral pharmaceutical composition 4D. It was administered twice daily (BID) to healthy volunteers in cohorts of 8 subjects (formulation 4D) to assess plasma levels, safety and to allow for any necessary dosing changes before dosing any subsequent subjects. The study was conducted in an on-site setting at dose initiation and dose escalation to assess safety and for sample collection for routine laboratory and pharmacokinetic analysis. Subjects were discharged and compliance with BID dosing was monitored by the staff by telephone twice daily. The initial dose was 0.5 mg BID, with dose escalation every 2 - 3 days until the maximum tolerated dose was observed or the maximum 2.5 BID dose was achieved. The staff had the discretion to change the initial dose and escalation rate to ensure subject safety.

[0189] Study endpoints: Plasma concentration data were used for bioavailability assessment. The pharmacokinetic parameters obtained included: area under the curve (AUC), maximum plasma concentration (Cmax) and time to Cmax (Tmax).

[0190] Safety and tolerability parameters were evaluated based on the occurrence of adverse events and the results of study-specified vital signs, neurological and physical examinations, ECG evaluations and clinical laboratory studies.

[0191] The dosing schedule was as follows:

[0192] Cohorts 1 and 2 (formulation 4D):

[0193]

[0194] Cohort 3 (formulation 4D):

[0195]

[0196] Cohort 4 (formulation 4D):

[0197]

[0198] Cohorts 5 and 6 (formulation 4E):

[0199]

[0200] Throughout the study, for cohorts 1 - 4, plasma levels obtained at dose titration on the inpatient days are shown in Figure 3 Plasma draws occurred throughout the dose titration schedule to assess overall plasma concentration. Time = 0 represents the pre-dose baseline corresponding to the titration day of the dosing schedule. The mean reflects all data obtained for 8 subjects. The initial dosing schedule for cohorts 3 and 4 was changed to accommodate a slower titration (0.25 mg dose increments).

[0201] Graphs of mean plasma levels obtained on hospital days at specific doses over the entire study period are shown in Figure 4 Pharmacokinetic modeling predicted that mean plasma levels (Css) of 8.4 ng / mL achieved 100% seizure protection in 50% of patients (equivalent to administration of approximately 1.1 - 1.25 mg BID).

[0202] When compared to immediate release formulations, the compositions in the study produced a favorable pharmacokinetic profile even when using twice the previously used dose, demonstrating twice-daily dosing and demonstrating a significant reduction in adverse events. Pharmacokinetic modeling accurately predicted the dose-exposure relationship across the entire dose titration.

[0203] Adverse events were mild and transient. Testing showed that approximately twice the dose expected for significant seizure control could be achieved; administration on a twice-daily schedule produced far higher and stable huperzine A plasma levels and reached drug plasma levels expected to provide significant seizure protection in patients with refractory epilepsy in adults and children.

[0204] Example 2: Evaluation of the safety and efficacy of a modified-release formulation of huperzine for the treatment of focal impaired awareness seizures (FIAS) in adults Planned number of participants:

[0205] The purpose of this study was to examine safety signals and demonstrate seizure reduction in adults with FIAS treated with a modified release formulation of huperzine as an add-on therapy in inpatient and outpatient studies using a pharmaceutical composition according to any of the embodiments described herein. In some embodiments, the pharmaceutical composition is 4F1 or 4F2.

[0206] Dose administration for each participant will start at 0.25 mg BID and be titrated up every 4 days to the maximum tolerated dose or a target dose of 1.75 mg BID. Participants who cannot tolerate the dose during dose escalation will have their dose reduced to the previously tolerated dose; if they cannot tolerate the lower dose, the participant will withdraw from the study.

[0207] Study design:

[0208] Sixteen participants will be enrolled and complete the study.

[0209] Pharmacology:

[0210] This study is a single-center, multi-site, open-label add-on study in otherwise healthy participants with frequent focal impaired awareness seizures.

[0211] Pre-screened eligible participants 18 years of age and older who have signed the informed consent will be included in the study. The study will include a 96-hour baseline continuous VEM period, a one-month outpatient dose escalation treatment period, and then a second 96-hour continuous VEM treatment period.

[0212] On Day 1 of the baseline period (after completion of physical and neurological examinations, vital signs, electrocardiogram (ECG), blood samples for CBC and chemistry, urine samples for standard urine analysis including creatinine and electrolytes), daily seizure counts will be initiated and collected by VEM with standard lead placement. Participants will continue on their stable antiepileptic treatment regimen as determined by their treating physician. After completion of the baseline period (5-day inpatient VEM), participants who have experienced at least 5 focal impaired awareness seizures will be immediately enrolled in treatment. They will initiate dose escalation of modified release huperzine to a target dose of 3.0 mg BID, 4.0 mg BID or the maximum tolerated dose. Modified release huperzine will be titrated over 28 days, increasing every 4 days. After reaching the target dose or maximum tolerated dose, participants will initiate a 96-hour inpatient VEM treatment period. After the inpatient VEM treatment period, participants may, at the discretion of the investigator, elect to further escalate the dose up to the maximum tolerated dose or the dose that completely eliminates seizures, and maintain that dose for the remaining outpatient titration period. For the duration of the outpatient titration period, a daily seizure diary will be maintained where the participant or caregiver should note the type of seizure and the time of day. Participants who cannot achieve the target dose of 3.0 mg BID or 4.0 mg BID will have their dose reduced to the previously tolerated dose. If the lower dose cannot be tolerated, the participant may withdraw from the study. Modified release huperzine will be administered to the participant 2 times per day (every 12 hours), in the morning and evening. Participants will discontinue the formulation 4F1 / 4F2 on the last day of inpatient VEM unless they elect to participate in an open label extension period during which they will continue to record their seizure diary and will have regular safety assessments.

[0213] Blood samples for pharmacology will be drawn on selected outpatient and inpatient study days. Adverse events (AE) and use of concomitant medications will be recorded throughout the study.

[0214] All participants who receive at least one dose of the study product will be included in the safety analysis which includes vital signs, clinical laboratory tests, physical and neurological examinations, electrocardiogram and adverse event monitoring.

[0215] Endpoints:

[0216] · Primary efficacy variable: Reduction in mean daily seizure count between the baseline (pre-treatment) and evaluation (during treatment) VEM periods.

[0217] · Secondary efficacy variables:

[0218] · Percentage reduction in mean daily seizure count from the baseline VEM period compared to the evaluation of the VEM period (during treatment)

[0219] · Percentage reduction in mean seizure frequency from the baseline period (screening / retrospective diary) compared to the last week of the titration treatment period

[0220] · Percentage of participants considered to be treatment responders, where treatment responders are defined as those participants with a ≥25%, ≥50%, ≥75%, ≥90% reduction in seizures from the baseline VEM period compared to the VEM treatment evaluation period

[0221] · Percentage reduction in mean seizure frequency at 1, 3, 6, 12 months during the extension period compared to baseline / retrospective diary

[0222] · Proportion of subjects with a 100% reduction in seizures

[0223] · Proportion of subjects requiring different doses of rescue medication

[0224] Figure 5

[0225] Plasma concentration data will be used to determine the dose, plasma level, and seizure effect relationship.

[0226] Urine samples will be subjected to standard urine analysis to test for drug elimination and the presence of potential metabolites.

[0227] To date, three patients have received dose titration as Figure 5 described, Figure 6A and the relevant mean plasma concentrations are also shown.

[0228] Figure 6B and Example 3: General procedure for preparing a pharmaceutical composition: A plot of plasma values against seizures from the FIAS trial is shown, correlated with seizure counts to assess the exposure effect on seizure reduction. The plot represents a single PK draw performed 4 hours (Tmax) after the morning dose, and seizure counts are based on a 28-day period. The plot indicates a significant correlation between exposure and seizure prevention.

[0229] The seizure counts for subjects 1001, 1002, and 2001 from baseline to the extended period dose of 3 mg BID are shown in Table 2 below.

[0230] Table 2

[0231]

[0232] ​

[0233] The pharmaceutical compositions described herein can generally be prepared as follows:

[0234] i. Using a fluidized bed coating apparatus (or similar particle coating manufacturing equipment), coated particles are manufactured using standard procedures and operating conditions. These procedures include:

[0235] ii. Preparing a solution for manufacturing modified release particles, such as a solution containing huperzine, binder, anti-caking agent, etc.

[0236] iii. Loading the uncoated core into the fluidized bed

[0237] iv. Adjusting all operating parameters, such as the nozzle and pressure, to an appropriate range to suit the appropriate batch size and the equipment used

[0238] v. Processing the coated pellets to remove agglomerates or fine particles outside the desired particle size distribution.

[0239] An exemplary process includes:

[0240] 1. Solution preparation

[0241] a. Heating a predetermined amount of distilled water to 70 °C.

[0242] b. Dissolving huperzine in absolute ethanol by stirring.

[0243] c. Adding HPMC to the heated water with continuous stirring if necessary.

[0244] d. Adding another aliquot of distilled water to the above solution; continue stirring until the powder is completely dissolved.

[0245] e. Adding PVP to the HPMC solution and dissolving it in the same way by continuous stirring.

[0246] f. Combining the HMPC / PVP solution with the huperzine ethanol solution. Rinse the container with distilled water and carefully pour the solution until the final weight reaches the target, and continue stirring for 5 minutes.

[0247] 2. Drug layer coating

[0248] Transfer sucrose spheres of the desired size to a fluidized bed processor, and coat the sucrose spheres with the above huperzine solution of 1.f. at a product temperature of 35 °C - 45 °C.

[0249] 3. Sustained release layer coating

[0250] Using the same product temperature range as described above, the pre-prepared plasticized ethylcellulose solution was coated onto the resulting huperzine-loaded sugar spheres until the theoretical weight gain target was reached.

[0251] 4. Table coating

[0252] A topcoat of HPMC or Opadry can be applied on top of the sustained release layer coating as described above.

Claims

1. A method of preparing a medicament for treating a disorder selected from the group consisting of nervous system disorders or seizure disorders, said treatment comprising administering to a patient in need thereof a pharmaceutical composition for oral delivery, said pharmaceutical composition comprising: 74% to 86% by weight of sugar sphere cores, wherein said sugar sphere cores have a particle size of 500 - 710 μm; A huperzine layer coating said sugar spheres, wherein said huperzine layer comprises 0.4% to 1% by weight of huperzine or a pharmaceutically acceptable salt of huperzine equivalent to 0.4% to 1% by weight of huperzine and one or more pharmaceutically acceptable excipients, wherein one or more pharmaceutically acceptable excipients are about 5% to about 7% by weight of hydroxypropyl methylcellulose and about 0.5% to about 1.5% by weight of polyvinylpyrrolidone; 7% to 16% by weight of a plasticized ethylcellulose polymer layer coating said huperzine layer, wherein said huperzine layer contains a therapeutically effective amount of huperzine; A curable surface coating comprising HPMC or Opadry; and Wherein said therapeutically effective amount of huperzine is a twice-daily dose of 3.0 mg to 4.0 mg or up to the maximum tolerated dose, Wherein said curable surface coating is located on the surface of said plasticized ethylcellulose polymer layer.

2. The method according to claim 1, wherein said seizure disorder is selected from the group consisting of epilepsy and focal impaired awareness seizures.

3. The method according to claim 1, wherein said seizure disorder is focal impaired awareness seizures.

4. The method according to claim 1, wherein said administration comprises administering one or more titration doses of said pharmaceutical composition, followed by administering a maintenance dose of said pharmaceutical composition, wherein said titration dose comprises 0.5 mg BID to 2.5 mg BID; and wherein said maintenance dose comprises 3.0 mg BID to 4.0 mg BID.

5. The method according to claim 1, said treatment comprising administering a first dosing regimen selected from at least one of a. to i. and a second dosing regimen selected from at least one of j. to o., provided that said second dosing regimen is incremented from said first dosing regimen, and further provided that the last dosing regimen is a maintenance dose and thus administration will continue for the time the patient requires its treatment: a. Optionally administer a 0.25 mg dose of huperzine A every 12 hours for at least two days; b. Optionally administer a 0.5 mg dose of huperzine A every 12 hours for at least two days; c. Optionally administer a 0.75 mg dose of huperzine A every 12 hours for at least two days; d. Optionally administer a 1 mg dose of huperzine A every 12 hours for at least two days; e. Optionally administer a 1.25 mg dose of huperzine A every 12 hours for at least two days; f. Optionally administer a 1.5 mg dose of huperzine A every 12 hours for at least two days; g. Optionally administer a 1.75 mg dose of huperzine A every 12 hours for at least two days; h. Optionally administer a dose of 2 mg of huperzine A every 12 hours for at least two days; i. Optionally administer a dose of 2.5 mg of huperzine A every 12 hours for at least two days; j. Optionally administer a dose of 2.75 mg of huperzine A every 12 hours for at least two days; k. Optionally administer a dose of 3.0 mg of huperzine A every 12 hours for at least two days; l. Optionally administer a dose of 3.25 mg of huperzine A every 12 hours for at least two days; m. Optionally administer a dose of 3.5 mg of huperzine A every 12 hours for at least two days; n. Optionally administer a dose of 3.75 mg of huperzine A every 12 hours for at least two days; o. Optionally administer a dose of 4.0 mg of huperzine A every 12 hours for at least two days; wherein the huperzine A in a.-o. is administered in the form of the pharmaceutical composition according to claim 1; and wherein the patient has a better side effect profile and / or a reduced seizure frequency.

6. The method according to claim 5, wherein the treatment comprises: a. Administer a dose of 0.5 mg of huperzine A every 12 hours for at least two days; b. Administer a dose of 0.75 mg of huperzine A every 12 hours for at least two days; c. Administer a dose of 1.75 mg of huperzine A every 12 hours for at least two days; d. Administer a dose of 3.0 mg of huperzine A every 12 hours for at least two days.

7. The method according to claim 6, wherein the administration in step d continues for the time the patient needs treatment.

8. The method according to claim 6, wherein the treatment further comprises, after step d: e. Administer a dose of 3.25 mg of huperzine A every 12 hours for the time the patient needs.

9. The method according to claim 6, wherein the treatment further comprises, after step d.: e. Administer a dose of 3.25 mg of huperzine A every 12 hours for at least two days; f. Administer a dose of 3.5 mg of huperzine A every 12 hours for the time the patient needs.

10. The method according to claim 6, wherein the treatment further comprises, after step d.: e. Administer a dose of 3.25 mg of huperzine A every 12 hours for at least two days; f. Administer a dose of 3.5 mg of huperzine A every 12 hours for at least two days; g. Administer a dose of 3.75 mg of huperzine A every 12 hours for the time the patient needs.

11. The method according to claim 6, wherein the treatment further comprises, after step d.: e. Administer a dose of 3.25 mg of huperzine A every 12 hours for at least two days; f. Administer a dose of 3.5 mg of huperzine A every 12 hours for at least two days; g. Administer a dose of 3.75 mg of huperzine A every 12 hours for at least two days; h. Administer a dose of 4.0 mg of huperzine A every 12 hours for the time the patient needs.

12. A method of preparing a medicament for treating a disorder in a patient in need thereof, said disorder being selected from the group consisting of neurological disorders and seizure disorders, wherein the patient has a favorable side effect profile, said treatment comprising administering a pharmaceutical composition for oral delivery, said pharmaceutical composition comprising: 74% to 86% by weight of sugar sphere cores, wherein the sugar sphere cores have a particle size of 500 - 710 μm; A huperzine layer coating the sugar spheres, wherein the huperzine layer comprises 0.4% to 1% by weight of huperzine or a pharmaceutically acceptable salt of huperzine equivalent to 0.4% to 1% by weight of huperzine and one or more pharmaceutically acceptable excipients, wherein the one or more pharmaceutically acceptable excipients are about 5% to about 7% by weight of hydroxypropyl methylcellulose and about 0.5% to about 1.5% by weight of polyvinylpyrrolidone; 7% to 16% by weight of a plasticized ethylcellulose polymer layer coating the huperzine layer, wherein the huperzine layer contains a therapeutically effective amount of huperzine; A curable surface coating comprising HPMC or Opadry, wherein the pharmaceutical composition is characterized in that the huperzine A in plasma has a C ss selected from the group consisting of: 9.0 to 11.0 ng / mL at a dose of 3.0 mg; 9.8 to 12 ng / mL at a dose of 3.25 mg; 10.7 to 13.1 ng / mL at a dose of 3.5 mg; 11.6 to 14.2 ng / mL at a dose of 3.75 mg; and 12.5 to 15.3 ng / mL at a dose of 4.0 mg, wherein the curable surface coating is located on the surface of the plasticized ethylcellulose polymer layer.

13. A method of preparing a medicament for treating a disorder in a patient in need thereof, said disorder being selected from the group consisting of neurological disorders and seizure disorders, wherein the patient has a favorable side effect profile, said treatment comprising administering a pharmaceutical composition for oral delivery, said pharmaceutical composition comprising: 74% to 86% by weight of sugar sphere cores, wherein the sugar sphere cores have a particle size of 500 - 710 μm; A huperzine layer coating the sugar spheres, wherein the huperzine layer comprises 0.4% to 1% by weight of huperzine or a pharmaceutically acceptable salt of huperzine equivalent to 0.4% to 1% by weight of huperzine and one or more pharmaceutically acceptable excipients, wherein the one or more pharmaceutically acceptable excipients are about 5% to about 7% by weight of hydroxypropyl methylcellulose and about 0.5% to about 1.5% by weight of polyvinylpyrrolidone; 7% to 16% by weight of a plasticized ethylcellulose polymer layer coating the huperzine layer, wherein the huperzine layer contains a therapeutically effective amount of huperzine; A curable surface coating comprising HPMC or Opadry, wherein the pharmaceutical composition is characterized in that, when administered at a therapeutically effective dose, the C of huperzine A in plasma ss is at least 8 ng / mL, wherein the curable surface coating is located on the surface of the plasticized ethylcellulose polymer layer.

14. A method of preparing a medicament for treating a disorder in a patient in need thereof, said disorder being selected from the group consisting of neurological disorders and seizure disorders, wherein the patient has a favorable side effect profile, said treatment comprising administering a pharmaceutical composition for oral delivery, said pharmaceutical composition comprising: 74% to 86% by weight of sugar sphere cores, wherein the sugar sphere cores have a particle size of 500 - 710 μm; A huperzine layer coating the sugar spheres, wherein the huperzine layer comprises 0.4% to 1% by weight of huperzine or a pharmaceutically acceptable salt of huperzine equivalent to 0.4% to 1% by weight of huperzine and one or more pharmaceutically acceptable excipients, wherein the one or more pharmaceutically acceptable excipients are about 5% to about 7% by weight of hydroxypropyl methylcellulose and about 0.5% to about 1.5% by weight of polyvinylpyrrolidone; A plasticized ethylcellulose polymer layer coating the huperzine layer, which is 7% to 16% by weight, wherein the huperzine layer contains a therapeutically effective amount of huperzine; A curable surface coating comprising HPMC or Opadry, wherein the pharmaceutical composition is characterized in that the C of huperzine in plasma max is 14 ng / mL to 20 ng / mL, and the T max is 4 hours to 6 hours. wherein the curable surface coating is located on the surface of the plasticized ethylcellulose polymer layer.

15. A method of preparing a medicament for reducing the frequency of seizures in a patient in need thereof, the treatment comprising administering to the patient one or more titrating doses of a pharmaceutical composition and then administering a maintenance dose of the pharmaceutical composition, wherein the pharmaceutical composition is for oral delivery and comprises: A sugar sphere core, which is 74% to 86% by weight, wherein the sugar sphere core has a particle size of 500 - 710 μm; A huperzine layer coating the sugar spheres, wherein the huperzine layer comprises 0.4% to 1% by weight of huperzine or a pharmaceutically acceptable salt of huperzine equivalent to 0.4% to 1% by weight of huperzine and one or more pharmaceutically acceptable excipients, wherein the one or more pharmaceutically acceptable excipients are about 5% to about 7% by weight of hydroxypropyl methylcellulose and about 0.5% to about 1.5% by weight of polyvinylpyrrolidone; A plasticized ethylcellulose polymer layer coating the huperzine layer, which is 7% to 16% by weight, wherein the huperzine layer contains a therapeutically effective amount of huperzine; A curable surface coating comprising HPMC or Opadry, wherein the titrating dose comprises 0.25 mg BID to 2.5 mg BID; and wherein the maintenance dose comprises 1.5 mg BID to 4.0 mg BID, wherein the curable surface coating is located on the surface of the plasticized ethylcellulose polymer layer.

16. The method according to claim 15, wherein the frequency of seizures in the patient is reduced by more than 50%.

17. A method of preparing a medicament for reducing the frequency of seizures in a patient in need thereof, the treatment comprising administering to the patient a pharmaceutical composition for oral delivery, the pharmaceutical composition comprising: A sugar sphere core, which is 74% to 86% by weight, wherein the sugar sphere core has a particle size of 500 - 710 μm; A huperzine layer coating the sugar spheres, wherein the huperzine layer comprises 0.4% to 1% by weight of huperzine or a pharmaceutically acceptable salt of huperzine equivalent to 0.4% to 1% by weight of huperzine and one or more pharmaceutically acceptable excipients, wherein the one or more pharmaceutically acceptable excipients are about 5% to about 7% by weight of hydroxypropyl methylcellulose and about 0.5% to about 1.5% by weight of polyvinylpyrrolidone; A plasticized ethylcellulose polymer layer coating the huperzine layer, which is 7% to 16% by weight, wherein the huperzine layer contains a therapeutically effective amount of huperzine; A curable surface coating comprising HPMC or Opadry, The pharmaceutical composition contains a therapeutically effective amount of huperzine, wherein the curable surface coating is located on the surface of the plasticized ethylcellulose polymer layer.

18. The method according to claim 17, wherein the therapeutically effective amount of huperzine is a twice-daily dose of 1.5 mg to 4.0 mg.

Images