Modified-release pharmaceutical compositions of huperzine and methods of use thereof

Abstract

To provide pharmaceutical compositions for modified release of huperzine.SOLUTION: Pharmaceutical compositions and methods described herein, allow for dosing of huperzine at higher therapeutic thresholds, while avoiding rapid serum peak plasma levels, thereby avoiding the adverse nausea and vomiting associated with the immediate release pharmaceutical compositions. Methods of treating neurological disorders and / or seizure disorders with the modified release compositions are also described.SELECTED DRAWING: Figure 5

Description

[Technical Field]

[0001] Related Applications This application is a part of the "EXTENDED RELEASE FO" filed on May 19, 2017. RMULATIONS OF HUPERZINE AND METHODS OF U This application is the benefit of U.S. Provisional Patent Application No. 62 / 508,554, entitled "SING THE SAME." and claims priority from the International Application Publication No. 2006 / 010999, the contents of which are incorporated herein by reference in their entirety. Summary of the Invention

[0002] Huperzine A is derived from the firmosus Huperzia serrata It is a naturally occurring sesquiterpene alkaloid compound found in the In some countries, Huperzine A is used to support memory. In China, Huperzine A is marketed as a dietary supplement for the treatment of dementia. It has been approved by the State Food and Drug Administration (SFDA).

[0003] Huperzine A has been administered to healthy volunteers and patients in numerous Chinese trials. It has been shown to be effective in treating Alzheimer's disease, benign senile forgetfulness, vascular dementia, myasthenia gravis, and integrative disorders. Acceptable safety and tolerability, and efficacy in ataxia and cocaine dependence The doses used in these studies were sufficient for oral or intramuscular administration. These studies demonstrated a favorable safety profile. However, some studies have shown transient dose-related nausea at higher dose levels.

[0004] To investigate the safety and tolerability of immediate release pharmaceutical compositions of Huperzine A, the applicant A dose-escalation study was conducted in patients with drug-resistant epilepsy. He experienced serious adverse events (nausea and vomiting) within the first 31 hours, which were probably due to immediate This is due to the rapid serum exposure of the time-release pharmaceutical composition (see below).

[0005] There are no published reports in the medical or patent literature regarding the efficacy of Huperzine A in patients with epilepsy. There are no clinical data available. Non-clinical data in rodent models suggest that Huperzine A has anticonvulsant properties. It has a very high anticonvulsant efficacy and is significantly different from available antiepileptic drugs (AEDs). However, the applicant has not yet determined whether the seizure disorder in a patient is related to the mechanism of action. To achieve therapeutic efficacy, higher doses of fluoxetine were administered than previously administered in clinical trials. We predict that perzin will be required (see below).

[0006] Huperzine A has additional beneficial effects in the areas of neurological disorders, seizure disorders, memory and language disorders Although immediate release pharmaceutical compositions of Huperzine A may result in side effects, especially in patients with chronic conditions, In patients with steroid use, dose-related adverse events may necessitate a higher treatment threshold for the treatment of disorders. Immediate release pharmaceutical compositions are inappropriate due to the rapid release associated with these pharmaceutical compositions. 1 / 2 of It has the additional disadvantage of requiring dosing four to six times daily. In patient populations where, for example, memory loss or seizures are involved, compliance may be poor in these patients. Dosing four to six times a day is unacceptable because it would be too much of a problem for the patient. delivers a pharmaceutical composition that reduces high peak-trough serum levels, It has been suggested that higher doses (e.g., up to 5 mg / day) may be safe. .

[0007] Sustained-release tablets containing huperzine A are disclosed in Chinese patent application CN101081217. However, these pharmaceutical compositions have been reported to be more effective than immediate release pharmaceutical compositions. , failing to significantly reduce peak plasma concentrations, and max It is not possible to extend As a result, these pharmaceutical compositions may cause serious side effects associated with rapid and high peak serum concentrations. Adverse events are not overcome and the drug must be administered 4 to 6 times daily, which is why immediate-release medications are not recommended. The pharmaceutical composition does not provide any additional benefits.

[0008] The present invention provides a desirable effect that cannot be achieved by the pharmaceutical compositions of huperzine known so far. Allows plasma exposure required to achieve efficacy while maintaining a safety profile becomes.

[0009] Embodiments of the present invention are directed to the treatment of various neurological disorders and diseases, including pain, Alzheimer's disease, and pharmaceutical compositions for oral delivery of huperzine that can be used to treat seizure disorders - Patents.com The modified release pharmaceutical compositions of huperzine described herein allow for the administration of huperzine Immediate adverse events that either limit the amount or completely prevent continued use of Huperzine the duration, severity, and / or risk of serious adverse events associated with the release pharmaceutical composition This allows for optimal effectiveness of Huperzine in reducing either

[0010] An embodiment of the present invention is (a) about 74-86% by weight of the sugar sphere core, and about 500-71% by weight of the sugar sphere core. (b) a sugar sphere core having a particle size of 0 μm; and (b) a huperzine layer coating the sugar sphere. , about 0.95% by weight to about 1% by weight of Huperzine or about 0.95% by weight to about 1% by weight of Huperzine A pharmaceutically acceptable salt of huperzine corresponding to huperzine, and one or more excipients. (c) a huperzine layer containing excipients in a total amount of about 5% by weight to about 9% by weight; A layer of approximately 7% to 16% by weight of plasticized ethyl cellulose polymer coating the polymer layer. wherein the huperzine layer is a plasticized ethyl cellulose polymer containing a therapeutically effective amount of huperzine. In some embodiments, huperzine is a pharmaceutical composition for oral delivery comprising a hydroxybenzoate layer. , Huperzine A or a pharmaceutically acceptable salt thereof.

[0011] Some embodiments of the present invention comprise (a) about 80% to about 83% by weight of the sugar sphere core. (b) a sugar sphere core having a particle size of approximately 500 to 710 μm; and (b) a coating film for coating the sugar sphere. A huperzine layer comprising about 0.95% to about 1% by weight of huperzine A, or about 0.95 % to about 1% by weight of huperzine A, a pharmaceutically acceptable salt of huperzine A equivalent to about 5% to about 6% by weight of hydroxypropyl methylcellulose, and about 0.95% by weight ~ Approximately 1% by weight of polyvinylpyrrolidone and (c) a huperzine layer containing about 8% by weight to about 12% by weight of a coating material for the huperzine layer. % plasticized ethyl cellulose polymer layer, wherein the huperzine layer comprises a therapeutically effective amount of huperzine. The present invention relates to a pharmaceutical composition comprising a layer of a plasticized ethyl cellulose polymer containing gin A.

[0012] Some embodiments of the present invention provide a method for treating a rheumatoid arthritis, wherein, when a therapeutically effective amount of the composition is orally administered to a human subject, Huperzine A C in plasma max is about 4ng / mL to about 8ng / mL, T maxAbout 4 o'clock 10 to 8 hours, and 1 / 2 a pharmaceutical composition characterized in that the time from the start of administration of the pharmaceutical composition to the end of administration is about 8 hours to about 12 hours In one embodiment, C max is about 4 ng / mL to about 6 ng / mL, and T m ax is about 4 to 8 hours, and t 1 / 2 The time is about 10 hours to about 12 hours. In this state, C max is approximately 6 ng / mL, and T max is about 4 hours, and t 1 / 2 is about 8 0.3 hours.

[0013] Some embodiments of the present invention provide a T max、 and at equivalent doses C of the administered immediate-release huperzine pharmaceutical composition max Compared to % Decreased C max The present invention relates to a pharmaceutical composition comprising a therapeutically effective amount of huperzine A, characterized by: In some embodiments, the C of immediate-release huperzine pharmaceutical compositions administered at equivalent doses m ax Compared to C max is reduced by 50%.

[0014] Some embodiments of the present invention are described in 50 mM phosphate (pH 6.8) at 37°C. When tested using a USP Type 1 apparatus at 50 rpm, approximately 36% to 46% of Huperzine About 61% to 77% of Huperzine is released after 2 hours, and about 61% to 77% of Huperzine is released after 4 hours. Approximately 84% to 97% of Huperzine is released after 8 hours, and approximately 89% or more of Huperzine is released after 12 hours. The present invention relates to pharmaceutical compositions that exhibit a delayed release dissolution profile.

[0015] In some embodiments of the present invention, a pharmaceutical composition according to any of the embodiments described herein The present invention describes a method for treating neurological and / or seizure disorders, comprising administering In some embodiments, the composition is administered once daily or twice daily. In embodiments, the composition is administered for at least 1 day, at least 2 days, at least 3 days, At least 4 days, at least 5 days, at least 6 days, at least 7 days, at least at least 8 days, at least 9 days, at least 10 days, at least 11 days, at least 1 2 days, at least 13 days, at least 14 days, at least 1 month, at least 2 months month, at least 3 months, at least 4 months, at least 5 months, at least 6 months or The composition is administered for as long as the subject requires treatment. It is administered with dimen- sion and the dose of huperzine is 0.25 m every 2 days or for up to 2 weeks. In some embodiments, the seizure disorder is treated with steroids, such as steroids, or topical steroids. Epilepsy or complex partial seizures.

[0016] In some embodiments of the present invention, a patient in need thereof may be provided with a better side effect profile. In patients experiencing a profile, The present invention describes a method for treating a disorder, the method comprising administering one or more titrated doses of huperzine. A, followed by a maintenance dose of huperzine A; A is administered in a modified release pharmaceutical composition of huperzine A. In some embodiments, the release The modified release pharmaceutical agent is a modified release pharmaceutical agent according to any embodiment described herein.

[0017] Some embodiments of the present invention provide a method for treating a patient in need thereof with a better side effect profile. Described herein is a method for treating neurological and / or seizure disorders in patients experiencing a leukemia. and in this method, administering at least one dosing regimen selected from a to h. administering a first dosing regimen (described further below); administering a second dosing regimen of at least one dosing regimen (described further below); the second dosing regimen is greater than the first dosing regimen, and The dosing regimen should be a maintenance dose, so that the patient continues treatment for as long as they require it. It shall be administered. a. Fupe at a dose of approximately 0.25 mg once approximately every 12 hours for at least 2 days and up to 2 weeks administering ludine A; b. Huperzia at a dose of approximately 0.5 mg once approximately every 12 hours for at least 2 days and up to 2 weeks administering Gin A; c. Fupe at a dose of approximately 0.75 mg once approximately every 12 hours for at least 2 days and up to 2 weeks administering ludine A; d. Huperzine at a dose of approximately 1 mg once approximately every 12 hours for at least 2 days and up to 2 weeks administering A; e. Fupe at a dose of approximately 1.25 mg once approximately every 12 hours for at least 2 days and up to 2 weeks administering ludine A; f. Huperziv at a dose of approximately 1.5 mg, once approximately every 12 hours for at least 2 days and up to 2 weeks administering Gin A; g. Fupe at a dose of approximately 1.75 mg once approximately every 12 hours for at least 2 days and up to 2 weeks administering ludine A; h. Huperzine at a dose of approximately 2 mg once approximately every 12 hours for at least 2 days and up to 2 weeks administering A; i. Administer Huperzine A at a dose of approximately 2.5 mg once approximately every 12 hours for at least 2 days. To give. Huperzine A of a-i is administered in a modified release pharmaceutical composition of huperzine A. In this embodiment, the modified release pharmaceutical composition is a pharmaceutical composition according to any embodiment described herein. It is a composite product.

[0018] In some embodiments, the method comprises administering a modified release pharmaceutical composition of huperzine A. For patients who need it and experience a better side effect profile, 1. A method of treating a disorder selected from the group consisting of neurological disorders and / or seizure disorders, The modified release pharmaceutical composition of huperzine A has a release rate of about 0.52 to about 0.82 mg at a dose of 0.25 mg. ng / mL, and approximately 1.91 to 2.99 ng / mL at a dose of 0.50 mg, and approximately 1.91 to 2.99 ng / mL at a dose of 0.75 mg. Approximately 3.56 to 5.55 ng / mL at a dose of 1 mg, and approximately 5.58 to 8.72 ng at a dose of 1 mg / mL, approximately 8.22 to approximately 12.84 ng / mL at a 1.25 mg dose, and approximately 1.5 mg at a 1.5 mg dose At a dose of 1.75 mg, the values ​​were approximately 9.02 to 14.09 ng / mL, and at a dose of 1.75 mg, the values ​​were approximately 10.04 to 15. 69 ng / mL, approximately 16 to approximately 25 ng / mL at a dose of 2.0 mg, and approximately 16 to approximately 25 ng / mL at a dose of 2.5 mg. 18.48 to about 28.88 ng / mL of Huperzine A in plasma C ss In some embodiments, the modified release pharmaceutical composition is The article is according to any embodiment described herein.

[0019] In some embodiments, the method comprises administering a modified release pharmaceutical composition of huperzine A. In patients in need thereof who experience a better side effect profile, 1. A method of treating a disorder selected from the group consisting of neurological disorders and / or seizure disorders, The modified release pharmaceutical composition of huperzine A, when administered in a therapeutically effective amount, has a plasma huperzine A concentration. Luzhin A C ss The method is characterized in that the concentration of the antibody is at least 8 ng / mL. do.

[0020] In some embodiments, the method comprises administering a modified release pharmaceutical composition of huperzine A. For patients who need it and experience a better side effect profile, 1. A method for treating a disorder selected from the group consisting of neurological disorders and seizure disorders, comprising administering to a subject a therapeutically effective amount of Hupelamine. The modified release pharmaceutical composition of azithromycin A is prepared by orally administering a therapeutically effective amount of the pharmaceutical composition to a human subject. Sometimes the C of huperzine in plasma max Approximately 0.76 ng / mL to approximately 1.19 ng / mL Being, T max is approximately 4 hours to approximately 6.25 hours, and AUC 0-8 is about The method is described below, characterized by a 4.18 μg.h / L to approximately 6.53 μg.h / L Posted.

[0021] In some embodiments, the method comprises administering a modified release pharmaceutical composition of huperzine A. For patients who need it and experience a better side effect profile, 1. A method for treating a disorder selected from the group consisting of neurological disorders and seizure disorders, comprising administering to a subject a therapeutically effective amount of Hupelamine. The modified release pharmaceutical composition of azithromycin A is prepared by orally administering a therapeutically effective amount of the pharmaceutical composition to a human subject. Sometimes the C of huperzine in plasma max Approximately 2.51ng / mL to approximately 3.93ng / mL Being, T max is approximately 4 hours to approximately 6.25 hours, and AUC 0-8 is about A method is described in which the pH is between 13.76 and about 21.5. [Brief explanation of the drawings]

[0022] [Figure 1] FIG. 1 shows modeled plasma levels of Huperzine A following immediate release dosing for an example 2 mg twice daily titration schedule. [Figure 2] FIG. 1 shows modeled plasma levels of Huperzine A modified-release pharmaceutical composition 4A based on a titration schedule of 0.5 mg Huperzine A twice daily on days 1-2, 1 mg Huperzine A twice daily on days 3-4, 1.5 mg Huperzine A twice daily on days 5-6, and 2 mg twice daily on days 7-11. [Figure 3] 1 is a schematic diagram showing the composition of the present invention: the white inner circle is a sugar sphere, the middle circle is a huperzine layer, and the outer circle is a plasticized ethyl cellulose polymer. [Figure 4] FIG. 1 shows in vitro dissolution profiles of Pharmaceutical Composition 1A (solid line with small circle), Composition 1B (dashed line with small square), Composition 2A (solid line with small triangle), Composition 2B (dashed line with small triangle), Composition 2C (solid line with small triangle), Composition 3A (solid line with large circle), Composition 3B (dashed line with large square), Composition 3C (dashed line with large up-pointing triangle), Composition 4A (solid line with large down-pointing triangle), Composition 4B (dashed line with small diamond), Composition 4C (solid line with asterisk). [Figure 5] FIG. 1 shows in vitro dissolution profiles of Composition 4D (solid line with upward pointing triangle), Composition 4E (solid line with small diamond), Composition 4A (dashed line with large square), Composition 4F-1 (solid line with small downward pointing triangle), and Composition 4F-2 (solid line with circle). [Figure 6] FIG. 1 shows the in vivo plasma concentrations in dogs of Pharmaceutical Composition 4A (solid line with downward pointing triangle) and Pharmaceutical Composition 2C (solid line with upward pointing triangle) at a dose of 0.49 mg / kg. [Figure 7]FIG. 1 shows in vivo human plasma concentrations over time taken during a dose titration of 0.25 mg (small filled circle), 0.5 mg (large circle), 0.75 mg (large filled square), 1 mg (large square), 1.25 mg (small filled triangle), 1.50 mg (small triangle), 1.75 mg (small filled diamond), 2.0 (small diamond), and 2.5 mg (square with X). [Figure 8] FIG. 1 shows the in vivo plasma concentration (Css) in humans at various doses of Pharmaceutical Composition 4D. [Figure 9] FIG. 1 shows in vivo plasma concentrations and mean plasma concentrations (dashed diamond line) for three human patients (circles, triangles, and squares) sampled during a dose titration of 0.25 mg, 0.5 mg, 0.75 mg, and 1.25 mg. DETAILED DESCRIPTION OF THE INVENTION

[0023] definition The specific processes, compositions, or methodologies described may vary, and the present invention is not limited to these. The terminology used in the description is intended to describe only a particular version or embodiment. It is intended for purposes of illustration only and is not intended to limit the scope of the invention. Unless otherwise specified, all technical and scientific terms used herein are understood to be within the meaning of the present invention by those skilled in the art. All publications mentioned herein have the same meaning as understood by the Nothing in this specification shall be construed as an admission that the present invention is not based on prior invention. Nothing in this document should be construed as an admission that you do not have any right to antedate such disclosure.

[0024] Also, as used in this specification and the appended claims, the singular forms "a," "a" and "b" are used interchangeably. "n" and "the" refer to plural words unless the context clearly dictates otherwise. Thus, for example, reference to "symptoms" includes those symptoms known to those skilled in the art. and the like.

[0025] As used herein, the term "about" means plus or minus the numerical value of the number with which it is used. This means minus 10%. Therefore, approximately 50 mL means a range of 45 mL to 55 mL. Taste.

[0026] The terms "administering" or "administration" and the like refer to administering a composition (or a mixture) of the present invention to a subject in need of treatment. For example, a composition according to any embodiment described herein. More preferably, the subject is a mammal, more preferably a human. The present invention relates to any of the methods described herein. This includes administering a pharmaceutical composition according to an embodiment alone or in combination with another therapeutic agent. The compositions according to any embodiment described herein may be administered in combination with another therapeutic agent. When present, the pharmaceutical composition and the other therapeutic agent may be administered at the same time or at different times.

[0027] As used herein, a "serious adverse event" refers to any event that (a) causes discomfort to the subject and (b) causes substantial interference with or disables the subject's normal activities; (c) is life-threatening to the subject; (d) is for use result in dose-limiting toxicity, or (e) require additional medication, or combinations thereof, to combat the adverse event. For example, any adverse event that requires continued administration of Huperzine Pharmaceutical Composition When a subject experiences nausea and vomiting upon administration of a huperzine pharmaceutical composition that requires administration of an antiemetic to continue the administration of the huperzine pharmaceutical composition, If the subject experiences vomiting and / or nausea, the subject has a serious adverse event.

[0028] As used herein, an "amyloid-related disorder" includes a "limited" disorder that is confined to one organ. localized amyloidosis, or systemic amyloidosis, which spreads to several organs Diseases associated with amyloid accumulation include secondary amyloidosis, which can be either: The familial type of secondary amyloidosis, also seen in familial Mediterranean fever (FMF), and and chronic infections (including other forms of systemic amyloidosis seen in long-term hemodialysis patients). It may be associated with localized amyloidosis (e.g., ulcerative colitis) or chronic inflammation (e.g., rheumatoid arthritis). These include, but are not limited to, type II diabetes and related disorders, scrapie, Spongiform encephalitis, Creutzfeldt-Jakob disease, Alzheimer's disease, senile systemic amyloidosis Neurodegenerative diseases such as cerebrovascular disease (SSA), cerebral amyloid angiopathy, and Parkinson's disease, These include prion protein-related disorders (such as prion-associated encephalopathy), and rheumatoid arthritis.

[0029] The phrase "better side effect profile" refers to the improved efficacy of the modified release pharmaceutical composition of Huperzine. Immediate release pharmaceutical compositions of huperzine at equivalent doses experienced by a patient or group of patients during treatment with When compared with and / or (3) side effect(s) or serious adverse events occurring with less severity ( (multiple possible)

[0030] "C max " is the peak plasma concentration of a drug after administration to a subject.

[0031] As used herein, the term "dose" refers to, for example, the amount of any inactive ingredient or salt. This refers to the amount of active compound, such as Huperzine or Huperzine A, not including huperzine.

[0032] As used herein, the term "effective amount" refers to the amount of a substance that is effective for a particular purpose, e.g., as determined by a researcher or clinician. Drugs or medicines that induce a biological or medical response in tissues, systems, animals or humans It refers to an amount of a drug or a combination of drugs or pharmaceutical agents.

[0033] As used herein, the term "epilepsy" refers to a persistent condition that causes epileptic seizures. Characterized by predisposing factors and the neurobiological, cognitive, psychological, and social consequences of the condition An epileptic seizure is a brain disorder caused by abnormal excessive or simultaneous neurotransmitters in the brain. The temporary occurrence of signs and / or symptoms due to activity.

[0034] "Plasticized ethylcellulose The term "plasticized ethyl cellulose" is used in conjunction with, for example, "plasticized ethyl cellulose." yl cellulose), and some trade names, including non-proprietary names, synonyms, and some trade names, e.g. Those skilled in the art will appreciate that it is also known as "SuRelease®."

[0035] The term "hydroxypropyl methylcellulose" is used in many non-proprietary applications, e.g., "H PMC," "Hypromellose," "Hydroxypropyl methylcellulose," "Hypromellose "Hypromellose", synonyms, and some trade names, e.g., Methoc Those skilled in the art will appreciate that it is also known by the trademark el™.

[0036] The term "huperzine" refers to huperzine A unless otherwise defined in a specific embodiment. , Huperzine B, or Huperzine C, or a pharmaceutically acceptable salt or solution thereof Huperzine A is (1R,9S,13E)-1-amino-13-ethyl ether. Lithium-11-methyl-6-azatricyclo[7.3.1.02,7]trideca-2(7 Huperzine B is (4aR,5R,10bR), 3,10-trien-5-one. )-2,3,4,4a,5,6-Hexahydro-12-methyl-1H-5,10b-proline Huperzine C is peno-1,7-phenanthroline-8(7H)-one. 9S,13R)-1-amino-13-ethenyl-11-methyl-6-azatricyclo[7 .3.1.02,7]trideca-2(7),3,10-trien-5-one. [ka] In any of the embodiments described herein, preferably the huperzine is huperzine A. .

[0037] The term "maintenance dose" as used herein refers to a dose that maintains a desired level of a drug in the blood. In some embodiments, the maintenance dose refers to the dose of huperzine administered to maintain the therapeutic This is the effect size.

[0038] The term "modified release pharmaceutical composition of huperzine" refers to any oral pharmaceutical composition of huperzine. Huperzine release characteristics, such as time, course, and / or location, are different from immediate-release Huperzine. The compound is selected to achieve a therapeutic or convenience objective not provided by the gin.

[0039] The term "neurological disorders" includes, but is not limited to, seizure disorders, Alzheimer's disease, and amyloid-related disorders such as Tourette's disease and the amyloid disorders described herein, Mental disorders such as stress groups, post-traumatic stress disorder (PTSD), panic and anxiety disorders, and developmental disorders such as schizophrenia, fragile X syndrome and autism, pain, alcohol drug addiction such as alcoholism, neurodegenerative diseases such as Parkinson's disease and Huntington's disease, as well as stroke and ischemic brain injury, amyotrophic lateral sclerosis, and epilepsy. Neurotoxicity includes neurotoxicity caused by exposure to neurotoxins, including but not limited to chemical warfare agents. This includes any disorder, symptom, or effect that is associated with or involved in the disease.

[0040] The terms "patient" and "subject" are used interchangeably and throughout this specification Prophylactic use of a pharmaceutical composition according to any of the embodiments described herein Animals, generally mammals, that are the subject of treatment (prophylaxis) etc. Used in context to describe an animal, preferably a human. In the treatment of a specific infection, condition, or disease state, the term patient refers to that specific animal. .

[0041] "Pharmaceutically acceptable" means that the carrier, diluent or excipient is compatible with the other ingredients of a pharmaceutical composition. This means that the product must be suitable for use in a facility and must not be harmful to its recipients.

[0042] The term "a pharmaceutically acceptable salt of huperzine equivalent to about 1% by weight of huperzine" means that the salt of huperzine that when converted to huperzine yields about 1% by weight of huperzine free base Similarly, "about 0.5% by weight to about 1.5% by weight of Huperzine" refers to a pharmaceutically acceptable salt. "A pharmaceutically acceptable salt equivalent to about 0.9% by weight to about 1% by weight of Huperzine" "A pharmaceutically acceptable salt thereof," "equivalent to about 0.95% by weight to about 1% by weight of Huperzine," The terms "pharmaceutically acceptable salt" and the like mean that when the salt is converted into Huperzine, , about 0.5% to about 1.5% by weight, about 0.9% to about 1% by weight, about 0.95% by weight It refers to a pharmaceutically acceptable salt of huperzine that provides about 1% by weight of huperzine free base. For example, 6 grams of Huperzine A is required to provide 1% by weight of 600 g of a pharmaceutical composition. However, 6.89 g of Huperzine A HCl salt is required to achieve 1% by weight of Huperzine A. Let's say.

[0043] The term "polyvinylpyrrolidone" Examples of the term include "PVP" and "polyvinylpyrrolidone". It is also known by several non-proprietary names, such as "done," "povidone," and "polyvidone." Those skilled in the art will understand that polyvinylpyrrolidone is It will also be understood that polyvinyl alcohols are referred to by their k number, which indicates the average molecular weight of the vinyl alcohol. Examples of polyvinylpyrrolidone include polyvinylpyrrolidone K30 and polyvinylpyrrolidone K10. , polyvinylpyrrolidone K360, polyvinylpyrrolidone K40, Not limited.

[0044] As used herein, the term "seizure disorder" refers to any disorder in which one or more seizures are a symptom. As used herein, a seizure refers to a condition in which abnormal electrical activity occurs in the brain. seizures may be caused by a seizure disorder or may be non-epileptic seizures that do not involve abnormal electrical activity in the brain. Seizures may be caused by, but are not limited to, psychological problems, psychological stress, trauma, low blood pressure, due to blood sugar, low blood sodium, fever, alcohol use, drug use, or unknown causes Types of seizures and seizure disorders include, but are not limited to, seizures Epilepsy (intractable epilepsy, etc.), generalized seizures, primary generalized seizures, absence seizures, myoclonus Partial seizures, complex partial seizures with or without generalized seizures (e.g., focal seizures with impaired consciousness) with seizures (FIAS), Lennox-Gastaut syndrome, Dravet syndrome, and febrile seizures In some embodiments, the seizure disorder may be a generalized epilepsy plus (GEFS+). is epileptic.

[0045] As used herein, the term "therapeutic" refers to the treatment of an undesirable condition or condition in a patient. means an agent used to treat, combat, mitigate, prevent, or ameliorate a disease In part, embodiments of the present invention are directed to the treatment of neurodegenerative disorders, such as seizure disorders, including epilepsy. Regarding treatment.

[0046] The term "therapeutically effective amount" refers to a dose that is effective to treat, cure, prevent, or otherwise address a disease, disorder, or adverse event. "Amount" means any amount that results in improved relief or a slowing of the rate of progression of a disease or disorder. The term also includes within its scope amounts effective to enhance normal physiological function.

[0047] The term "t" 1 / 2 " is the time it takes for the peak plasma concentration to reach half of its original value after administration to a subject. This is the time it takes.

[0048] "t max " refers to the C max This means the time it takes to reach

[0049] As used herein, the terms "treat," "treated," or "treating" The term includes therapeutic treatment and prophylactic or preventative treatment. refers to both a therapeutic and ancillary means, the purpose of which is to eliminate an undesirable physiological condition, disorder, or is to prevent or slow (alleviate) a disease or to produce a beneficial or desired clinical outcome. For purposes of this invention, beneficial or desirable clinical outcomes include: , including, but not limited to, alleviation of symptoms; reduction in the severity of a condition, disorder or disease; Stabilization of the condition of a disorder or disease (i.e., it does not worsen); Delay in onset or slowing of progression; improvement in the state of a condition, disorder, or disease; and remission (partial (partial or total), detectable or undetectable, or a condition, disorder, or disease The treatment includes enhancing or improving the clinical efficacy of the drug without excessive levels of side effects. The treatment involves eliciting a significant response. This also includes prolonging survival compared to

[0050] In some embodiments, the compounds and methods disclosed herein may be used to treat such It can be used for or in the object that needs it, As used herein, the phrase "in need of" means that the subject identified as having a specific method or treatment need and for that specific purpose It means that a treatment is given to a subject.

[0051] Generally speaking, the term "organization" refers to a group of similarly specialized organizations united in performing a particular function. It refers to a collection of cells that have been separated.

[0052] The embodiments described herein are described in terms of "comprising" However, any embodiment described herein may be modified so that the pharmaceutical composition or method is The embodiments of the claims or claims and the embodiments described herein are specifically described. "consists" means containing only the elements, steps, or ingredients specified "ists of" or "consisting of" perspective? Also, the pharmaceutical composition or method may be described by specific ingredients or steps and specific It is intended to include only those matters which do not materially affect the basic and novel characteristics of the claimed invention. Taste "consisting essentially of f)" or "consists essentially of It can also be explained from the perspective of

[0053] Pharmaceutical Composition An embodiment of the present invention is a modified release oral pharmaceutical composition of huperzine, more specifically huperzine Applicant has demonstrated that twice-daily dosing produces therapeutically effective plasma concentrations of huperzine. However, the rapid high serum peak associated with serious adverse (and dose-limiting) side effects of huperzine We have discovered a modified release pharmaceutical composition of huperzine that overcomes these levels.

[0054] For example, to illustrate the benefits of modified-release pharmaceutical compositions of huperzine A in treating seizure disorders. To achieve this, the therapeutic threshold (C) of approximately 16.5 ng / mL (2 mg dose) of huperzine A in serum was max The applicant's non-clinical animal data, the dog data generated by the applicant, Pharmacokinetics (see below), allometric scaling, and modeling of However, the applicant's In an unpublished dose-escalation study, high levels above approximately 5 ng / mL were observed, particularly within the first 31 hours. Peak serum levels have been shown to have a high potential for causing nausea and vomiting. In this study, 7 out of 8 subjects experienced nausea and / or vomiting within the first 31 hours. These subjects had a mean time to first nausea of ​​17.7 hours and a mean time to first nausea of ​​4.8 hours. One subject did not experience nausea and presented with huperzine plasma levels of 100 ng / mL. Plasma levels above 5 ng / mL were not achieved until 42 hours after dosing. The results showed a time-concentration relationship, with plasma exposures of 4-5 ng / mL within the first 31 hours. This indicates that drug-related adverse events may occur when the Before the immediate-release dose-escalation study, It was unclear whether the plasma concentration threshold would be exceeded. Twice-daily dosing of Ludin A results in an early serum peak associated with nausea and vomiting. Furthermore, peak-to-trough serum exposures are predicted to fluctuate below the therapeutic threshold. Furthermore, it is predicted that one missed dose of Huperzine will result in a subject not achieving the therapeutic threshold. Not only does the immediate release dose become full, but the subject experiences a rapid, high peak serum concentration when the immediate release dose is resumed. exposure, which can result in nausea and vomiting with each missed dose (Figure 1). This makes immediate release pharmaceutical compositions a poor and potentially undesirable treatment option. In contrast, the invention developed by the applicant and described herein and a therapeutic threshold is reached, and a modified release pharmaceutical composition different from an immediate release pharmaceutical composition is used. Serum exposure levels were initially maintained below the 5 ng / mL threshold, thereby providing immediate release pharmaceutical The harmful nausea and vomiting associated with the composition are avoided. Furthermore, once therapeutic levels are reached, If an elephant misses one dose, plasma concentrations will not fall low enough to cause serious adverse events. (Figure 2).

[0055] Applicant has discovered that huperzine provides unexpected properties relative to other oral pharmaceutical compositions of huperzine. These pharmaceutical compositions have been shown to increase serum peaks. A higher therapeutic threshold can be achieved without the side effects associated with steroid use, and twice-daily administration is also possible. Medication becomes possible.

[0056] In an embodiment, the orally administrable modified-release pharmaceutical composition of huperzine of the present invention comprises a soluble component. A huperzine layer coating the soluble core, and a huperzine layer coating the soluble core. The huperzine layer comprises a polymer coating containing huperzine in a therapeutically effective amount.

[0057] In some embodiments of the present invention, the dissolvable core is a completely dissolvable core. In embodiments, the core is a sugar sphere. In some embodiments, the sugar sphere is a mixture of sucrose and decanol. In some embodiments, the sucrose comprises at least 62% by weight of sucrose. In a further embodiment, the sugar spheres are Suglets® sugar spheres. In some embodiments, the sugar spheres have a particle size of about 250 μm to about 1700 μm. In some embodiments, the sugar spheres are between about 250 μm and about 355 μm, between about 500 μm and about 600 μm. μm, approximately 600 μm to approximately 710 μm, approximately 710 μm to approximately 850 μm, approximately 850 μm to approximately 1 000μm, about 850μm to about 1180μm, about 1000μm to about 1180μm, about 10 00 μm to about 1400 μm, about 1400 μm to about 1700 μm, and combinations thereof In a further embodiment, the sugar spheres are selected from a particle size of about 500 μm to about 600 μm. In some embodiments, the particle size is selected from a particle size of about 600 μm to about 710 μm. In some embodiments, the sugar spheres have a particle size selected from about 500 μm to about 710 μm. The sugar spheres are Suglets® PF006.

[0058] In a further embodiment, the sugar spheres comprise about 74% to about 86% by weight of the pharmaceutical composition. In some embodiments, the sugar spheres comprise about 79% to about 84% by weight of the pharmaceutical composition. In some embodiments, the sugar spheres comprise about 80% to about 86% by weight of the pharmaceutical composition. In some embodiments, the sugar spheres comprise about 80% to about 83% by weight of the pharmaceutical composition. In some embodiments, the sugar spheres comprise about 81% to about 83% by weight of the pharmaceutical composition. In embodiments, the sugar spheres comprise about 81% to about 82.8% by weight of the pharmaceutical composition. In some embodiments, the sugar spheres comprise 81.5% to 83.0% by weight. In some embodiments, the sugar spheres comprise about 79.1% to about 80% by weight of the pharmaceutical composition. In some embodiments, the sugar spheres comprise about 80% to about 81% by weight of the pharmaceutical composition. In some embodiments, the sugar spheres comprise about 81% to about 82% by weight of the pharmaceutical composition. In some embodiments, the sugar spheres comprise about 81% to about 81.9% by weight of the pharmaceutical composition. In some embodiments, the sugar spheres comprise about 81.9% to about 82.8% by weight of the pharmaceutical composition. In some embodiments, the sugar spheres comprise about 82% to about 83% by weight of the pharmaceutical composition. In this form, the sugar spheres comprise from about 82.8% to about 83.7% by weight of the pharmaceutical composition.

[0059] In some embodiments, the weight percent of sugar spheres in the pharmaceutical composition is about 74% by weight, about 75% by weight, %, about 76% by weight, about 77% by weight, about 78% by weight, about 79% by weight, about 80% by weight, about 81 %, about 82%, about 83%, about 84%, about 85%, and about 86% by weight %, and the lower limit of about 86 wt%, about 85 wt%, about 84 wt%, 83 wt%, 82 wt%, 8 1% by weight, 80% by weight, 79% by weight, 78% by weight, 77% by weight, 76% by weight, 75% by weight and an upper limit of 74 wt. %.

[0060] In some embodiments, the weight percent of sugar spheres in the pharmaceutical composition is about 74% by weight, about 75% by weight, %, about 76% by weight, about 77% by weight, about 78% by weight, about 79% by weight, about 80% by weight, about 81 %, about 82%, about 83%, about 84%, about 85%, or about 86% by weight %.

[0061] 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 derived from Huperzia serrata (h In some embodiments, the extract is Huperzia serrata. The Huperzine A extract is approximately 99% Huperzine A.

[0062] In some embodiments, the weight percent of huperzine in the pharmaceutical composition is from about 0.5% by weight to about 1.5% by weight of Huperzine, or equivalent to 0.5% to about 1.5% by weight of Huperzine In some embodiments, the pharmaceutical composition includes a pharmaceutically acceptable salt of huperzine. The weight percent of Huperzine is about 0.9% to about 1% Huperzine, or 0.9% Contains a pharmaceutically acceptable salt of huperzine equivalent to about 1% by weight of huperzine. In some embodiments, the weight percent of huperzine in the pharmaceutical composition is from about 0.95% to about 1% by weight. % huperzine, or huperzine equivalent to 0.95% to about 1% by weight huperzine In some embodiments, the huperzine in the pharmaceutical composition includes a pharmaceutically acceptable salt of The weight percent is about 1% by weight of huperzine or a pharmaceutically acceptable salt equivalent to about 1% by weight of huperzine. In some embodiments, the weight percent of huperzine in the pharmaceutical composition is about 0.5% by weight, approximately 0.6% by weight, approximately 0.7% by weight, approximately 0.8% by weight, approximately 0.9% by weight, approximately 1% by weight, about 1.1% by weight, about 1.2% by weight, about 1.3% by weight, about 1.4% by weight, and The lower limit of about 1.5% by weight and the lower limits of about 1.5%, about 1.4%, about 1.3%, and 1.2% by weight are also included. Amount%, 1.1% by weight, 1% by weight, 0.9% by weight, 0.8% by weight, 0.7% by weight, 0.6% by weight Huperzine in an amount between about 0.5% by weight and an upper limit of about 0.6% by weight Amount%, about 0.7% by weight, about 0.8% by weight, about 0.9% by weight, about 1% by weight, about 1.1% by weight , about 1.2 wt. %, about 1.3 wt. %, about 1.4 wt. %, and about 1.5 wt. % lower limits; and 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%, and 0.5 wt% % of huperzine. In embodiments, the weight percent of huperzine in the pharmaceutical composition is 0.5 weight percent, about 0.6 weight percent, Approximately 0.7% by weight, approximately 0.8% by weight, approximately 0.9% by weight, approximately 1% by weight, approximately 1.1% by weight, approximately 1 0.2% by weight, about 1.3% by weight, about 1.4% by weight, and about 1.5% by weight, or Hupel 0.5% by weight, about 0.6% by weight, about 0.7% by weight, about 0.8% by weight, about 0.9% by weight %, about 1% by weight, about 1.1% by weight, about 1.2% by weight, about 1.3% by weight, about 1.4% by weight, and about 1.5% by weight of a pharmaceutically acceptable salt of huperzine. In embodiments, the huperzine layer comprises a therapeutically effective amount of huperzine.

[0063] In some embodiments, the huperzine layer further comprises one or more excipients. In some embodiments, the total amount of excipients is about 5% to about 10% by weight of the pharmaceutical composition. In some embodiments, the total amount of excipients is about 5% to about 9% by weight of the pharmaceutical composition. In some embodiments, the total amount of excipients is about 5% to about 7% by weight of the pharmaceutical composition. In some embodiments, the total amount of excipients in the huperzine layer is about 5% by weight of the pharmaceutical composition, about 6% by weight, about 7% by weight, about 8% by weight, about 9% by weight, or about 10% by weight In some embodiments, the excipient is hydroxypropyl methylcellulose or poly vinylpyrrolidone and combinations thereof.

[0064] In some embodiments, hydroxypropyl methylcellulose is used, e.g., Meth Low or very low viscosity cellulose, such as cel™ hydroxypropyl methylcellulose In a further embodiment, the hydroxypropyl methylcellulose is In some embodiments, the methylcellulose is Methocel VLV or the like. The amount of hydroxypropyl methylcellulose in the hydroxypropyl methylcellulose layer is about 6% by weight of the composition. In some embodiments, the hydroxypropyl methyl acrylate in the hydroxypropyl methyl acrylate layer is about 7% by weight. In some embodiments, the amount of cellulose is from about 5% to about 6% by weight of the composition. The amount of hydroxypropyl methylcellulose in the hydroxypropyl methylcellulose layer is about 6% by weight. In some embodiments, the amount of hydroxypropyl methylcellulose in the hydroxypropyl methylcellulose layer is In a further embodiment, the hydroxypropyl methylcellulose is about 5% by weight. The amount of Methocel VLV in the fuperidin layer was It accounts for approximately 6.1% by weight of the product.

[0065] In some embodiments of the present invention, polyvinylpyrrolidone is used in oral pharmaceutical compositions. In a further embodiment, the polyvinylpyrrolidone is any polyvinylpyrrolidone suitable for The huperzine layer is polyvinylpyrrolidone K30. The amount of polyvinylpyrrolidone is about 0.5% to about 1.5% by weight of the composition. In some embodiments, the polyvinylpyrrolidone in the huperzine layer is about 0.95% by weight of the composition. In some embodiments, the amount of polyvinylpyrrolidone in the huperzine layer is from about 1% to about 1% by weight. The amount of the donor is from about 0.90% to about 1% by weight of the composition. The polyvinylpyrrolidone in the cellulose layer is about 1% by weight of the composition. The polyvinylpyrrolidone is polyvinylpyrrolidone K30, and the polyvinylpyrrolidone in the Huperzine layer is The amount of vinylpyrrolidone K30 is about 1% by weight of the composition.

[0066] In some embodiments, one or more excipients in the huperzine layer are hydroxypropyl In some embodiments, the combination is methylcellulose and polyvinylpyrrolidone. In the Huperzine layer, the one or more excipients are about 5% to about 7% by weight of hydroxypropyl ... methylcellulose and about 0.5% to about 1.5% by weight of polyvinylpyrrolidone. In some embodiments, the one or more excipients in the huperzine layer comprise about 6% by weight of hydroxybenzoates. The composition is hydroxypropyl methylcellulose and about 1% by weight of polyvinylpyrrolidone.

[0067] In some embodiments of the present invention, the polymer coating coats the huperzine layer. The layer is a polyacrylamide polymer or ethyl cellulose polymer layer. In some embodiments, the polymer coating is a non-polyamide coating on the huperzine layer. In some embodiments, the polymer coating is a hydroxypropyl acrylate polymer. A layer of plasticized ethyl cellulose polymer coating the cellulose layer. In one embodiment, the plasticized ethyl cellulose is SuRelease® Ethyl Cellulose. In some embodiments, the plasticized ethyl cellulose is SurRelease. Registered trademark Type B NF E.

[0068] In some embodiments, the plasticized ethyl cellulose polymer comprises about 7% to about 10% by weight of the composition. In some embodiments, the plasticized ethyl cellulose polymer comprises about 16% by weight of the composition. In some embodiments, the plasticized ethylcellulose comprises about 8% to about 13% by weight of the composition. The base polymer comprises about 7% to about 12% by weight of the composition. The plasticized ethyl cellulose polymer comprises about 8% to about 12% by weight of the composition. In some embodiments, the plasticized ethyl cellulose polymer comprises from about 9% to about 11% by weight of the composition. In some embodiments, the plasticized ethyl cellulose polymer comprises about 100% of the composition. In some embodiments, the plasticized ethyl cellulose polyol comprises from 9% to about 10% by weight. In some embodiments, the mer comprises about 8.3% to about 9.2% by weight of the pharmaceutical composition. The plasticized ethyl cellulose polymer is about 9.2% to about 10.1% by weight of the pharmaceutical composition. In some embodiments, the plasticized ethyl cellulose polymer comprises about In some embodiments, the plasticized ethyl cellulose comprises 10.1% to about 11% by weight. The polymer comprises about 11% to about 12% by weight of the pharmaceutical composition. The plasticized ethylcellulose polymer is about 12% to about 12.9% by weight of the pharmaceutical composition. In some embodiments, the plasticized ethyl cellulose polymer comprises about Contains 15% to about 16% by weight.

[0069] In some embodiments, the weight percent of plasticized ethyl cellulose polymer in the composition is 7 Weight%, 8% by weight, 9% by weight, 10% by weight, 11% by weight, 12% by weight, 13% by weight, 14 %, 15% by weight, and 16% by weight, and the lower limits are 16%, 15%, and 14% by weight. , 13 wt%, 12 wt%, 11 wt%, 10 wt%, 9 wt%, 8 wt%, and 7 wt% The upper limit of the amount of %.

[0070] In some embodiments, the pharmaceutical composition comprises: a) a soluble core according to any embodiment described herein for a soluble core; b) Huperzine or Huperzine according to any embodiment described herein for the huperzine layer A huperzine layer containing a pharmaceutically acceptable salt of huperzine is coated on the dissolvable core. a layer of huperzine that c) A polymer coating the huperzine layer according to any embodiment described herein. and a coating.

[0071] In some embodiments of the present invention, the pharmaceutical composition for oral delivery comprises (a) about 74% by weight to Approximately 86% by weight of sugar sphere cores having a particle size of approximately 500 to 710 μm; b) a huperzine layer coating the sugar spheres, containing about 0.95% to about 1% by weight of huperzine; Huperzine or a drug equivalent to about 0.95% to about 1% by weight of huperzine and one or more excipients, in a total amount of from about 5% to about 9% by weight. % of an excipient; and (c) a coating of the huperzine layer, % to about 16% by weight of a plasticized ethyl cellulose polymer layer, and the huperzine layer is and a plasticized ethyl cellulose polymer layer containing a therapeutically effective amount of huperzine. In an embodiment, the huperzine is huperzine A. In a further embodiment, one or more excipients The excipient is a combination of hydroxypropyl methylcellulose and polyvinylpyrrolidone. In a further embodiment, the one or more excipients are about 6% by weight of hydroxypropylmethylcellulose. It is a combination of ethyl cellulose and about 1% by weight of polyvinylpyrrolidone. In embodiments, the hydroxypropyl methylcellulose is a low viscosity hydroxypropyl methylcellulose. The polyvinylpyrrolidone is polyvinylpyrrolidone K30, The plasticized ethyl cellulose is SurRelease® Type B NF E .

[0072] In some embodiments of the present invention, the pharmaceutical composition comprises: (a) about 79% to about 84% by weight (b) a sugar sphere core having a particle size of about 500 to 710 μm; and A coating layer of huperzine containing about 0.95% by weight to about 1% by weight of huperzine, or or a pharmaceutically acceptable salt of huperzine equivalent to about 0.95% by weight to about 1% by weight of huperzine. hydroxypropyl methylcellulose, and about 0.95% by weight of a salt thereof. (c) a huperzine layer containing about 1% by weight of polyvinylpyrrolidone; A layer of about 8% to about 13% by weight of a plasticized ethyl cellulose polymer layer covering the film. the huperzine layer comprises a plasticized ethyl cellulose polymer layer containing a therapeutically effective amount of huperzine; In a further embodiment, the huperzine is huperzine A. In a further embodiment, Huperzine is Huperzine A, and hydroxypropyl methylcellulose is a low viscosity huperzine. hydroxypropyl methylcellulose, and polyvinylpyrrolidone is polyvinylpyrrolidone. The plasticized ethyl cellulose is SurRelease® Tycoon K30. Hydroxypropyl methylcellulose is a low viscosity hydroxypropyl methylcellulose. Pyrmethylcellulose, and polyvinylpyrrolidone is polyvinylpyrrolidone K30 Plasticized ethyl cellulose is SurRelease® Type B NF E is.

[0073] In some embodiments of the present invention, the pharmaceutical composition comprises: (a) about 80% to about 83% by weight (b) a sugar sphere core having a particle size of about 500 to 710 μm; and A coating layer of huperzine containing about 0.95% by weight to about 1% by weight of huperzine, or or a pharmaceutically acceptable salt of huperzine equivalent to about 0.95% by weight to about 1% by weight of huperzine. salts, about 5% to about 6% by weight of hydroxypropyl methylcellulose, and about 0. (c) a Huperzine layer containing 95% by weight to about 1% by weight of polyvinylpyrrolidone; A layer of about 8% to about 12% by weight of a plasticized ethyl cellulose polymer coating the polymer layer. wherein the huperzine layer is a plasticized ethyl cellulose polymer containing a therapeutically effective amount of huperzine. In a further embodiment, the huperzine is huperzine A and a hydroxyl group. Hydroxypropyl methylcellulose is a low viscosity hydroxypropyl methylcellulose. Polyvinylpyrrolidone is Polyvinylpyrrolidone K30, and plasticized ethyl cellulose is , SurRelease® Type B NF E.

[0074] In some embodiments of the present invention, the pharmaceutical composition comprises: (a) about 81% to about 82% by weight of (b) a sugar sphere core having a particle size of about 500 to 710 μm; and A coating layer of huperzine containing about 0.95% by weight to about 1% by weight of huperzine, or or a pharmaceutically acceptable salt of huperzine equivalent to about 0.95% by weight to about 1% by weight of huperzine. salts, about 5% to about 6% by weight of hydroxypropyl methylcellulose, and about 0. (c) a Huperzine layer containing 95% by weight to about 1% by weight of polyvinylpyrrolidone; about 10% to about 11% by weight of a plasticized ethyl cellulose polymer coating the polymer layer; a layer, the huperzine layer being a plasticized ethyl cellulose polymer containing a therapeutically effective amount of huperzine; In a further embodiment, the huperzine is huperzine A and a polymer layer. Hydroxypropyl methylcellulose is a low viscosity hydroxypropyl methylcellulose, Polyvinylpyrrolidone is Polyvinylpyrrolidone K30, Plasticized Ethylcellulose is a SurRelease® Type B NF E.

[0075] In some embodiments of the present invention, the pharmaceutical composition comprises: (a) about 81.5% by weight of sugar sphere cores; (b) a sugar sphere core having a particle size of about 500 to 710 μm; and (b) a sugar sphere coating. A huperzine layer containing about 1% by weight of huperzine or equivalent to 1% by weight of huperzine 5.9% by weight of hydroxypropylmethylcellulose, a pharmaceutically acceptable salt of huperzine, (c) a Huperzine layer containing cellulose and about 1% by weight of polyvinylpyrrolidone; A layer of approximately 10.7% by weight of plasticized ethyl cellulose polymer coating the cellulose layer. The huperzine layer is a plasticized ethyl cellulose polymer containing a therapeutically effective amount of huperzine. In a further embodiment, the huperzine is huperzine A and Hydroxypropyl methylcellulose is a low viscosity hydroxypropyl methylcellulose, Nylpyrrolidone is Polyvinylpyrrolidone K30, and plasticized ethyl cellulose is S urRelease® Type B NF E.

[0076] In some embodiments of the present invention, the pharmaceutical composition comprises: (a) about 82% to about 83% by weight (b) a sugar sphere core having a particle size of about 500 to 710 μm; and A coating layer of huperzine containing about 0.95% by weight to about 1% by weight of huperzine, or or a pharmaceutically acceptable salt of huperzine equivalent to about 0.95% by weight to about 1% by weight of huperzine. salts, about 5% to about 6% by weight of hydroxypropyl methylcellulose, and about 0. (c) a Huperzine layer containing 95% by weight to about 1% by weight of polyvinylpyrrolidone; A layer of about 9% to about 10% by weight of a plasticized ethyl cellulose polymer coating the polymer layer. wherein the huperzine layer is a plasticized ethyl cellulose polymer containing a therapeutically effective amount of huperzine. In a further embodiment, the huperzine is huperzine A and a polymer layer. Hydroxypropyl methylcellulose is a low viscosity hydroxypropyl methylcellulose, Polyvinylpyrrolidone is Polyvinylpyrrolidone K30, Plasticized Ethylcellulose is a SurRelease® Type B NF E.

[0077] In some embodiments of the present invention, the pharmaceutical agent comprises: (a) about 83% by weight of the sugar sphere core; (b) a sugar sphere core having a particle size of approximately 500 to 710 μm, and (b) a coating for the sugar sphere. Huperzine layer, containing about 1% by weight of huperzine or a huperzine equivalent to 1% by weight of huperzine a pharmaceutically acceptable salt of cellulose, about 6% by weight of hydroxypropyl methylcellulose, and and about 1% by weight of polyvinylpyrrolidone, and (c) a Huperzine layer containing the Huperzine layer. A layer of about 9% by weight of plasticized ethyl cellulose polymer coating the Huperzine layer. and a plasticized ethyl cellulose polymer layer containing a therapeutically effective amount of huperzine. In one embodiment, the huperzine is huperzine A and hydroxypropylmethylcellulose. The base is low viscosity hydroxypropyl methylcellulose, and the polyvinylpyrrolidone is Polyvinylpyrrolidone K30, plasticized ethyl cellulose, SurRelease (registered trademark) Type B NF E.

[0078] In some embodiments of the present invention, the pharmaceutical composition comprises a huperzine layer and a plasticized ethylcellulose layer. It further includes a seal coat layer between the base layer.

[0079] In some embodiments, (a) about 75% to about 76% by weight of the sugar sphere cores, (b) sugar sphere cores with a particle size of 500-710 μm and (b) Huperzi coating on the sugar spheres. a hydroxybenzoate layer containing about 0.9% to about 1% by weight of huperzine, or about 0.9% of huperzine % to about 1% by weight of a pharmaceutically acceptable salt of Huperzine, and about 5% to about 6% by weight of a pharmaceutically acceptable salt of Huperzine. % by weight of hydroxypropyl methylcellulose, and about 0.9% to about 1% by weight of poly(ethylene glycol). (c) a huperzine layer containing vinylpyrrolidone; and (c) a sheet coating the huperzine layer. A coating layer containing about 1% to about 2% by weight of hydroxypropyl methylcellulose. and (d) a seal coat layer containing about 15% by weight to about 16% by weight of a huperzine layer. % plasticized ethyl cellulose polymer layer, wherein the huperzine layer contains a therapeutically effective amount of huperzine. and a plasticized ethyl cellulose polymer layer containing ludine. In a further embodiment, the huperzine is huperzine A and is hydroxypropyl methyl The cellulose is low viscosity hydroxypropyl methylcellulose and polyvinylpyrrolidone. The polymer is polyvinylpyrrolidone K30, and the plasticized ethyl cellulose is SurRele ase® Type B NF E.

[0080] An embodiment of the present invention is a pharmaceutical composition according to any embodiment described herein, When a therapeutically effective amount of the pharmaceutical composition is orally administered to a human subject, the C ma x is about 4 ng / mL to about 8 ng / mL, and T max is about 4 to about 8 hours, t 1 / 2 In one embodiment, the pharmaceutical composition is characterized in that the onset of the inflammatory response is about 8 hours to about 12 hours. So, C max is about 4 ng / mL to about 6 ng / mL, and T max Approximately 4 hours to 8 hours Between t 1 / 2 In one embodiment, C max is about 6 ng / mL, and T max is about 4 hours, and t 1 / 2 is approximately 8.3 hours.

[0081] A further embodiment of the present invention is a pharmaceutical composition according to any of the embodiments described herein. Therefore, immediate release huperzine pharmaceuticals containing a therapeutically effective amount of huperzine and administered at equivalent doses Composition C max Compared to T max is about 4 to about 8 hours, and C max is about Some embodiments include pharmaceutical compositions characterized by a 25% to about 75% reduction in blood cholesterol. In the form of immediate release huperzine pharmaceutical composition C max Compared to C max is 50% It is declining.

[0082] Some embodiments describe a pharmaceutical composition according to any embodiment described herein, This was performed in a USP type 1 apparatus at 50 rpm in 50 mM phosphate (pH 6.8) at 37°C. When tested according to the procedure, approximately 36% to 46% of Huperzine was released after 2 hours. Approximately 61% to 77% of huperzine was released after 4 hours, and approximately 84% to 97% of huperzine was released after 4 hours. Dissolution profile shows that approximately 89% of Huperzine is released after 8 hours and approximately 89% of Huperzine is released after 12 hours. Indicates the file.

[0083] Some embodiments describe a pharmaceutical composition according to any embodiment described herein, This was performed in a USP type 1 apparatus at 50 rpm in 50 mM phosphate (pH 6.8) at 37°C. When tested according to the procedure, approximately 36% of Huperzine was released after 2 hours, and approximately 10% of Huperzine was released. 63% is released after 4 hours, and approximately 84% of Huperzine is released after 8 hours. The dissolution profile shows that approximately 89% or more of the active ingredient is released after 12 hours.

[0084] Some embodiments describe a pharmaceutical composition according to any embodiment described herein, This was performed in a USP type 1 apparatus at 50 rpm in 50 mM phosphate (pH 6.8) at 37°C. When tested according to the procedure, approximately 46% of Huperzine was released after 2 hours, and approximately 10% of Huperzine was released. 77% is released after 4 hours, and approximately 97% of Huperzine is released after 8 hours. The dissolution profile shows that more than 99% of the active ingredient is released after 12 hours.

[0085] Some embodiments describe a pharmaceutical composition according to any embodiment described herein, This was performed in a USP type 1 apparatus at 50 rpm in 50 mM phosphate (pH 6.8) at 37°C. When tested according to the procedure, approximately 43% of Huperzine was released after 2 hours, and approximately 10% of Huperzine was released. 68% is released after 4 hours, and approximately 88% of Huperzine is released after 8 hours. The dissolution profile shows that approximately 96% or more of the active ingredient is released after 12 hours.

[0086] Some embodiments describe a pharmaceutical composition according to any embodiment described herein, This was performed in a USP type 1 apparatus at 50 rpm in 50 mM phosphate (pH 6.8) at 37°C. When tested according to the procedure, approximately 38% of Huperzine was released after 2 hours, and approximately 10% of Huperzine was released. 61% is released after 4 hours, and approximately 84% of Huperzine is released after 8 hours. The dissolution profile shows that approximately 94% or more of the active ingredient is released after 12 hours.

[0087] Upon oral administration of the pharmaceutical composition to a human subject, the plasma concentration maintained within the first 31 hours is The pharmaceutical composition characterized by having a saturation of less than 5 ng / mL is in accordance with some embodiments of the present invention. Another embodiment.

[0088] In any of the embodiments described herein, huperzine is huperzine A or a pharmaceutical In any embodiment, huperzine A is a commercially available salt of Huperzia serrata extract. In any embodiment, the Huperzia serrata extract is about 99% Huperzia serrata extract. It is A.

[0089] In any of the embodiments described herein, the pharmaceutical composition is for oral delivery. The pharmaceutical compositions of the present invention are formulated for oral administration, e.g., as tablets, sprinkles, capsules, or the like. In one embodiment, the method of any of the embodiments described herein may be in the form of a tablet or pill. In some embodiments, the pharmaceutical composition is formulated for oral administration in the form of a capsule. The pharmaceutical compositions according to any embodiment described herein may be formulated for oral administration in the form of a tablet. 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 substances is well known in the art and is well known in the art for tablet formulations. These include additives, lubricants, flavoring agents, preservatives, wetting agents, emulsifying agents, and dispersing agents.

[0090] As illustrated below and as shown in the examples below, applicants have The pharmaceutical compositions described in any of the embodiments have been shown to have unexpected and unpredictable properties. did.

[0091] Applicant has developed a composition comprising an inert core layer, a huperzine layer coating the core layer, and A number of pharmaceutical compositions were prepared containing a polymer layer coating the huperzine layer. [Table 1] TIFF0007737427000003.tif46165

[0092] As shown in Figure 4, the dissolution profiles of Compositions 1A and 1B were very rapid. Therefore, it is more similar to an immediate-release pharmaceutical composition than a modified-release pharmaceutical composition, and the release occurs in about 30 minutes. Microcrystalline cellulose spheres were used for sustained release / release of pharmaceuticals. This result is unexpected, as the core is known to those skilled in the art to be suitable for regulating the release of Additionally, MCC compositions 1A and 1B contain Eudragit coatings on the Huperzine layer. The dissolution rate was predicted to be even slower for Eudragit. Furthermore, considering the dissolution profiles of Compositions 1 and 2, one skilled in the art would recognize that compositions containing sugar spheres It was unexpected that sugar spheres would provide an advantage over MCC spheres. Because of this, the dissolution profile of the sugar sphere composition is significantly lower than that of the composition containing water-insoluble MCC spheres. MCC compositions 2A, 2B, 2C, 3A, 3B, and 3C are expected to be more rapid. had a longer release profile but a very rapid initial release (rapid release), or However, sugar sphere compositions 4A, 4B, 4D, 4E, 4F-1 and 4F-2, especially 4D, 4F-1, and 4F-2, showed unexpectedly slow initial growth. It has a rapid dissolution rate, releasing approximately 85-90% (or more) of Huperzine after 12 hours. This makes it ideal for modified-release pharmaceutical compositions of huperzine (see Figure 5 and Table 2). . [Table 2]

[0093] In some embodiments, the compositions described herein exhibit a dissolution profile as defined in Table 2. In some embodiments, the dissolution process comprises: The profile is compared with any of compositions 4A, 4D, 4F-1, and 4F-2. , have an F2 of greater than 50%. F2 is a factor that assesses the similarity of two dissolution curves. This is understood by those skilled in the art and is represented by the formula: F2=50xlog{[1+(1 / n)Σ(RT)^2]^-0.5x100} where n is the number of time points evaluated, R = reference value at a given time, and T = equivalent The test value is in hours.

[0094] Pharmacokinetic studies in dogs further demonstrate the advantages of composition 4A over, e.g., the MCC composition. (See Figure 6). The following pharmacokinetic parameters were observed in this study (Table 3 and See Example 2). [Table 3]

[0095] As shown in Table 3 and Figure 6, MCC Composition 2C releases huperzine, but not huperzine. The release and subsequent absorption of the drug is sufficient to keep up with the clearance of the drug from the body. Not so fast, but 1 / 2 was only slightly extended from 1.25 hours to 2 hours. Therefore, patients need to take Huperzine in Composition 2C 4 to 6 times a day. However, composition 4A offers little advantage over immediate release pharmaceutical compositions. It has an ideal pharmacokinetic profile for twice-daily dosing, which means it can be easily removed from the body. It demonstrated higher overall absorption without being cleared very rapidly.

[0096] In human Phase 1b clinical trials, patients requiring higher doses of Huperzine, e.g. In patients with dysarthria (see Example 3), Composition 4D reduced the severity of the disease compared to an immediate release preparation. showed a dramatic reduction in serious adverse events, demonstrated twice-daily dosing, and is predicted to provide significant protection. The favorable pharmacokinetic profile, showing achievable drug plasma levels, is further illustrated. .

[0097] Treatment method The pharmaceutical composition according to any embodiment described herein may be administered to a patient in need thereof. , are useful in the treatment of neurological disorders and / or seizure disorders. They are useful in the treatment of neurological dysfunction It can be administered therapeutically to treat, prevent, or slow the onset of In some embodiments, methods of treating neurological and / or seizure disorders are described. In some embodiments, the pharmaceutical composition according to any embodiment described herein may be used to treat Alzheimer's disease. amyloid-related disorders such as Marger's disease and the amyloid disorders described herein, Tourette's syndrome Mental disorders such as post-traumatic stress disorder (PTSD), panic and anxiety disorders, Obsessive-compulsive disorder, and developmental disorders such as schizophrenia, fragile X syndrome and autism, pain, Drug addiction, such as cocaine addiction, and neurodegenerative diseases, such as Parkinson's disease and Huntington's disease , as well as stroke and ischemic brain injury, amyotrophic lateral sclerosis, epilepsy, and neurotoxicity ( associated with or related to exposure to neurotoxins, including but not limited to chemical weapons The present invention describes a method for treating a neurological disorder selected from any disorder, symptom, or effect that affects a person's neurological condition. It is listed.

[0098] In embodiments, the present invention provides a method for treating epilepsy (including intractable epilepsy), generalized seizures, primary generalized seizures, and the like. Absence seizures, myoclonic seizures, partial seizures, complex partial seizures with or without generalized seizures Minute seizures (e.g., focal impairment of awareness seizures (FIAS)), Lennox-Gastaut syndrome, Doraemon syndrome seizures and seizures selected from the group consisting of Be's syndrome, generalized epilepsy with febrile seizures plus (GEFS+) In some embodiments, the seizure disorder is epilepsy. be.

[0099] The pharmaceutical compositions according to any embodiment described herein may be used to treat neurological disorders such as epilepsy and seizures. may be administered therapeutically to treat, prevent, or slow the onset of neuronal dysfunction, or the onset of seizures associated with other disorders to protect against further seizures associated with epilepsy For example, the compound can be administered prophylactically to avoid or forestall The pharmaceutical composition according to any embodiment described herein is for treating stroke and the consequences of stroke. delaying the progression of seizures and epilepsy in patients at risk of developing seizures as a result of Or, it can be administered prophylactically to stop the progression of the disease.

[0100] In a further embodiment, a patient in need thereof is provided with any of the embodiments described herein. and administering a pharmaceutical composition comprising the compound of formula (I) to treat epilepsy, intractable epilepsy, and FIAS. It describes how to do this.

[0101] In some embodiments, the pharmaceutical compositions of the present invention have a better side effect profile. and is administered at a dose that reduces seizures by at least 10%. Preferably, the reduction is at least 20%. , 50%, 75% or eliminates seizure episodes. Pharmaceutical compositions according to any embodiment prevent the onset of a seizure or eliminate the seizure altogether.

[0102] In a further embodiment, the present invention provides a method for the treatment of neurotoxins (including but not limited to neurotoxins such as chemical warfare agents). Treat any disorder, symptom, or effect related to or involving exposure to The method provides a method of administering to a patient in need thereof any of the embodiments described herein. The method includes administering a pharmaceutical composition according to the method.

[0103] In some embodiments, the dose of huperzine in the pharmaceutical composition of the present invention is preferably 1 In some embodiments, the dose is preferably greater than 6.5 mg / day. In some embodiments, the dose is about 0.01 mg / day, about 0.05 mg / day, Approx. 0.1mg / day, approx. 0.25mg / day, approx. 0.5mg / day, approx. 0.75mg / day, approx. 0 .8mg / day, approximately 1mg / day, approximately 1.1mg / day, approximately 1.25mg / day, approximately 1.5mg / day, about 1.75 mg / day, about 2 mg / day, about 2.2 mg / day, about 2.25 mg / day, about 2 0.5mg / day, approximately 3.0mg / day, approximately 3.5mg / day, approximately 4.0mg / day, approximately 4.5mg / day, approximately 5.0 mg / day, approximately 5.5 mg / day, approximately 6.0 mg / day, and approximately 6.5 mg / day The lower limit of about 6.5 mg / day, about 6.0 mg / day, about 5.5 mg / day, about 5 mg / day, and about 4.5mg / day, approximately 4.0mg / day, approximately 3.5mg / day, approximately 3.0mg / day, approximately 2.5m g / day, about 2.25mg / day, about 2.2mg / day, about 2mg / day, about 1.75mg / day, Approximately 1.5mg / day, approximately 1.25mg / day, approximately 1.1mg / day, approximately 1mg / day, approximately 0.75 mg / day, about 0.8mg / day, about 0.5mg / day, about 0.25mg / day, about 0.1mg / day daily, between an upper limit of about 0.05 mg / day and an upper limit of about 0.01 mg / day. In a further embodiment, the dose is from about 0.01 mg / day to about 0.8 mg / day. The dosage is from about 0.25 mg / day to about 5 mg / day. In some embodiments, the dosage is In some embodiments, the dose is about 0.25 mg / day to about 0.5 mg / day. In some embodiments, the dose is about 0.75 mg / day. In some embodiments, the dose is from about 1 mg / day to about 5 mg / day. In some embodiments, the dose is from about 1.25 mg / day to about 1. In some embodiments, the dose is from about 1.5 mg / day to about 1.75 mg / day. In some embodiments, the dose is from about 1.75 mg / day to about 2.0 mg / day. In some embodiments, the dose is from about 2.0 mg / day to about 2.25 mg / day In some embodiments, the dose is about 2.25 mg / day to about 2.5 mg / day. In some embodiments, the dose is from about 2.5 mg / day to about 2.75 mg / day. In some embodiments, the dose is from about 2.75 mg / day to about 3.0 mg / day. In some embodiments, the dose is from about 3.0 mg / day to about 3.25 mg / day. In some embodiments, the dose is from about 3.25 mg / day to about 3.50 mg / day. In embodiments, the dose is from about 3.50 mg / day to about 3.75 mg / day. In some embodiments, the dosage is from about 3.75 mg / day to about 4.0 mg / day. In some embodiments, the dose is from about 4.0 mg / day to about 4.25 mg / day. In some embodiments, the dose is about 4.25 mg / day to about 4.5 mg / day. The dose is about 4.5 mg / day to about 4.75 mg / day. In some embodiments, the dose In some embodiments, the dose is about 4.75 mg / day to about 5 mg / day. In some embodiments, the dose is from about 0.5 mg / day to about 5 mg / day. In some embodiments, the dose is from about 0.5 mg / day to about 2.2 mg / day. g / day. In some embodiments, the dose is about 5 mg / day. In some forms, the dosage is about 0.5 mg / day, about 1 mg / day, about 1.1 mg / day, about 1 mg / day, and about 1 mg / day. .5mg / day, approximately 2.0mg / day, approximately 2.50mg / day, approximately 3.0mg / day, approximately 3.5m g / day or about 3.6 mg / day. In some embodiments, any of the methods described herein The daily dose according to this embodiment is administered twice daily. In some embodiments, the dose is about 0.25 mg twice daily to about 2.5 mg twice daily. In some embodiments, Doses are approximately 0.25 mg twice a day, approximately 0.5 mg twice a day, or approximately 0.75 mg twice a day. 1.0 mg twice a day, 1.1 mg twice a day, 1.25 mg twice a day, 0.5mg twice daily, 1.75mg twice daily, 1.8mg twice daily, 2.0mg twice daily twice a day, 2.25 mg twice a day, or 2.5 mg twice a day.

[0104] In some embodiments, about 0.05 mg / day to about 7 mg / day, about 0.05 mg / day to about 5 mg / day mg / day, approximately 0.05 mg / day to approximately 0.8 mg / day, approximately 0.05 mg / day to approximately 0.4 mg / day, about 0.05 mg / day to about 0.02 mg / day, or 0.05 mg / day to about 0.0 Doses of 1 mg / day may also be used. In some embodiments, these doses are used to Any neurological disorder can be treated. In some embodiments, these doses are used to: Symptoms or effects associated with or related to exposure to neurotoxins, such as chemical warfare agents, may be treated.

[0105] In some embodiments, the present disclosure provides a modified-release pharmaceutical formulation of huperzine to a patient in need thereof. One or more titration doses of the pharmaceutical composition are administered, followed by oral release of a maintenance dose of huperzine thereafter. and administering a controlled release pharmaceutical composition, wherein the patient experiences a better side effect profile. Methods for treating neurological and / or seizure disorders are provided. In some embodiments, the methods include: The modified release pharmaceutical composition of huperzine administered at a titration dose is In a further embodiment, the modified release pharmaceutical composition is administered in titrated doses. The modified-release pharmaceutical composition of huperzine is a modified-release pharmaceutical composition of huperzine administered at a maintenance dose. In a further embodiment, the huperzine is huperzine A. In an embodiment, the modified-release pharmaceutical composition of huperzine comprises a soluble core, a coating of the soluble core, and The active Huperzine A layer that coats the active Huperzine A layer and the polymer coating that coats the active Huperzine A layer. In a further embodiment, the modified-release huperzine pharmaceutical composition comprises In some embodiments, the release of huperzine is The controlled release pharmaceutical composition is a pharmaceutical composition according to any embodiment described herein, In some embodiments, the oral administration of huperzine and the maintenance dose are the same pharmaceutical composition. The modified release pharmaceutical composition may be a pharmaceutical composition comprising huperzine A according to any of the embodiments described herein. a pharmaceutical composition comprising huperzine A, wherein the titration dose and the maintenance dose are the same. In some embodiments, the patient may be given a low dose over a period of several days to several weeks until a maintenance dose is reached. Titrate the dose from low to high doses.

[0106] Some embodiments provide a method for treating a patient in need thereof that provides a better side effect profile. The present invention describes a method for treating neurological and / or seizure disorders in patients experiencing The method includes administering a first dosing regimen of at least one dosing regimen selected from a-h. administering a compound (described further below), at least one compound selected from a-i administering a second dosing regimen (described further below), 2 dosage regimens is more than the first dosage regimen, and the last dosage regimen is It is intended to be a maintenance dose and therefore administered as long as the patient requires the treatment. Let's say. a. Approximately 0.01 mg to approximately 0.25 mg once every 12 hours for at least 2 days to a maximum of 2 weeks administering a mg dose of huperzine, b. Approximately 0.26 mg to approximately 0.5 mg once every 12 hours for at least 2 days to a maximum of 2 weeks administering a dose of huperzine in a dose of 100 mg / kg; c. Approximately 0.51 mg to approximately 0.75 mg once approximately every 12 hours for at least 2 days to a maximum of 2 weeks administering a mg dose of huperzine, d. Approximately 0.76 mg to 1 mg once every 12 hours for at least 2 days to a maximum of 2 weeks administering a dose of huperzine; e. Approximately 1.1 mg to 1.25 mg once every 12 hours for at least 2 days to a maximum of 2 weeks administering a dose of huperzine in a dose of 100 mg / kg; f. Approximately 1.26 mg to 1.5 mg once every 12 hours for at least 2 days to a maximum of 2 weeks administering a dose of huperzine in a dose of 100 mg / kg; Approximately 1.51 mg to 1.75 g once every 12 hours for at least 2 days to a maximum of 2 weeks administering a mg dose of huperzine, h. Approximately 1.76 mg to approximately 2 mg once every 12 hours for at least 2 days to a maximum of 2 weeks administering a dose of huperzine; and i. about 2.1 mg to about 2.5 mg once about every 12 hours for at least 2 days administering perzin; Huperzine a-i is administered in a modified release pharmaceutical composition. The controlled release pharmaceutical composition is a pharmaceutical composition according to any embodiment described herein. In some embodiments, each dose before the maintenance dose is administered for 2 days to 2 weeks.

[0107] Some embodiments provide a method for treating a patient in need thereof that provides a better side effect profile. The present invention describes a method for treating neurological and / or seizure disorders in patients experiencing The method includes administering a first dosing regimen of at least one dosing regimen selected from a-h. administering a compound (described further below), at least one compound selected from a-i administering a second dosing regimen (described further below), 2 dosage regimens is more than the first dosage regimen, and the last dosage regimen is It is intended to be a maintenance dose and therefore administered as long as the patient requires the treatment. Let's say. a. Fupe at a dose of approximately 0.25 mg once approximately every 12 hours for at least 2 days and up to 2 weeks administering luzin; b. Huperzia at a dose of approximately 0.5 mg once approximately every 12 hours for at least 2 days and up to 2 weeks administering gin, c. Fupe at a dose of approximately 0.75 mg once approximately every 12 hours for at least 2 days and up to 2 weeks administering luzin; d. Huperzine at a dose of approximately 1 mg once approximately every 12 hours for at least 2 days and up to 2 weeks administering e. Fupe at a dose of approximately 1.25 mg once approximately every 12 hours for at least 2 days and up to 2 weeks administering luzin; f. Huperziv at a dose of approximately 1.5 mg, once approximately every 12 hours for at least 2 days and up to 2 weeks administering gin, g. Fupe at a dose of approximately 1.75 mg once approximately every 12 hours for at least 2 days and up to 2 weeks administering luzin; h. Huperzine at a dose of approximately 2 mg once approximately every 12 hours for at least 2 days and up to 2 weeks administering i. Huperzine at a dose of approximately 2.5 mg administered once approximately every 12 hours for at least 2 days including Huperzine a-i is administered in a modified release pharmaceutical composition. The controlled release pharmaceutical composition is a pharmaceutical composition according to any embodiment described herein. In some embodiments, each dose before the maintenance dose is administered for 2 days to 2 weeks. At least one medication regimen selected from a to i Any combination of these ingredients may allow for any combination of dosing regimens. It will be understood that a minimum of two dosing regimens (one initial dose less than the maintenance dose) is therefore recommended. and one maintenance dose) and increased to a maximum of nine dosing regimens (a-h). The dosage regimen and maintenance dose i) are described.

[0108] In some embodiments, the method comprises administering any dosing regimen selected from: (The last dose specified is the maintenance dose): [Table 4]

[0109] In some embodiments, the method comprises: a. Administer approximately 0.25 mg of Huperzine A once every 12 hours for 2 days to 2 weeks. To do, b. Administer approximately 0.5 mg of Huperzine A once every 12 hours for 2 days to 2 weeks. To do so, c. Huperzine A at a dose of approximately 0.75 mg administered once approximately every 12 hours for 2 days to 2 weeks. To do, d. Administer Huperzine A at a dose of approximately 1 mg once approximately every 12 hours for at least 2 days. This includes:

[0110] In some embodiments, step d is administered for as long as the patient is in need of treatment. .

[0111] In some embodiments, the method further comprises, after step d: e. Fupe at a dose of approximately 1.25 mg once approximately every 12 hours for as long as the patient needs it. further comprising administering ludin A.

[0112] In some embodiments, the method further comprises, after step d: e. Administer approximately 1.25 mg of Huperzine A once every 12 hours for 2 days to 2 weeks. To do, f. Administer approximately 1.5 mg of Huperzine A once every 12 hours for 2 days to 2 weeks. It further includes:

[0113] In some embodiments, the method further comprises, after step d: e. Administer approximately 1.25 mg of Huperzine A once every 12 hours for 2 days to 2 weeks. To do, f. Administer approximately 1.5 mg of Huperzine A once every 12 hours for 2 days to 2 weeks. To do so, g. Fupe at a dose of approximately 1.75 mg once approximately every 12 hours for as long as the patient needs it. further comprising administering ludin A.

[0114] In some embodiments, the method further comprises, after step d: e. Administer approximately 1.25 mg of Huperzine A once every 12 hours for 2 days to 2 weeks. To do, f. Administer approximately 1.5 mg of Huperzine A once every 12 hours for 2 days to 2 weeks. To do so, g. Administer approximately 1.75 mg of Huperzine A once every 12 hours for 2 days to 2 weeks. To do, h. Huperzine at a dose of approximately 2 mg once every 12 hours for as long as the patient needs it. further comprising administering A.

[0115] In some embodiments, the method further comprises, after step d: e. Administer approximately 1.25 mg of Huperzine A once every 12 hours for 2 days to 2 weeks. To do, f. Administer approximately 1.5 mg of Huperzine A once every 12 hours for 2 days to 2 weeks. To do so, g. Administer approximately 1.75 mg of Huperzine A once every 12 hours for 2 days to 2 weeks. To do, h. Administer approximately 2 mg of Huperzine A once every 12 hours for 2 days to 2 weeks. and, i. Hupelamine at a dose of approximately 2.5 mg once every 12 hours for as long as the patient needs it. The method further comprises administering gin A.

[0116] Some embodiments of the present disclosure include administering a modified release pharmaceutical composition of huperzine. In patients who need it and experience a better side effect profile, and a method for treating neurological disorders and / or seizure disorders, comprising administering to a subject a controlled-release pharmaceutical composition of huperzine. The composition comprises a C of huperzine in plasma selected from the following: ss Features: [Table 5]

[0117] In some embodiments, the Css of huperzine in plasma is selected from: [Table 6]

[0118] In some embodiments, the Css of huperzine in plasma is selected from: [Table 7] In a further embodiment, the modified release pharmaceutical composition is a pharmaceutical composition according to any of the embodiments described herein. It is a pharmaceutical composition.

[0119] In some embodiments, the method comprises administering a modified release pharmaceutical composition of huperzine A. For patients who need it and experience a better side effect profile and a method for treating neurological disorders and / or seizure disorders, comprising administering a modified-release humerus to a subject. The pharmaceutical composition, when administered in a therapeutically effective amount, has a plasma Css of huperzine of about 0.6n Some methods are described that are characterized by a concentration of 100 mg / mL to about 12 ng / mL. In embodiments, the Css of huperzine in plasma is about 2n when administered in a therapeutically effective amount. In some embodiments, the C of huperzine in plasma is between about 100 mg / mL and about 12 ng / mL. When administered in a therapeutically effective amount, the ss is about 4 ng / mL to about 12 ng / mL. In some embodiments, the Css of huperzine in plasma is In some embodiments, the plasma Huperzia concentration is about 6 ng / mL to about 12 ng / mL. When administered at a therapeutically effective dose, the Css of gin is approximately 4 ng / mL to approximately 10 ng / mL. In some embodiments, the Css of huperzine in plasma is administered in a therapeutically effective amount. In some embodiments, the plasma concentration is about 4 ng / mL to about 8 ng / mL. The Css of Huperzine is approximately 6.4 ng / mL to approximately 10 nM when administered at a therapeutically effective dose. In some embodiments, the Css of huperzine in plasma is at least 100 mg / mL. In some embodiments, the plasma Huperzin-3000 is about 8 ng / mL when administered at 200 mg / mL. The Css of the gin is at least 8 ng / mL when administered in a therapeutically effective amount. In certain embodiments, the modified release pharmaceutical composition comprises a pharmaceutical composition according to any of the embodiments described herein. It is a composition.

[0120] Some embodiments of the present disclosure provide a modified release pharmaceutical composition of huperzine to a patient in need thereof.

[0013] A method of treating a neurological disorder or a seizure disorder comprising administering a composition comprising: When a pharmaceutical composition is orally administered to a human subject in an amount of 100 mg / kg or more, the pharmaceutical composition exhibits pharmacokinetic properties as defined in Table 4. In some embodiments, the modified release of huperzine is The pharmaceutical composition is a pharmaceutical composition according to any embodiment described herein. In an embodiment, the huperzine pharmaceutical preparation is Pharmaceutical Composition 4D. [Table 8] In some embodiments, the drug when a therapeutically effective amount of the pharmaceutical composition is orally administered to a human subject The kinetic profile is as defined in Table 5. [Table 9] In some embodiments, the drug when a therapeutically effective amount of the pharmaceutical composition is orally administered to a human subject The kinetic profile is as defined in Table 6. [Table 10]

[0121] Some embodiments of the present disclosure provide a modified release pharmaceutical composition of huperzine to a patient in need thereof.

[0013] A method of treating a neurological disorder or a seizure disorder comprising administering a composition comprising: When a pharmaceutical composition is orally administered to a human subject in an amount of 100 mg / kg or more, the pharmaceutical composition exhibits pharmacokinetic properties as defined in Table 7. In some embodiments, the modified release of huperzine is The pharmaceutical composition is a pharmaceutical composition according to any embodiment described herein. In an embodiment, the huperzine pharmaceutical preparation is Pharmaceutical Composition 4E. [Table 11]

[0122] In some embodiments, a therapeutically effective amount of the pharmaceutical composition when orally administered to a human subject The pharmacokinetic profile is as defined in Table 8. [Table 12]

[0123] In some embodiments, a therapeutically effective amount of the pharmaceutical composition when orally administered to a human subject The pharmacokinetic profile is as defined in Table 9. [Table 13]

[0124] Some embodiments of the present disclosure provide a modified release pharmaceutical composition of huperzine to a patient in need thereof. 1. A method of treating a neurological disorder and / or a seizure disorder, comprising administering a composition comprising: When a therapeutically effective amount of the pharmaceutical composition is orally administered to a human subject, the pharmaceutical composition exhibits the properties defined in Table 10. In some embodiments, huperzine has a pharmacokinetic profile. The modified release pharmaceutical composition is a pharmaceutical composition according to any embodiment described herein. In some embodiments, the huperzine pharmaceutical preparation is Pharmaceutical Composition 4D. [Table 14] TIFF0007737427000017.tif87165

[0125] In some embodiments, a therapeutically effective amount of the pharmaceutical composition when orally administered to a human subject The pharmacokinetic profile is as defined in Table 11. [Table 15] TIFF0007737427000019.tif217166

[0126] In some embodiments, a therapeutically effective amount of the pharmaceutical composition when orally administered to a human subject The pharmacokinetic profile is as defined in Table 12. [Table 16] TIFF0007737427000021.tif89165

[0127] Some embodiments of the present disclosure provide a modified release pharmaceutical composition of huperzine to a patient in need thereof. 1. A method of treating a neurological disorder and / or a seizure disorder, comprising administering a composition comprising: When a therapeutically effective amount of the pharmaceutical composition is orally administered to a human subject, the pharmaceutical composition exhibits the properties defined in Table 13. In some embodiments, huperzine has a pharmacokinetic profile. The modified release pharmaceutical composition is a pharmaceutical composition according to any embodiment described herein. In some embodiments, the huperzine pharmaceutical preparation is Pharmaceutical Composition 4E. [Table 17]

[0128] In some embodiments, a therapeutically effective amount of the pharmaceutical composition when orally administered to a human subject The pharmacokinetic profile is as defined in Table 14. [Table 18]

[0129] In some embodiments, a therapeutically effective amount of the pharmaceutical composition when orally administered to a human subject The pharmacokinetic profile is as defined in Table 15. [Table 19]

[0130] Some embodiments of the present disclosure provide a modified release pharmaceutical composition of huperzine to a patient in need thereof.

[0013] A method of treating a neurological disorder or a seizure disorder comprising administering a composition comprising: When the pharmaceutical composition is orally administered to a human subject in an amount of 100 mg / kg or more, the pharmaceutical composition exhibits a therapeutic activity against a drug as defined in Table 16. In some embodiments, the method comprises administering a controlled release kinetic profile of huperzine. The term "pharmaceutical composition" refers to a pharmaceutical composition according to any embodiment described herein. In an embodiment, the huperzine pharmaceutical preparation is Pharmaceutical Composition 4F-1. [Table 20]

[0131] Some embodiments of the present disclosure provide a modified release pharmaceutical composition of huperzine to a patient in need thereof.

[0013] A method of treating a neurological disorder or a seizure disorder comprising administering a composition comprising: When the pharmaceutical composition is orally administered to a human subject in an amount of 100 mg / kg or more, the pharmaceutical composition exhibits a therapeutic activity against a drug as defined in Table 17. In some embodiments, the method comprises administering a controlled release kinetic profile of huperzine. The term "pharmaceutical composition" refers to a pharmaceutical composition according to any embodiment described herein. In an embodiment, the huperzine pharmaceutical preparation is Pharmaceutical Composition 4F-1. [Table 21]

[0132] Some embodiments of the present disclosure provide a modified release pharmaceutical composition of huperzine to a patient in need thereof. 1. A method of treating a neurological disorder and / or a seizure disorder, comprising administering a composition comprising: When a therapeutically effective amount of the pharmaceutical composition is orally administered to a human subject, the pharmaceutical composition exhibits a therapeutic activity as defined in Table 18. In some embodiments, huperzine has a pharmacokinetic profile. The modified release pharmaceutical composition is a pharmaceutical composition according to any embodiment described herein. In some embodiments, the huperzine pharmaceutical preparation is Pharmaceutical Composition 4F-1. [Table 22]

[0133] The pharmaceutical compositions of the present invention may be administered in combination with other therapeutic agent(s). The choice of therapeutic agent that can be co-administered with the composition will depend, in part, on the condition being treated. For example, the compounds of the present invention may be effective in treating syncope, fatigue, muscle spasms, aura, amnesia, anxiety, and constipation. Epilepsy, including seizures, headache, drowsiness, or staring spells or other agents used to treat other symptoms and side effects commonly associated with seizures, e.g., Acetaminophen, acetazolamide, alprazolam, armodafinil, benzodiazepines Zepine, brivaracetam, buspirone, cannabinoids, carbamazepine, carisoprod chlordiazepoxide, chlorzoxazone, clobazam, clonazepam, clorazepam Pate, cyclobenzaprine, diazepam, divalproex, erenumab-ao oe, eslicarbazine, ethosuximide, ezogabine , felbamate, flunarizine, fosphenytoin, gabapentin, hydroxyzine , ibuprofen, lacosamide, lamotrigine, levetiracetam, lorazepam, metaxamic acid Ron, methocarbamol imipramine, methsuximide, modafinil, naproxen, Nitrazepam, oxcarbazepine, perampanel, phenobarbital, phenytoin , pregabalin, primidone, propranolol, rufinamide, stiripentol, te iagabine, topiramate, valproic acid, vigabatrin, and zonisamide or combinations thereof It may be administered in combination with other drugs, such as a combination drug.

[0134] Such other therapeutic agent(s) may be administered in combination with Huperzi according to any of the embodiments described herein. The administration of the compound may be prior to, concurrently with, or following administration of the compound pharmaceutical composition.

[0135] Example Although the present invention has been described in considerable detail with reference to certain preferred embodiments thereof, other Therefore, the spirit and scope of the appended claims shall be construed as including the same herein. The present invention should not be limited to the illustrated and preferred embodiments. Reference is now made to the following non-limiting examples, which are for illustrative purposes only. and should not be construed as limiting the invention in any manner.

[0136] Example 1: In Vitro Dissolution Test The composition was prepared by subjecting the USP 1000 psi to 50 rpm in 50 mM phosphate (pH 6.8) at 37°C. The test was carried out according to the Type 1 apparatus. The results are shown in Figure 4.

[0137] Example 2: Pharmacokinetic study in dogs Research objectives The purpose of this study was to evaluate the plasma drug efficacy of modified-release Huperzine Composition 4A in male Beagle dogs. Huperzine A was monitored in plasma for up to 24 hours.

[0138] Preparation of Vehicles and Pharmaceutical Compositions Animals were dosed with a nominal dose of 5.45 mg / kg of modified-release huperzine A (Composition 4A , equivalent to 0.049 mg / kg Huperzine A).

[0139] Animal specifications The study included three non-naive male beagle dogs (Marshall B) weighing ≥6 kg. The animals were collected from the Institute of Animal Science (IAS) and the University of Tokyo. A staff veterinarian performed a general health physical examination before allocation to the study. They were allowed to acclimate to the testing facility.

[0140] environmental conditions Animals were maintained at a constant relative humidity (target average range 40%-70%) and temperature (target average range 18°C- A controlled and monitored room (multiple rooms) was maintained at 26°C with 10-20 air changes per hour. The rooms were kept in one room, except when research activities required interruptions. There was a 2 hour light / dark cycle.

[0141] Containment During their lifetime, the animals were maintained in accordance with the National Research Council's Guide for the Care and Use of Laboratory Animals. The mice were housed individually in stainless steel mesh cages.

[0142] Diet and Feeding The animals were fed twice daily. Dogs were given approximately 220 grams of certified canine chow (Bei jing Vital Keao Feed Co., Ltd., Beijing, P. These amounts were adjusted based on the food consumption of the group, group or individual intakes, as needed. It may be adjusted based on individual weight changes in the body and / or validated dietary changes.

[0143] drinking water RO (reverse osmosis) water was available ad libitum to all animals.

[0144] environmental enhancement Reinforcement toys were provided.

[0145] Dosage Administration of Pharmaceutical Compositions Modified-release Huperzine A Composition 4A was administered orally via capsule delivery.

[0146] Dose Administration: a. The practitioner uses the other hand to pull down the lower jaw and return the capsule to the back of the throat. Use your index finger or hand to push the capsule through the pharynx. b. The capsule is then soaked in water. Can be moistened to facilitate dosing, and water can be used to make the capsule easier to swallow if needed c. After administering the dose, gently stroke the dog's throat or Swallowing can be induced by tapping the patient under the chin. d. Immediately after capsule administration, To aid in swallowing, animals were given water by mouth at a dose of approximately 10 mL per animal. The animal's mouth was then inspected to ensure the dose had been swallowed.

[0147] Observation and testing Cage-side observations were made twice daily for general health and appearance.

[0148] On the day of dosing, animals were observed before and after each sample collection time point. General condition, behavior, activity, and excretion were monitored. , breathing, or any other abnormal observations recorded during the study were recorded in the raw data.

[0149] body weight All animals were weighed on the day of dosing prior to dosing to determine the dosage to be administered. .

[0150] Data Analysis and Reporting Plasma concentration versus time data were analyzed using the WinNonlin software program (version 6 .3, Pharsight, Mountain View, CA) The analysis was carried out using the statement approach. max , T max

[0151] For each sample, clearance, T 1 / 2 , AUC 0-t , AUC 0-inf , MRT 0-t , MRT 0-inf , and graphs of plasma concentration versus time profiles were reported. The results of this study are summarized in Figure 5.

[0152] Example 3: Bioavailability of modified-release huperzine A after multiple doses in healthy subjects Assessment of viability, safety and tolerability A single-center, remote / outpatient, dose-escalation study was conducted using oral pharmaceutical composition 4D. Elephants were used to assess plasma levels, safety, and to determine the required dose before dosing any subsequent subjects. To allow for medication changes, four cohorts (pharmaceutical composition 4D) and two cohorts (pharmaceutical composition 4D) were included. and two cohorts (pharmaceutical composition 4E) of a total of three subjects, administered twice daily (BID). This study was conducted to evaluate safety, as well as routine laboratory and pharmacokinetic analyses. Remotely performed at the time of medication initiation and dose escalation to collect specimens for Subjects were discharged and compliance with BID dosing was assessed by on-site staff twice daily. The initial dose was 0.5 mg BID, and the maximum tolerated dose was observed. or increased every 2–3 days until a maximum dose of 2.5 mg BID was achieved To ensure subject safety, the initial dose and escalation rate may be changed at the discretion of site staff. It was possible.

[0153] Study endpoint: Plasma concentration data were used to assess bioavailability. The derived pharmacokinetic parameters included the area under the curve (AUC), maximum serum concentration (C ma x ), and C max Time (T max ) is included.

[0154] Safety and tolerability parameters include the occurrence of adverse events and study-specific Vital signs, neurological and physical examinations, ECG evaluations, and results of clinical laboratory studies was evaluated based on the following.

[0155] The dosing schedule was as follows: [Table 23]

[0156] Plasma levels collected at dose escalation in hospitalized patients during the study period for Cohorts 1–4 are shown in Figure 7. Plasma withdrawals were performed throughout the dose titration schedule to assess total plasma concentrations. = 0 represents the pre-dose baseline on the titration day corresponding to the dosing schedule. This reflects all data available for 8 subjects. Cohorts 3 and 4 The initial dosing schedule was modified to allow for slower titration (0.25 mg dose increments). I did.

[0157] A graph of the mean plasma levels in hospitalized patients over the study period at specific doses is shown in Figure 8. % of patients achieve 100% seizure prevention (dosage approximately 1.1-1.25 mg BID) pharmacokinetic modeling revealed a mean plasma level of 8.4 ng / mL ( CSS).

[0158] The compositions of this study provided a favorable pharmacokinetic profile and were compared to immediate release preparations. Compared to the previously used dose, twice-daily dosing demonstrated a significant reduction in adverse events. Pharmacokinetic modeling demonstrated a positive dose-exposure relationship across dose titration. was accurately predicted.

[0159] Adverse events were mild and transient. Studies have demonstrated significant seizure control. Approximately twice the predicted dose was shown to be achievable and given on a twice-daily schedule. Huperzine A is a soluble fiber that is absorbed into the bloodstream and absorbed into the bloodstream. Drug plasma levels predicted to provide significant seizure protection in patients with refractory epilepsy We achieved this.

[0160] Example 4: Modified Release of Huperzine for the Treatment of Focal Impairment of Awareness Attacks (FIAS) in Adults Evaluating the safety and efficacy of pharmaceutical compositions The purpose of this study is to evaluate the efficacy and safety of a pharmaceutical composition according to any of the embodiments described herein in hospitalized patients. In a controlled-release pharmaceutical composition of huperzine as add-on therapy in a patient and outpatient study To examine safety signals and demonstrate seizure reduction in well-treated adults with FIAS In some embodiments, the pharmaceutical composition is 4F1 or 4F-2.

[0161] Each participant was dosed starting at 0.25 mg BID every 4 days up to the maximum tolerated dose. or gradually increase to a target dose of 1.75 mg BID. If the medication is tolerated during dose escalation Participants who are unable to tolerate the dose will have their dose reduced to their previous tolerated dose, and if they are unable to tolerate the lower dose, , participants will be excluded from the study.

[0162] Number of participants: Sixteen participants will be enrolled in and complete the study.

[0163] Research design: This study was conducted in a single-center setting in otherwise healthy participants with frequent focal impaired consciousness attacks. This is a multi-site, open-label, add-on study.

[0164] Pre-qualified eligible participants aged 18 years or older who signed informed consent were The study consisted of a 96-hour baseline continuous VEM period, a 1-month external vein occlusion period, and The study consisted of a dose-escalation treatment period for patients receiving the first 96-hour treatment, and a second 96-hour continuous VEM treatment period. There are.

[0165] On day 1 of the baseline period (physical and neurological examination, vital signs, electrocardiogram ( ECG), blood samples for CBC and chemistry, standard urine including creatinine and electrolytes Begin by counting the number of daily seizures (after completing the urine sample collection for the test) and use standard lead placement. Participants were required to have a stable anticonvulsant drug regimen as determined by their treating physician. Continue anticonvulsant treatment regimen. Complete baseline period (5-day inpatient VEM). Upon completion of the study, participants who experienced at least five focal loss of consciousness attacks were immediately enrolled in treatment. Participants will receive up to a target dose of 1.75 mg BID of the modified-release pharmaceutical composition of huperzine. Dose escalation is initiated to either the maximum tolerated dose or the maximum tolerated dose. , titrated over 28 days, increasing every 4 days until the target dose or maximum tolerated dose is reached Participants were maintained on that dose for the remainder of the outpatient titration period, followed by a 96-hour Initiate an inpatient VEM treatment period. Daily seizure diaries are kept by participants or caregivers to record seizure types and Record the time and date of administration during the outpatient titration period. Participants who are unable to achieve this will have their medication reduced to the dose previously tolerated. If they are unable to do so, the participant may be excluded from the study. The controlled release pharmaceutical composition is administered twice a day (every 12 hours), in the morning and in the evening. Participants will not receive controlled-release Huperzine unless they choose to participate in the open-label extension period. The drug was discontinued on the last day of hospitalization for VEM, during which time seizure diaries were kept and regularly updated. Conduct a safety assessment.

[0166] Blood samples for pharmacology will be collected on selected outpatient and inpatient study days. Adverse events (AEs) and concomitant medication use will be recorded throughout the study.

[0167] All participants receiving at least one dose of the modified-release pharmaceutical composition of huperzine Ital signs, clinical tests, physical and neurological examinations, electrocardiograms, and adverse event monitoring The product will be subject to safety analysis, including:

[0168] Endpoint: Primary efficacy variable: Daily baseline (pre-treatment) and evaluation (on-treatment) VEM periods Reduction in the average number of seizures.

[0169] Secondary efficacy variables: - Percent reduction in mean daily seizure count from baseline VEM period compared to evaluation VEM period ( (under treatment) - baseline period (screening / retrospective date) compared with the last week of the titration treatment period Percent reduction in the average number of seizures from - ≥ 25% reduction in seizures from baseline VEM period compared to VEM treatment evaluation period Percentage of participants considered treatment responders, defined as a 0% or greater or 75% or greater reduction Baseline / retrospective diary of mean number of seizures at 1, 3, 6, and 12 months during the extension period Percentage decrease - Percentage of subjects with 100% reduction in seizures - Proportion of subjects requiring rescue medication at different doses

[0170] Pharmacology: Plasma concentration data will be used to determine the relationship between dose, serum level, and seizure effect.

[0171] Urine samples were subjected to standard urinalysis, removal of the test drug, and the presence of potential metabolites. do.

[0172] To date, three patients have received two to three doses, as described in Figure 9 and Table 19. undergoing titration. [Table 24]

[0173] Example 5: General procedure for preparing pharmaceutical compositions: The pharmaceutical compositions described herein may generally be prepared as follows:

[0174] Fluidized bed coating equipment (or similar coating particle manufacturing equipment) is used to Procedures and operating conditions are used to produce coated particles. These procedures include: Included:

[0175] Solutions for producing modified-release particles, such as huperzine, binders, anti-caking agents, etc. Preparation of a solution containing

[0176] The uncoated cores are added to the fluidized bed.

[0177] All operating parameters, nozzles, pressure, appropriate batch size and Adjust to the appropriate range for the device.

[0178] The coated pellets are treated to remove any agglomerates or fines outside the desired particle size distribution. Remove.

[0179] An exemplary process includes: 1. Solution Preparation a. Heat a specified amount of distilled water to 70 degrees Celsius. b. Dissolve Huperzine in absolute ethanol by stirring. c. Add HPMC to the heated water, stirring continuously if necessary. d. Add another portion of distilled water to the above solution and continue stirring until the powder is completely dissolved. e. Add PVP to the HPMC solution and dissolve equally with continuous stirring. f. Combine the HMPC / PVP solution and the Huperzine ethanol solution. Use distilled water to rinse the container and carefully pour in the solution until the final weight is reached and continue stirring for an additional 5 minutes. 2. Drug layer coating a. Sucrose spheres of the desired size were transferred to a fluid bed processor, and the huperzine solution from 1f above was coated onto the sugar spheres at a product temperature of 35-45°C. 3. Coating of sustained release layer a. Coat the resulting huperzine-loaded sugar spheres with the previously prepared plasticized ethyl cellulose solution using the same product temperature range as above until the theoretical weight gain is achieved. I did it. The present disclosure includes, for example, the embodiments described in the following sections. Section 1. a. about 74% to about 86% by weight of sugar sphere cores, said sugar sphere cores having a particle size of about 500 to 710 μm; b. a huperzine layer coating the sugar sphere, the huperzine layer comprising about 0.95% to about 1% by weight of huperzine or a pharmaceutically acceptable salt of huperzine equivalent to about 0.95% to about 1% by weight of huperzine, and one or more excipients, the total amount of which is about 5% to about 9% by weight; c. A pharmaceutical composition for oral delivery comprising a plasticized ethylcellulose polymer layer of about 7% to about 16% by weight coating the huperzine layer, the huperzine layer comprising a therapeutically effective amount of huperzine. Section 2. Item 1. The pharmaceutical composition according to Item 1, wherein the huperzine is huperzine A or a pharmaceutically acceptable salt thereof. Section 3. Item 1. The pharmaceutical composition according to Item 1, further comprising a seal coat layer between the huperzine layer and the plasticized ethyl cellulose polymer layer, coating the huperzine layer. Section 4. Item 1. The pharmaceutical composition according to Item 1, wherein the one or more excipients are selected from hydroxypropylmethylcellulose, polyvinylpyrrolidone, and a combination thereof. Section 5. Item 1. The pharmaceutical composition according to Item 1, wherein the one or more excipients are selected from low-viscosity hydroxypropyl methylcellulose, polyvinylpyrrolidone K30, and a combination thereof. Section 6. Item 1. The pharmaceutical composition according to Item 1, wherein the one or more excipients are a combination of about 5% to about 7% by weight of hydroxypropylmethylcellulose and about 0.5% to about 1.5% by weight of polyvinylpyrrolidone. Section 7. Item 1. The pharmaceutical composition according to Item 1, wherein the plasticized ethyl cellulose is SurRelease® Type B NF E. Section 8. Item 1. The pharmaceutical composition according to Item 1, wherein the huperzine is huperzine A, the one or more excipients are a combination of low-viscosity hydroxypropyl methylcellulose and polyvinylpyrrolidone K30, and the plasticized ethylcellulose is SurRelease® Type B NF E. Section 9. Item 1. The pharmaceutical composition according to Item 1, comprising about 80% to about 86% by weight of the sugar spheres. Section 10. Item 2. The pharmaceutical composition according to Item 1, wherein the plasticized ethyl cellulose polymer layer is about 7% by weight to about 12% by weight. Section 11. a. about 79% to about 84% by weight of the sugar sphere cores; b. a huperzine layer coating the sugar spheres, the huperzine layer comprising about 0.95% to about 1% by weight of huperzine A or a pharmaceutically acceptable salt of huperzine A equivalent to about 0.95% to about 1% by weight of huperzine A, about 6% by weight of hydroxypropylmethylcellulose, and about 0.95% to about 1% by weight of polyvinylpyrrolidone; c. The pharmaceutical composition of item 1, comprising a plasticized ethylcellulose polymer layer of about 8% to about 13% by weight coating the huperzine layer, the plasticized ethylcellulose polymer layer containing a therapeutically effective amount of huperzine A. Section 12. a. about 80% to about 83% by weight of sugar sphere cores, said sugar sphere cores having a particle size of about 500 to 710 μm; b. a huperzine layer coating the sugar spheres, the huperzine layer comprising about 0.95% to about 1% by weight of huperzine A, about 5% to about 6% by weight of hydroxypropyl methylcellulose, and about 0.95% to about 1% by weight of polyvinylpyrrolidone; c. The pharmaceutical composition of item 1, comprising a plasticized ethylcellulose polymer layer of about 8% to about 12% by weight coating the huperzine layer, the plasticized ethylcellulose polymer layer containing a therapeutically effective amount of huperzine A. Section 13. a. about 81% to about 82% by weight of sugar sphere cores, said sugar sphere cores having a particle size of about 500 to 710 μm; b. a huperzine layer coating the sugar spheres, the huperzine layer comprising about 0.95% to about 1% by weight of huperzine A, about 5% to about 6% by weight of hydroxypropyl methylcellulose, and about 0.95% to about 1% by weight of polyvinylpyrrolidone; c. The pharmaceutical composition of Item 1, comprising a plasticized ethylcellulose polymer layer of about 10% to about 11% by weight coating the huperzine layer, the plasticized ethylcellulose polymer layer containing a therapeutically effective amount of huperzine A. Section 14. a. about 82% to about 83% by weight of sugar sphere cores, said sugar sphere cores having a particle size of about 500 to 710 μm; b. a huperzine layer coating the sugar spheres, the huperzine layer comprising about 0.95% to about 1% by weight of huperzine A, about 6% by weight of hydroxypropyl methylcellulose, and about 0.95% to about 1% by weight of polyvinylpyrrolidone; c. The pharmaceutical composition of item 1, comprising a plasticized ethylcellulose polymer layer of about 9% to about 10% by weight coating the huperzine layer, the plasticized ethylcellulose polymer layer containing a therapeutically effective amount of huperzine A. Section 15. a. about 76% to about 76% by weight of sugar sphere cores, said sugar sphere cores having a particle size of about 500 to 710 μm; b. a huperzine layer coating the sugar spheres, the huperzine layer comprising about 0.9% to about 1% by weight of huperzine A, about 5% to about 6% by weight of hydroxypropyl methylcellulose, and about 0.9% to about 1% by weight of polyvinylpyrrolidone; c. a seal coat layer that coats the huperzine layer and contains about 1% to about 2% by weight of hydroxypropyl methylcellulose; and Item 3. The pharmaceutical composition of Item 2, comprising a plasticized ethylcellulose polymer layer of about 15% to about 16% by weight coating the seal coat layer, the huperzine layer comprising a therapeutically effective amount of huperzine A. Section 16. Item 1. The pharmaceutical composition according to item 1, wherein the pharmaceutical composition is in a capsule. Section 17. When a therapeutically effective amount of the pharmaceutical composition is orally administered to a human subject, the C max T is approximately 4 ng / mL to approximately 8 ng / mL, and T is approximately 4 hours to approximately 8 hours max , about 8 hours to about 12 hours 1 / 2 A pharmaceutical composition comprising huperzine A, characterized by: Section 18. Said C max is about 4 ng / mL to about 6 ng / mL, and max is about 4 hours to about 8 hours, 1 / 2 Item 18. The pharmaceutical composition according to Item 17, wherein the duration of the incubation period is about 10 hours to about 12 hours. Section 19. Said C max is about 6 ng / mL, and the T max is about 4 hours, and 1 / 2 Item 18. The pharmaceutical composition according to Item 17, wherein the solubility is about 8.3 hours. Section 20. C of immediate-release huperzine pharmaceutical compositions administered at equivalent doses max Compared to the T of about 4 to about 8 hours max , and C, which is reduced by about 25% to about 50% max A pharmaceutical composition comprising a therapeutically effective amount of huperzine, Section 21. Said C max Item 21. The pharmaceutical composition according to Item 20, wherein the amount of steroid hormone produced is reduced by about 50%. Section 22. Item 1. The pharmaceutical composition according to Item 1, wherein when tested in a USP Type 1 apparatus at 50 rpm in 50 mM phosphate (pH 6.8) at 37°C, the dissolution profile is such that about 36% to about 46% of the huperzine is released after 2 hours, about 61% to about 77% of the huperzine is released after 4 hours, about 84% to about 97% of the huperzine is released after 8 hours, and about 89% or more of the huperzine is released after 12 hours. Section 23. Item 1. The pharmaceutical composition of item 1, when tested in a USP Type 1 apparatus at 50 rpm in 50 mM phosphate (pH 6.8) at 37°C, exhibits a dissolution profile in which about 36% of the huperzine is released after 2 hours, about 63% of the huperzine is released after 4 hours, about 84% of the huperzine is released after 8 hours, and about 89% or more of the huperzine is released after 12 hours. Section 24. Item 1. The pharmaceutical composition of item 1, when tested in a USP Type 1 apparatus at 50 rpm in 50 mM phosphate (pH 6.8) at 37°C, exhibits a dissolution profile in which about 46% of the huperzine is released after 2 hours, about 77% of the huperzine is released after 4 hours, about 97% of the huperzine is released after 8 hours, and about 99% or more of the huperzine is released after 12 hours. Section 25. Item 1. The pharmaceutical composition of item 1, when tested in a USP Type 1 apparatus at 50 rpm in 50 mM phosphate (pH 6.8) at 37°C, exhibits a dissolution profile in which about 43% of the huperzine is released after 2 hours, about 68% of the huperzine is released after 4 hours, about 88% of the huperzine is released after 8 hours, and about 96% or more of the huperzine is released after 12 hours. Section 26. Item 1. The pharmaceutical composition of item 1, when tested in a USP Type 1 apparatus at 50 rpm in 50 mM phosphate (pH 6.8) at 37°C, exhibits a dissolution profile in which about 38% of the huperzine is released after 2 hours, about 61% of the huperzine is released after 4 hours, about 84% of the huperzine is released after 8 hours, and about 94% or more of the huperzine is released after 12 hours. Section 27. A method for treating a disorder selected from a neurological disorder or a seizure disorder, comprising administering the pharmaceutical composition of paragraph 1 to a patient in need thereof. Section 28. 28. The method of paragraph 27, wherein the seizure disorder is selected from epilepsy and complex partial seizures. Section 29. 28. The method of claim 27, wherein the pharmaceutical composition is administered twice daily. Section 30. said administering a. administering one or more titrated doses of said pharmaceutical composition; thereafter b. The method of claim 27, comprising administering a maintenance dose of the pharmaceutical composition, wherein the maintenance dose is a therapeutically effective amount. Section 31. 28. The method of claim 27, wherein the patient experiences a better side effect profile, the method comprising administering a first dosage regimen of at least one dosage regimen selected from a to h, and administering a second dosage regimen of at least one dosage regimen selected from a to i; a. Optionally administering Huperzine A at a dose of about 0.25 mg once about every 12 hours for at least 2 days and up to 2 weeks; b. Optionally administering Huperzine A at a dose of about 0.5 mg once about every 12 hours for at least 2 days and up to 2 weeks; c. Optionally administering Huperzine A at a dose of about 0.75 mg once about every 12 hours for at least 2 days and up to 2 weeks; d. Optionally administering Huperzine A at a dose of about 1 mg once about every 12 hours for at least 2 days and up to 2 weeks; e. Optionally administering Huperzine A at a dose of about 1.25 mg once about every 12 hours for at least 2 days and up to 2 weeks; f. Optionally administering Huperzine A at a dose of about 1.5 mg once about every 12 hours for at least 2 days and up to 2 weeks; g. Optionally administering Huperzine A at a dose of about 1.75 mg once about every 12 hours for at least 2 days and up to 2 weeks. h. Optionally administering Huperzine A at a dose of about 2 mg once about every 12 hours for at least 2 days and up to 2 weeks; i. A method of optionally administering a dose of about 2.5 mg of huperzine A about once every 12 hours for at least two days, wherein the second dosage regimen is higher than the first dosage regimen, and wherein the final dosage regimen is the maintenance dose, and thus is administered for as long as the patient requires the treatment, and wherein the huperzine A of a-i is administered in the pharmaceutical composition described in item 1. Section 32. a. Administering Huperzine A at a dose of approximately 0.25 mg once approximately every 12 hours for 2 days to 2 weeks; b. Administering Huperzine A at a dose of approximately 0.5 mg once approximately every 12 hours for 2 days to 2 weeks; c. Administering Huperzine A at a dose of approximately 0.75 mg once approximately every 12 hours for 2 days to 2 weeks; d. The method of claim 31, comprising administering a dose of about 1 mg of huperzine A once about every 12 hours for at least two days. Section 33. 33. The method of paragraph 32, wherein step d is administered for as long as the patient is in need of treatment. Section 34. 33. The method of claim 32, further comprising, after step d, administering huperzine A at a dose of about 1.25 mg once every 12 hours for as long as the patient needs it. Section 35. After step d, e. Administering huperzine A at a dose of approximately 1.25 mg once approximately every 12 hours for 2 days to 2 weeks; f. The method of paragraph 32, further comprising administering huperzine A at a dose of about 1.5 mg once every 12 hours for as long as the patient needs it. Section 36. After step d, e. Administering huperzine A at a dose of approximately 1.25 mg once approximately every 12 hours for 2 days to 2 weeks; f. Administering huperzine A at a dose of approximately 1.5 mg once approximately every 12 hours for 2 days to 2 weeks; g. The method of paragraph 32, further comprising administering huperzine A at a dose of about 1.75 mg once every 12 hours for as long as the patient needs it. Section 37. After step d, e. Administering huperzine A at a dose of approximately 1.25 mg once approximately every 12 hours for 2 days to 2 weeks; f. Administering huperzine A at a dose of approximately 1.5 mg once approximately every 12 hours for 2 days to 2 weeks; g. Administering approximately 1.75 mg of huperzine A once every 12 hours for 2 days to 2 weeks. h. The method of paragraph 32, further comprising administering a dose of about 2.0 mg of huperzine A once about every 12 hours for as long as the patient needs it. Section 38. After step d, e. Administering huperzine A at a dose of approximately 1.25 mg once approximately every 12 hours for 2 days to 2 weeks; f. Administering huperzine A at a dose of approximately 1.5 mg once approximately every 12 hours for 2 days to 2 weeks; g. Administering approximately 1.75 mg of huperzine A once every 12 hours for 2 days to 2 weeks. h. Administering approximately 2.0 mg of huperzine A once approximately every 12 hours for 2 days to 2 weeks; i. The method of paragraph 32, further comprising administering Huperzine A at a dose of about 2.5 mg once every 12 hours for as long as the patient needs it. Section 39. 1. A method of treating a disorder selected from the group consisting of neurological disorders and seizure disorders in a patient in need thereof, wherein the patient experiences a better side effect profile, the method comprising administering one or more titrated doses of huperzine A, and thereafter administering a therapeutically effective amount of said huperzine A, wherein said huperzine A is administered in a modified-release pharmaceutical composition. ,method. Section 40. Item 40. The method of item 39, wherein the modified-release pharmaceutical composition comprises a dissolvable core, an active huperzine A layer coating the dissolvable core, and a polymer coating coating the huperzine A layer, wherein the huperzine A layer comprises a therapeutically effective amount of huperzine. Section 41. 1. A method of treating a disorder selected from the group consisting of neurological disorders and seizure disorders in a patient in need thereof, wherein the patient experiences a better side effect profile, comprising administering a first dosage regimen of at least one dosage regimen selected from a-h (described below) and administering a second dosage regimen of at least one dosage regimen selected from a-i (described below); a. Administering Huperzine A at a dose of approximately 0.25 mg once approximately every 12 hours for at least 2 days and up to 2 weeks; b. Administering Huperzine A at a dose of approximately 0.5 mg once approximately every 12 hours for at least 2 days and up to 2 weeks; c. Administering Huperzine A at a dose of approximately 0.75 mg once approximately every 12 hours for at least 2 days and up to 2 weeks; d. Administering Huperzine A at a dose of approximately 1 mg once approximately every 12 hours for at least 2 days and up to 2 weeks; e. Administering huperzine A at a dose of approximately 1.25 mg once approximately every 12 hours for at least 2 days and up to 2 weeks; f. Administering huperzine A at a dose of approximately 1.5 mg once approximately every 12 hours for at least 2 days and up to 2 weeks; g. Administering huperzine A at a dose of approximately 1.75 mg once approximately every 12 hours for at least 2 days and up to 2 weeks; h. Administering huperzine A at a dose of approximately 2 mg once approximately every 12 hours for at least 2 days and up to 2 weeks; i. Administering a dose of about 2.5 mg of huperzine A about once every 12 hours for at least two days, wherein the second dosage regimen is greater than the first dosage regimen and the final dosage regimen is the maintenance dose, and thus will be administered for as long as the patient requires the treatment, and wherein the huperzine A of a-i is administered in a modified release pharmaceutical composition. Section 42. a. Administering Huperzine A at a dose of approximately 0.25 mg once approximately every 12 hours for 2 days to 2 weeks; b. Administering Huperzine A at a dose of approximately 0.5 mg once approximately every 12 hours for 2 days to 2 weeks; c. Administering Huperzine A at a dose of approximately 0.75 mg once approximately every 12 hours for 2 days to 2 weeks; d. The method of claim 41, comprising administering a dose of about 1 mg of huperzine A once about every 12 hours for at least two days. Section 43. 43. The method of paragraph 42, wherein step d is administered for as long as the patient is in need of treatment. Section 44. 43. The method of claim 42, further comprising, after step d, administering huperzine A at a dose of about 1.25 mg once every 12 hours for as long as the patient needs it. Section 45. After step d, e. Administering huperzine A at a dose of approximately 1.25 mg once approximately every 12 hours for 2 days to 2 weeks; f. The method of paragraph 42, further comprising administering Huperzine A at a dose of about 1.5 mg once every 12 hours for as long as the patient needs it. Section 46. After step d, e. Administering huperzine A at a dose of approximately 1.25 mg once approximately every 12 hours for 2 days to 2 weeks; f. Administering huperzine A at a dose of approximately 1.5 mg once approximately every 12 hours for 2 days to 2 weeks; g. The method of paragraph 42, further comprising administering huperzine A at a dose of about 1.75 mg once every 12 hours for as long as the patient needs it. Section 47. After step d, e. Administering huperzine A at a dose of approximately 1.25 mg once approximately every 12 hours for 2 days to 2 weeks; f. Administering huperzine A at a dose of approximately 1.5 mg once approximately every 12 hours for 2 days to 2 weeks; g. Administering approximately 1.75 mg of huperzine A once every 12 hours for 2 days to 2 weeks. h. The method of paragraph 42, further comprising administering Huperzine A at a dose of about 2 mg once every 12 hours for as long as the patient needs it. Section 48. After step d, e. Administering huperzine A at a dose of approximately 1.25 mg once approximately every 12 hours for 2 days to 2 weeks; f. Administering huperzine A at a dose of approximately 1.5 mg once approximately every 12 hours for 2 days to 2 weeks; g. Administering approximately 1.75 mg of huperzine A once every 12 hours for 2 days to 2 weeks. h. Administering approximately 2 mg of huperzine A once every 12 hours for 2 days to 2 weeks; i. The method of paragraph 42, further comprising administering Huperzine A at a dose of about 2.5 mg once every 12 hours for as long as the patient needs it. Section 49. 1. A method of treating a disorder selected from the group consisting of neurological disorders and seizure disorders to a patient in need thereof, wherein the patient experiences a better side effect profile, the method comprising administering a modified-release pharmaceutical composition of huperzine A, wherein the modified-release pharmaceutical composition of huperzine A has a RI 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, and about 3.56 ng / mL at a dose of 0.75 mg. at a dose of 1.5 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. ss A method characterized by: Section 50. 1. A method of treating a disorder selected from the group consisting of neurological disorders and seizure disorders to a patient in need thereof, wherein said patient experiences a better side effect profile, comprising administering a modified-release pharmaceutical composition of huperzine A, wherein said modified-release pharmaceutical composition of huperzine A, when administered in a therapeutically effective amount, reduces the C of huperzine A in plasma by 100% or more. ss is at least 8 ng / mL. Section 51. 1. A method of treating a disorder selected from the group consisting of neurological disorders and seizure disorders to a patient in need thereof, wherein said patient experiences a better side effect profile, comprising administering a modified-release pharmaceutical composition of huperzine A, wherein said modified-release pharmaceutical composition of huperzine A reduces the C of huperzine in plasma when a therapeutically effective amount of said pharmaceutical composition is orally administered to a human subject. max is about 0.76 ng / mL to about 1.19 ng / mL, T max is approximately 4 hours to approximately 6.25 hours, and AUC 0-8 is about 4.18 to about 6.53. Section 52. 1. A method of treating a disorder selected from the group consisting of neurological disorders and seizure disorders to a patient in need thereof, wherein said patient experiences a better side effect profile, comprising administering a modified-release pharmaceutical composition of huperzine A, wherein said modified-release pharmaceutical composition of huperzine A reduces the C of huperzine in plasma when a therapeutically effective amount of said pharmaceutical composition is orally administered to a human patient. max is about 2.51 ng / mL to about 3.93 ng / mL, T max is approximately 4 hours to approximately 6.25 hours, and AUC 0-8 is about 13.76 to about 21.5.

Claims

1. A modified-release pharmaceutical composition comprising: a dissolvable core, a huperzine A layer coating the dissolvable core, and a polymer coating coating the huperzine A layer, the dissolvable core is a sugar sphere core having a particle size of about 500 to 710 μm; the huperzine A layer comprises about 0.8% to about 1.2% huperzine A by weight of the pharmaceutical composition, about 5% to about 6% hydroxypropyl methylcellulose by weight of the pharmaceutical composition, and about 0.5% to about 1.5% polyvinylpyrrolidone by weight of the pharmaceutical composition; and A modified-release pharmaceutical composition wherein the polymer coating is a plasticized ethyl cellulose polymer layer.

2. 2. The pharmaceutical composition of claim 1, wherein the sugar sphere cores constitute about 74-86% by weight of the pharmaceutical composition.

3. A pharmaceutical composition described in claim 1 or 2, wherein the polymer coating is a plasticized ethyl cellulose polymer layer of about 7% to about 16% by weight of the pharmaceutical composition.

4. When orally administered to human subjects, the C of huperzine in plasma ｍａｘ is about 4 ng / mL to about 8 ng / mL, and T ｍａｘ is about 4 hours to about 8 hours, and t １／２ The pharmaceutical composition according to any one of claims 1 to 3, wherein the duration of exposure is about 8 hours to about 12 hours.

5. Said C ｍａｘ is about 4 ng / mL to about 6 ng / mL, and the T ｍａｘ is about 4 hours to about 8 hours, and １／２ The pharmaceutical composition of claim 4, wherein the incubation time is from about 10 hours to about 12 hours.

6. Said C ｍａｘ is about 6 ng / mL, and the T ｍａｘ is about 4 hours, and the t １／２ 5. The pharmaceutical composition of claim 4, wherein the solubility is about 8.3 hours.

7. T of about 4 to about 8 hours ｍａｘ The pharmaceutical composition according to any one of claims 1 to 3, characterized in that

8. 4. The pharmaceutical composition of claim 1, wherein the composition exhibits a dissolution profile, when tested according to USP Type 1 apparatus at 50 rpm in 50 mM phosphate (pH 6.8) at 37°C, of ​​which about 36% to about 46% of the huperzine is released after 2 hours, about 61% to about 77% of the huperzine is released after 4 hours, about 84% to about 97% of the huperzine is released after 8 hours, and about 89% or more of the huperzine is released after 12 hours.

9. 4. The pharmaceutical composition of claim 1, wherein the composition exhibits a dissolution profile, when tested according to USP Type 1 apparatus at 50 rpm in 50 mM phosphate (pH 6.8) at 37°C, of ​​which about 36% of the huperzine is released after 2 hours, about 63% of the huperzine is released after 4 hours, about 84% of the huperzine is released after 8 hours, and about 89% or more of the huperzine is released after 12 hours.

10. 4. The pharmaceutical composition of claim 1, wherein the composition exhibits a dissolution profile in accordance with USP Type 1 apparatus at 50 rpm in 50 mM phosphate (pH 6.8) at 37°C, wherein about 46% of the huperzine is released after 2 hours, about 77% of the huperzine is released after 4 hours, about 97% of the huperzine is released after 8 hours, and about 99% or more of the huperzine is released after 12 hours.

11. 4. The pharmaceutical composition of claim 1, wherein the composition exhibits a dissolution profile, when tested according to USP Type 1 apparatus at 50 rpm in 50 mM phosphate (pH 6.8) at 37°C, of ​​which about 43% of the huperzine is released after 2 hours, about 68% of the huperzine is released after 4 hours, about 88% of the huperzine is released after 8 hours, and about 96% or more of the huperzine is released after 12 hours.

12. 4. The pharmaceutical composition of claim 1, wherein the composition exhibits a dissolution profile, when tested according to USP Type 1 apparatus at 50 rpm in 50 mM phosphate (pH 6.8) at 37°C, of ​​which about 38% of the huperzine is released after 2 hours, about 61% of the huperzine is released after 4 hours, about 84% of the huperzine is released after 8 hours, and about 94% or more of the huperzine is released after 12 hours.

13. The pharmaceutical composition according to any one of claims 1 to 12, for the treatment of a disorder selected from a neurological disorder or a seizure disorder.

14. 14. The pharmaceutical composition of claim 13, wherein the seizure disorder is selected from epilepsy and complex partial seizures.

15. The pharmaceutical composition according to any one of claims 1 to 14, which is administered twice a day.

16. The pharmaceutical composition comprises: a. administering one or more titrated doses of said pharmaceutical composition; thereafter b. administering a maintenance dose of said pharmaceutical composition. The pharmaceutical composition according to any one of claims 1 to 15, characterized by:

17. 17. The pharmaceutical composition of claim 16, characterized by administering a first dosage regimen, which is at least one dosage regimen selected from the following a to h, and administering a second dosage regimen, which is at least one dosage regimen selected from the following a to i, wherein the second dosage regimen is greater than the first dosage regimen, and further wherein the last dosage regimen is the maintenance dose, and wherein the huperzine A of a to i is administered in the pharmaceutical composition of any one of claims 1 to 3: a. optionally administering huperzine A at a dose of about 0.25 mg once about every 12 hours for at least 2 days and up to 2 weeks; b. Optionally administering huperzine A at a dose of about 0.5 mg once about every 12 hours for at least 2 days and up to 2 weeks; c. Optionally administering Huperzine A at a dose of about 0.75 mg once about every 12 hours for at least 2 days and up to 2 weeks; d. Optionally administering Huperzine A at a dose of about 1 mg once about every 12 hours for at least 2 days and up to 2 weeks; e. Optionally administering huperzine A at a dose of about 1.25 mg once about every 12 hours for at least 2 days and up to 2 weeks; f. Optionally administering huperzine A at a dose of about 1.5 mg once about every 12 hours for at least 2 days and up to 2 weeks; g. Optionally administering huperzine A at a dose of about 1.75 mg once about every 12 hours for at least 2 days and up to 2 weeks; h. Optionally administering huperzine A at a dose of about 2 mg once about every 12 hours for at least 2 days and up to 2 weeks; i. Optionally administer Huperzine A at a dose of about 2.5 mg once about every 12 hours for at least 2 days.

18. a. administering huperzine A at a dose of about 0.25 mg once about every 12 hours for 2 days to 2 weeks; b. administering huperzine A at a dose of about 0.5 mg once about every 12 hours for 2 days to 2 weeks; c. administering huperzine A at a dose of about 0.75 mg once about every 12 hours for 2 days to 2 weeks; and d. administering huperzine A at a dose of about 1 mg once about every 12 hours for at least 2 days; 18. The pharmaceutical composition according to claim 17, characterized by:

19. 20. The pharmaceutical composition of claim 18, wherein step d is administered for as long as the patient receiving the pharmaceutical composition is in need of treatment.

20. After step d, e. The pharmaceutical composition of claim 18, further comprising administering huperzine A at a dose of about 1.25 mg once every 12 hours for as long as the patient receiving the pharmaceutical composition needs it.

21. After step d, e. administering huperzine A at a dose of about 1.25 mg once about every 12 hours for 2 days to 2 weeks; f. Administering a dose of about 1.5 mg of huperzine A once about every 12 hours for as long as the patient receiving said pharmaceutical composition needs it.

20. The pharmaceutical composition of claim 18, further comprising:

22. After step d, e. administering huperzine A at a dose of about 1.25 mg once about every 12 hours for 2 days to 2 weeks; f. administering huperzine A at a dose of about 1.5 mg once about every 12 hours for 2 days to 2 weeks; g. Administering huperzine A at a dose of about 1.75 mg once every 12 hours for as long as said patient requires it.

20. The pharmaceutical composition of claim 18, further comprising:

23. After step d, e. administering huperzine A at a dose of about 1.25 mg once about every 12 hours for 2 days to 2 weeks; f. administering huperzine A at a dose of about 1.5 mg once about every 12 hours for 2 days to 2 weeks; g. Administering huperzine A at a dose of about 1.75 mg once about every 12 hours for 2 days to 2 weeks; h. Administering a dose of about 2.0 mg of huperzine A once about every 12 hours for as long as the patient receiving said pharmaceutical composition needs it.

20. The pharmaceutical composition of claim 18, further comprising:

24. After step d, e. administering huperzine A at a dose of about 1.25 mg once about every 12 hours for 2 days to 2 weeks; f. administering huperzine A at a dose of about 1.5 mg once about every 12 hours for 2 days to 2 weeks; g. Administering huperzine A at a dose of about 1.75 mg once about every 12 hours for 2 days to 2 weeks; h. administering huperzine A at a dose of about 2.0 mg once about every 12 hours for 2 days to 2 weeks; i. administering a dose of about 2.5 mg of huperzine A once about every 12 hours for as long as the patient receiving said pharmaceutical composition needs it; 20. The pharmaceutical composition of claim 18, further comprising:

25. 15. The pharmaceutical composition of any one of claims 1 to 14, for use in treating a disorder selected from the group consisting of neurological disorders and seizure disorders, characterized by administering one or more titrated doses of huperzine A, and thereafter administering a therapeutically effective amount of huperzine A, wherein huperzine A is administered in the pharmaceutical composition.

26. 15. A pharmaceutical composition for use in treating a disorder selected from the group consisting of neurological disorders and seizure disorders, comprising administering a first dosage regimen, which is at least one dosage regimen selected from a-h (described below), administering a second dosage regimen, which is at least one dosage regimen selected from a-i (described below), and wherein the second dosage regimen is greater than the first dosage regimen, and further wherein the final dosage regimen is the maintenance dose, and wherein a-i Huperzine A is administered in the pharmaceutical composition. a. administering huperzine A at a dose of about 0.25 mg once about every 12 hours for at least 2 days and up to 2 weeks; b. administering huperzine A at a dose of about 0.5 mg once about every 12 hours for at least 2 days and up to 2 weeks; c. administering huperzine A at a dose of about 0.75 mg once about every 12 hours for at least 2 days and up to 2 weeks; d. administering huperzine A at a dose of about 1 mg once about every 12 hours for at least 2 days and up to 2 weeks; e. administering huperzine A at a dose of about 1.25 mg once about every 12 hours for at least 2 days and up to 2 weeks; f. administering huperzine A at a dose of about 1.5 mg once about every 12 hours for at least 2 days and up to 2 weeks; g. Administering huperzine A at a dose of about 1.75 mg once about every 12 hours for at least 2 days and up to 2 weeks; h. Administering Huperzine A at a dose of about 2 mg once about every 12 hours for at least 2 days and up to 2 weeks.

27. a. administering huperzine A at a dose of about 0.25 mg once about every 12 hours for 2 days to 2 weeks; b. administering huperzine A at a dose of about 0.5 mg once about every 12 hours for 2 days to 2 weeks; c. administering huperzine A at a dose of about 0.75 mg once about every 12 hours for 2 days to 2 weeks; d. Administering a dose of about 1 mg of Huperzine A once about every 12 hours for at least 2 days.

27. The pharmaceutical composition of claim 26, characterized by:

28. 28. The pharmaceutical composition of claim 27, wherein step d is administered for as long as the patient receiving said pharmaceutical composition is in need of treatment.

29. After step d, e. The pharmaceutical composition of claim 27, further comprising administering huperzine A at a dose of about 1.25 mg once every 12 hours for as long as the patient receiving the pharmaceutical composition needs it.

30. After step d, e. administering huperzine A at a dose of about 1.25 mg once about every 12 hours for 2 days to 2 weeks; f) The pharmaceutical composition of claim 27, further comprising administering huperzine A at a dose of about 1.5 mg once every 12 hours for as long as the patient receiving the pharmaceutical composition needs it.

31. After step d, e. administering huperzine A at a dose of about 1.25 mg once about every 12 hours for 2 days to 2 weeks; f. administering huperzine A at a dose of about 1.5 mg once about every 12 hours for 2 days to 2 weeks; g. The pharmaceutical composition of claim 27, further comprising administering huperzine A at a dose of about 1.75 mg once every 12 hours for as long as the patient receiving the pharmaceutical composition needs it.

32. After step d, e. administering huperzine A at a dose of about 1.25 mg once about every 12 hours for 2 days to 2 weeks; f. administering huperzine A at a dose of about 1.5 mg once about every 12 hours for 2 days to 2 weeks; g. Administering huperzine A at a dose of about 1.75 mg once about every 12 hours for 2 days to 2 weeks; h) The pharmaceutical composition of claim 27, further comprising administering huperzine A at a dose of about 2 mg once every 12 hours for as long as the patient receiving the pharmaceutical composition needs it.

33. After step d, e. administering huperzine A at a dose of about 1.25 mg once about every 12 hours for 2 days to 2 weeks; f. administering huperzine A at a dose of about 1.5 mg once about every 12 hours for 2 days to 2 weeks; g. Administering huperzine A at a dose of about 1.75 mg once about every 12 hours for 2 days to 2 weeks; h. administering huperzine A at a dose of about 2 mg once about every 12 hours for 2 days to 2 weeks; i. The pharmaceutical composition of claim 27, further comprising administering huperzine A at a dose of about 2.5 mg once every 12 hours for as long as the patient receiving said pharmaceutical composition needs it.

34. 1. A pharmaceutical composition for use in treating a disorder selected from the group consisting of neurological disorders and seizure disorders, wherein the C of huperzine A in plasma is selected from the group consisting of about 0.52 to about 0.82 ng / mL at a 0.25 mg dose, about 1.91 to about 2.99 ng / mL at a 0.50 mg dose, about 3.56 to about 5.55 ng / mL at a 0.75 mg dose, about 5.58 to about 8.72 ng / mL at a 1 mg dose, about 8.22 to about 12.84 ng / mL at a 1.25 mg dose, about 9.02 to about 14.09 ng / mL at a 1.5 mg dose, about 10.04 to about 15.69 ng / mL at a 1.75 mg dose, about 16 to about 25 ng / mL at a 2.0 mg dose, and about 18.48 to about 28.88 ng / mL at a 2.5 mg dose. ｓｓ The pharmaceutical composition according to any one of claims 1 to 3, characterized in that

35. 1. A pharmaceutical composition for use in treating a disorder selected from the group consisting of neurological disorders and seizure disorders, comprising: a pharmaceutical composition for use in treating a disorder selected from the group consisting of a neurological disorder and a seizure disorder, the pharmaceutical composition ... ｓｓ The pharmaceutical composition according to any one of claims 1 to 3, characterized in that the IL-12 concentration is at least 8 ng / mL.

36. A pharmaceutical composition for use in treating a disorder selected from the group consisting of neurological disorders and seizure disorders, wherein a therapeutically effective amount of the pharmaceutical composition when orally administered to a human subject reduces the C of huperzine in plasma. ｍａｘ is about 0.76 ng / mL to about 1.19 ng / mL, T ｍａｘ is about 4 hours to about 6.25 hours, and AUC ０－８ The pharmaceutical composition according to any one of claims 1 to 3, wherein the β-amino acid residue is about 4.18 to about 6.

53.

37. A pharmaceutical composition for use in treating a disorder selected from the group consisting of neurological disorders and seizure disorders, wherein a therapeutically effective amount of said pharmaceutical composition when orally administered to a human patient reduces the C of huperzine in plasma. ｍａｘ is about 2.51 ng / mL to about 3.93 ng / mL, T ｍａｘ is about 4 hours to about 6.25 hours, and AUC ０－８ The pharmaceutical composition according to any one of claims 1 to 3, wherein the β-glucan is about 13.76 to about 21.5.

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