Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
  • A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
  • A61K31/341—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide not condensed with another ring, e.g. ranitidine, furosemide, bufetolol, muscarine
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/13—Amines
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
  • A61K31/27—Esters, e.g. nitroglycerine, selenocyanates of carbamic or thiocarbamic acids, meprobamate, carbachol, neostigmine
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
  • A61K31/445—Non condensed piperidines, e.g. piperocaine
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
  • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia

Definitions

• the present disclosure relates to pharmaceutical compounds and compositions for the treatment of Alzheimer's disease.
• the present disclosure relates to the use of pharmaceutical compositions comprising ANAVEX2-73 (also A2-73) for the treatment of Alzheimer's disease.
• ANAVEX2- 73 or A-273 (tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine hydrochloride) is a compound which is believed to bind to sigma-1 and muscarinic acetylcholine receptors with affinities in the low micromolar range.
• ANAVEX2-73 has the chemical structure:
• the sigma-1 receptor is a chaperone protein in the endoplasmic reticulum (ER) that chaperones the IP3 receptor at the ER and mitochondrion interface to ensure proper Ca 2+ signaling from the ER into the mitochondrion.
• ER endoplasmic reticulum
• the sigma-1 receptor translocates and counteracts the arising apoptosis.
• the sigma-l receptor is a receptor chaperone essential for the metabotropic receptor signaling and for the survival against cellular stress. See Centr. Nerv. Syst. Agents Med. Chem. 9(3), 184-189 (2009).
• ANAVEX2-73 showed neuroprotective potential against amyloid toxicity in mice.
• ANAVEX2-73 has been reported as attenuating oxidative stress, caspases induction, cellular loss and learning and memory deficits observed in mice one week after the i.c.v. injection of an oligomeric preparation of amyloid 625-35 peptide ( ⁇ 2 5-35) - See J. Psychopharmacol. 25(8), 1101-1117 (2011). More recently, it has been reported that ANAVEX2-73 blocked the ⁇ 25 -3 5 - induced P-Akt decrease and P-GSK-3 increase, indicating activation at the PI3K neuroprotective pathway.
• ANAVEX2-73 attenuated the hyperphosphorylation of Tau on physiological epitopes (AT-8 antibody clone) and on pathological epitopes (AT-100 clone). ANAVEX2-73 also has been reported to decrease the ⁇ -35-induced endogenous ⁇ - 42 seeding.
• the present disclosure comprises a pharmaceutical composition for the treatment of Alzheimer's disease comprising a therapeutically effective amount of ANAVEX2-73.
• ANAVEX2-73 is characterized by the PXRD pattern shown in FIG. 1 as well as characterized by the thermogravimetric analysis of FIG. 2a or FIG. 2b and characterized by the differential scanning calorimetry analysis of FIG. 3a, 3b, or 3c.
• composition wherein the ANAVEX2-73 is characterized by the particle shapes or sizes as depicted in FIG. 4a, FIG. 4b, or FIG. 4c. Specific reference is made to a particle size of between 1 and 50 pm.
• therapeutically effective amount of ANAVEX2-73 include about 1 mg to about 60 mg and particularly about 30 mg to about 50 mg. Further noted are therapeutically effective amounts of about 3 mg to about 5 mg, and particularly for intravenous administration. Oral dosage forms are noted.
• combination dosages comprising at least one acetylcholinesterase inhibitor with particular reference to donepezil, galantamine, rivastigmine, or memantine.
• the present disclosure contemplates a method of treating Alzheimer's disease in a subject comprising administering to the subject a pharmaceutical compositions and combinations noted above.
• Contemplated dosage regimens include administering to the subject a pharmaceutical composition comprising ANAVEX2-73 according to an intermittent dosing regimen of at least two cycles, each cycle comprising (a) a dosing period during which a therapeutically effective amount of said pharmaceutical composition is administered to said patient and, thereafter, (b) a resting period.
• the dosing period and the resting period are of the same duration or are of different durations.
• the dosing period and the resting period in the range of a lower limit of about 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, and 14 days to an upper limit of about 28 days, 27 days, 26 days, 25 days, 24 days, 23 days, 22 days, 21 days, 20 days, 19, days, 18 days, 17 days, 16 days, 15 days, and 14 days.
• the dosing period of between about 1 day and 12 days and the resting period is between about 1 day and 12 days with particular reference to a dosing period is 12 days and resting period is 12 days.
• ANAVEX2-73 is about 1 mg to about 60 mg and particularly about 30 mg to about 50 mg, and particularly for oral dosage forms. Also contemplated are ANAVEX2-73 dosages of about 3 mg to about 5 mg and particularly with intravenous administration.
• FIG. 1 depicts a powder X-ray diffraction (PXRD) pattern of ANAVEX2-73, according to an embodiment of the present disclosure
• FIG. 2a depicts a thermogravimetric analysis (TGA) of ANAVEX2-73, according to an embodiment of the present disclosure
• FIG. 2b depicts a thermogravimetric analysis (TGA) of ANAVEX2-73, according to an embodiment of the present disclosure
• FIG. 3a depicts differential scanning calorimetry (DSC) analysis data for ANAVEX2-73, according to an embodiment of the present disclosure
• FIG. 3b depicts differential scanning calorimetry (DSC) analysis data for ANAVEX2-73, according to an embodiment of the present disclosure
• FIG. 3c depicts differential scanning calorimetry (DSC) analysis data for ANAVEX2-73, according to an embodiment of the present disclosure
• FIG. 4a depicts an SEM micrograph demonstrating the size and morphology of the particles of ANAVEX2-73, according to an embodiment of the present disclosure
• FIG. 4b depicts an SEM micrograph demonstrating the size and morphology of the particles of ANAVEX2-73, according to an embodiment of the present disclosure
• FIG. 4c depicts an SEM micrograph demonstrating the size and morphology of the particles of ANAVEX2-73, according to an embodiment of the present disclosure
• FIG. 5 is a plot illustrating P300 ERP wave data for twelve patients at baseline and day 36 following the on-off-on ANAVEX2-73 dosing regimen, as compared to a healthy control group;
• FIG. 6 illustrates P300 amplitude data for twelve patients at baseline and day 36 following the on-off-on ANAVEX2-73 dosing regimen, as compared to a healthy control group;
• FIG. 7 illustrates P300 amplitude data for twelve patients at day 36 (1 month) following the on-off-on ANAVEX2-73 dosing regimen, as compared to historical donepezil and control data;
• FIG. 8 illustrates electroencephalographic (EEG) peak alpha frequency (PAF) data for twelve patients at baseline and day 36 following the on-off-on ANAVEX2-73 dosing regimen, as compared to a healthy control group; and
• FIG. 9 illustrates an electroencephalographic (EEG) power spectrum indicating the peak alpha frequency (PAF).
• the present disclosure generally relates to pharmaceutical compounds and compositions for the treatment of Alzheimer's disease. More particularly, the present disclosure relates to the use of pharmaceutical compositions containing ANAVEX2-73 for the treatment of Alzheimer's disease.
• ANAVEX2-73 can be produced by charging a solution of tetra hydro -N,N - dimethyl-2,2-diphenyl-3-furanmethanamine free base in ethyl acetate with isopropanol. The ethylacetate is removed by distillation and the remaining isopropanol solution containing tetrahydro-N,N-dimethyl-2,2- diphenyl-3-furanmethanamine free base is clear filtered.
• Aqueous hydrochloric acid (1.1 eq) is charged to the isopropanol solution and the formed crystalline HCI salt of tetrahydro-N,N-dimethyl-2,2-diphenyl-3- furanmethanamine, tetrahydro-N,N-dimethyl-2,2-diphenyl-3- furanmethanamine hydrochloride (ANAVEX2-73), is isolated by filtration and dried under vacuum at 55°C for 3 days.
• the ANAVEX 2-73 thus obtained, is characterized by powder X-ray diffraction (PXRD), thermogravimetric analysis (TGA), differential scanning calorimetry (DSC), and scanning electron microscopy (SEM), as shown in FIGs. 1-4.
• FIG. 1 depicts a powder X-ray diffraction (PXRD) pattern for ANAVEX2-73, according an embodiment of the present disclosure.
• the PXRD pattern shown in FIG. 1 was collected using a Siemens D5000 powder diffracto meter with CuKa radiation (1.54056 A). The tube voltage and amperage were set at 40 kV and 40 mA, respectively. The divergence slit and antiscattering slit settings were variable for the illumination on the 20 mm sample area. Each sample was scanned between 5° and 40° in 2 ⁇ with a step size of 0.02°. The measurement time per step was 2 seconds. The instrument was previously calibrated using a silicon standard. As shown in FIG. 1, the PXRD indicates that the ANAVEX2-73 material is highly crystalline with several characteristic peaks in the 10-20° 2 ⁇ range.
• FIGs. 2a and 2b depict thermogravimetric analysis (TGA) data for ANAVEX2-73, according to an embodiment of the present disclosure.
• the weight loss of the sample as a function of temperature was measured using the Thermal Advantage TGA Q5000IR (TA instrument) module.
• the samples ( ⁇ 7.8 mg) was placed onto the platinum pan (100 ⁇ _) and heated from 25°-350° at a heating rate of 10°C/min under nitrogen purge.
• the TGA (and derivative of weight change) curves indicate that the minor weight change at around 80°C followed by continuous weight loss from 150°C with two major steps (first one with ⁇ 29% at 228°C) up to 275°C.
• the initial weight loss could be attributed to the evaporation of adsorbed water or solvent of crystallization and the latter weight changes may be attributed to the degradation of impure solid phases (or impurities) followed by a melt- degradation of ANAVEX2-73.
• FIGs. 3a, 3b, and 3c depict differential scanning calorimetry (DSC) data for ANAVEX2-73, according to an embodiment of the present disclosure.
• the thermal behavior of ANAVEX2-73 was studied using a Thermal Advantage DSC Q1000 (TA instruments) equipped with a refrigerated cooling system. The instrument had been calibrated for temperature and enthalpy using indium. 1-2 mg of the sample was accurately weighed into a non-hermetic aluminum pan and crimped. The sample was scanned from 25°C to 275°C at a heating rate of 10°C/min under continuous nitrogen purge (50 mL/min). As shown in FIGs.
• the DSC thermograms indicate endothermic events with onset at ⁇ 80°C (minor) and 115°C (broad) followed by an exothermic peak and a sharp endothermic event with onset at 227°C.
• DSC analysis seemed to be in agreement with the TGA analysis suggesting that the compound was undergoing melt-degradation. However, start of the degradation of the main phase in the vicinity but before the melting is also possible.
• FIGs. 4a, 4b, and 4c depict scanning electron microscope (SEM) micrographs demonstrating the size and morphology of the particles of ANAVEX2-73, according to an embodiment of the present disclosure.
• the size and morphology of the particles was studied using a Philips XL30 (The Netherlands) scanning electron microscope (SEM).
• SEM scanning electron microscope
• the samples were sprinkled onto double-sided tape that had been secured onto an aluminum stub and then gold sputter-coated at mA for 40 seconds under an argon atmosphere.
• the particles were analyzed at suitable acceleration voltages and magnifications. Representative micrographs were taken and the particle size was estimated.
• the SEM micrographs demonstrated that ANAVEX2-73 is primarily comprised of aggregated crystals (prisms to blocks) with a primary particle size distribution between 1 and 50 pm.
• ANAVEX2-73 The safety of ANAVEX2-73 has been demonstrated in a randomized, placebo-controlled single ascending dose Phase 1 study of ANAVEX2-73 in 22 healthy male volunteers. See Poster: A Phase 1 Dose Escalation Study to Investigate Safety, Tolerability, and Pharmacokinetics of ANAVEX2-73 in Healthy Male Subjects, CNS Summit 2014, Boca Raton, FL, by Ole Voges, Ingo Weigmann, Norman Bitterlich, Christoph Schindler and Christopher Missling. Ascending single oral doses of 1 mg, 10 mg, 30 mg, 40 mg, 50 mg, and 55 mg of ANAVEX2-73 were safe and well tolerated in healthy subjects. No serious adverse events occurred.
• the maximum tolerable dose (MTD) and the minimum intolerable dose (MID) were defined as 55 mg and 60 mg, respectively.
• a highest doses, observed adverse events included moderate and reversible dizziness and headache, common in drugs that target the central nervous system.
• Blood pressure and resting heart rate and other clinical parameters such as vital signs and 12-lead electrocardiogram (ECG) did not show any clinically relevant or dose-dependent changes.
• ECG 12-lead electrocardiogram
• the QT interval and QTcB also did not reveal any clinically significant changes.
• the pharmacokinetics of ANAVEX2-73 was found to be suitable for daily oral dosing.
• ANAVEX2-73 The efficacy of ANAVEX2-73 polymorph for the treatment of Alzheimer's disease has been demonstrated by initial clinical data from an on-going Phase 2a clinical trial.
• the 36-day multicenter randomized clinical trial included both male and female mild-to-moderate Alzheimer's disease patients.
• ANAVEX2-73 was administered to twelve subjects as an add-on therapy to the donepezil current standard of care.
• ANAVEX2-73 was administered according to a two-period on-off-on cross-over dosing regimen in which the subjects were administered ANAVEX2-73 for 12 days (1 st period) followed by a 12-day wash-out period before being administered ANAVEX2-73 for a second 12-day period (2 nd period).
• Those subjects that were administered ANAVEX2-73 by oral administration during the 1 st period were administered ANAVEX2-73 intravenously during the 2 nd period, and vice versa. About half of the subjects were administered a 30 mg oral dosage form while the other half of subjects were administered a 50 mg oral dosage form.
• the intravenous dosage was either 3 mg or 5 mg, with about half of the subjects administered 3 mg and the other half administered 5 mg.
• EEG electroencephalographic
• EEG/ERP event related potentials
• ERPs Event related potentials
• EEG Event-related potentials
• ERPs provide a sensitive and reliable measure of the cognitive effects associated with early Alzheimer's disease. ERPs reflect well characterized brain responses to sensor, motor and cognitive events and have been found to be altered in Alzheimer disease patients beginning in the very early stages of the disease. See for example, New Encycl. Neurosci., Oxford Academic Press, p. 13-18 (2009).
• ERP tests on young presymptomatic individuals who carry mutations in the presenilin-1 and amyloid precursor protein genes show significant changes in ERP patterns years before the onset of behavioral symptoms and the development of Alzheimer's disease. See for example, Neurology 73, 1649-1655 (2009); Neurology 77, 469-475 (2011). ERPs have also been shown to reliably track the cognitive decline associated with Alzheimer's disease progression. For instance, ERP markers of cognitive function are increasingly altered in longitudinal studies on individuals with mild cognitive impairment (MCI) and Alzheimer's disease patients. See for example, Clin. Neurophysiol. 122, 1322-1326 (2011); Clin. Neurophysiol. 121, 194-199 (2010).
• MCI mild cognitive impairment
• ERPs have been shown to be sensitive to the effects of cognitive enhancers currently used for the treatment of Alzheimer's disease.
• ERP measures have been demonstrated to be reliable instruments for the assessment of the cognitive response to cholinesterase inhibitors, such as donepezil, and the effects of the selective NMDA antagonist memantine, as measured by ERPs, have been shown to correlate with changes in the Mini Mental State Examination (MMSE) score.
• MMSE Mini Mental State Examination
• auditory P300 component of the ERP has been widely applied in the study of age-related cognitive dysfunction because it is thought to reflect attentional and memory processes. Auditory P300 is a positive deflection occurring at about 300 ms from stimulus onset. It is generated by the activation of multiple neocortical and limbic regions. Auditory P300 has two functionally different components, an earlier P3a component that is maximal over frontocentral regions, and a later P3b component (hereafter "P300") that is maximal at the posterior scalp locations. See for example, Int. J. of Alzheimer's Pis. 2011, Article ID 653173, 1-7 (2011).
• Subjects were tested using a three-stimulus oddball paradigm. Stimuli comprised of standard tones (1000 Hz), target tones (2000 Hz) and unexpected distractor tones (white noise) that were played with probabilities of 0.75, 0.15, and 0.10. Tones were presented in pseudorandom order, so that target and distractor tones were never presented sequentially. Subjects were instructed to respond to the target stimuli by pressing a button with their dominant hand. For each test, between 300 and 400 stimuli were presented binaurally through insert ear phones at 70 dB volume. The tone duration for each stimulus was 100 ms with rise and fall times of 10 ms. The interstimulus interval was randomized between 1.5 and 2 s.
• Electroencephalographic (EEG) activity was recorded from seven electrode sites (Fz, Cz, Pz, F3, P3, F4, and P4) of the international 10-20 system using a COGNISIONTM Headset (Neuronetrix). Electrodes were referenced to averaged mastoids (Ml, M2) and Fpz served as the common electrode. The headset used for data collection had been validated to perform reliable ERP recordings when skin contact impedance was below 70 ⁇ ⁇ . Impedance was automatically checked at all electrodes after each target or distractor tone, and was kept below this limit throughout each test. Data was collected from -240 to 1,000 ms around the stimuli, digitized at 125 Hz, and bandpass filtered from 0.3 to 35 Hz. An automatic artifact threshold detection limit of ⁇ 100 pV was set for the tests. Trial sets of a deviant tone and the immediately preceding standard tones (epoch sets) with artifacts exceeding the threshold were rejected in real time and immediately repeated.
• FIG. 5 illustrates P300 ERP wave data for twelve patients at baseline and day 36 following the on-off-on ANAVEX2-73 dosing regimen, without any dose optimization.
• FIG. 5 also illustrates data for a healthy control group obtained from a manuscript that was recently submitted by Cecchi et al. to the journal Alzheimer's & Dementia.
• the P300 ERP wave data indicates that administration of ANAVEX2-73 improved measured cognitive performance as compared to the baseline data.
• the P300 ERP wave plot for subjects undergoing the ANAVEX2-73 dosage regimen more closely resembled the P300 ERP wave plot obtained for healthy subjects.
• FIG. 6 illustrates P300 amplitude data for twelve patients at baseline and day 36 following the on-off-on ANAVEX2-73 dosing regimen, as compared to the healthy control group.
• the same data is provided in Table 1.
• the P300 amplitude for subjects undergoing the ANAVEX2-73 dosage regimen increased by 38% as compared to the baseline P300 amplitude.
• the P300 amplitude for subjects undergoing the ANAVEX2-73 dosage regimen more closely resembled the P300 amplitude data obtained for the healthy control group than the baseline P300 amplitude data.
• Table 2 demonstrates the effects of the ANAVEX2-73 dosage regimen on the cognitive performance of the twelve subjects at baseline and day 36 following the on-off-on ANAVEX2-73 dosing regimen, as measured by the target detection task of the ERP test.
• Table 2 also provides target detection task data for the healthy control group.
• the button press accuracy was improved for subjects undergoing the ANAVEX2-73 dosage regimen as compared to the baseline.
• the median reaction time and the false alarm percentage was reduced for the ANAVEX2-73 administered subjects as compared to the baseline.
• the healthy control group out-performed the day 36 ANAVEX2-73 subjects in button press accuracy and median reaction time.
• the day 36 ANAVEX2-73 subjects out-performed the healthy control group in false alarm percentage.
• the data provided in Table 2 indicates that ANAVEX2-73 administration improves both the accuracy and the reaction time of subjects performing the target detection task of the ERP test.
• FIG. 7 illustrates P300 amplitude data for twelve patients at day 36 (1 month) following the on-off-on ANAVEX2-73 dosing regimen, as compared to historical donepezil and control data obtained from Clin. Neuropharmacol. 25(4), 207-215 (2002).
• the measured P300 amplitude change for subjects undergoing the ANAVEX2- 73 dosage regimen, as compared to the baseline P300 amplitude is about four times higher than the P300 amplitude change observed in historical data for patients administered donepezil at the 1 month time point.
• the percent P300 amplitude change after 1 month is greater than the percent P300 amplitude change observed in historical data for patients administered donepezil after 6 months.
• FIG. 8 illustrates electroencephalographic (EEG) peak alpha frequency (PAF) data for twelve patients at baseline and day 36 following the on-off-on ANAVEX2-73 dosing regimen, as compared to a healthy control group.
• Electroencephalographic (EEG) peak alpha frequency (PAF) measured in Hz, is a distinctive individual "fingerprint" that has been correlated to cognitive performance and reflects a trait or state of cognitive preparedness. Patients with Alzheimer's disease have been found to have reduced PAF when compared to age-matched controls.
• FIG. 9 illustrates an electroencephalographic (EEG) power spectrum indicating the peak alpha frequency (PAF).
• EEG electroencephalographic
• PAF peak alpha frequency
• FIG. 8 indicates that ANAVEX2-73 is able to shift PAF in subjects as compared to the measured PAF baseline.
• ANAVEX2-73 was found to improve the P300 signal in 10 out of the 12 patients (83%) studied.
• ANAVEX2-73 can be administered according to an intermittent dosing schedule, in which a subject is administered ANAVEX2-73 for a period of days, followed by a period of days in which no ANAVEX2-73 is administered, before administration of ANAVEX2-73 is once again resumed.
• the period of administration is of the same duration as the period of no administration. In other cases, the period of administration may be of a longer or shorter duration than the period of administration.
• ANAVEX2-73 is administered according to an intermittent dosing regimen of at least two cycles, each cycle comprising (a) a dosing period during which a therapeutically effective amount of ANAVEX2-73 is administered to a patient and thereafter (b) a resting period.
• the dosing period is for 1-12 days and the rest period is for 1-12 days.
• the dosing period can be 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, or 14 days.
• the resting period can be 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, or 14 days.
• the dosing period described herein can be in the range of a lower limit of about 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, and 14 days to an upper limit of about 28 days, 27 days, 26 days, 25 days, 24 days, 23 days, 22 days, 21 days, 20 days, 19, days, 18 days, 17 days, 16 days, 15 days, and 14 days.
• the resting period described herein can be in the range of a lower limit of about 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, and 14 days to an upper limit of about 28 days, 27 days, 26 days, 25 days, 24 days, 23 days, 22 days, 21 days, 20 days, 19, days, 18 days, 17 days, 16 days, 15 days, and 14 days.
• the intermittent dosage schedule described herein comprises an oral dosage form comprising about 30 mg ANAVEX2-73. In another embodiment, the intermittent dosage schedule described herein comprises an oral dosage form comprising about 50 mg ANAVEX2-73. In another embodiment, the intermittent dosage schedule described herein comprises an oral dosage form comprising between about 30 mg and 50 mg ANAVEX2-73. In another embodiment, the intermittent dosage schedule described herein comprises an oral dosage form comprising between about 1 mg and 55 mg ANAVEX2-73.
• the oral dosage form described herein can be in the range of a lower limit of about 1 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, and 30 mg ANAVEX2-73 to an upper limit of about 60 mg, 55 mg, 50 mg, 45 mg, 40 mg, 35 mg, and 30 mg ANAVEX2-73.
• the intermittent dosage schedule described herein comprises intravenous administration of about 3 mg ANAVEX2-73. In another embodiment, the intermittent dosage schedule described herein comprises intravenous administration of about 5 mg ANAVEX2-73. In another embodiment, the intermittent dosage schedule described herein comprises intravenous administration of between about 3 mg and 5 mg ANAVEX2-73. In another embodiment, the intermittent dosage schedule described herein comprises intravenous administration of between about 1 mg and 10 mg ANAVEX2-73.
• the intravenous administration described herein can be in the range of a lower limit of about 1 mg, 2 mg, 3 mg, 4 mg, and 5 mg ANAVEX2-73 to an upper limit of about 10 mg, 9 mg, 8 mg, 7 mg, 6 mg, and 5 mg ANAVEX2-73.
• compositions disclosed herein individually or in combination are employed in admixture with conventional excipients, i.e., pharmaceutically acceptable organic or inorganic carrier substances suitable for parenteral, enteral (e.g ., oral or inhalation) or topical application which do not deleteriously react with the active compositions.
• excipients i.e., pharmaceutically acceptable organic or inorganic carrier substances suitable for parenteral, enteral (e.g ., oral or inhalation) or topical application which do not deleteriously react with the active compositions.
• Suitable pharmaceutically acceptable carriers include but are not limited to water, salt solutions, alcohols, gum arabic, vegetable oils, benzyl alcohols, polyethylene glycols, gelatin, carbohydrates such as lactose, amylose or starch, magnesium stearate, talc, titanium dioxide, silicic acid, viscous paraffin, perfume oil, fatty acid esters, hydroxyl methylcellulose, polyvinyl pyrrolidone, etc.
• the pharmaceutical preparations can be sterilized and if desired mixed with auxiliary agents, e.g., lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, coloring, flavoring and/or aromatic substances and the like which do not deleteriously react with active compositions. They can also be combined where desired with other active agents, e.g., vitamins.
• auxiliary agents e.g., lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, coloring, flavoring and/or aromatic substances and the like which do not deleteriously react with active compositions.
• auxiliary agents e.g., lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, coloring, flavoring and/or aromatic substances and the like which do not deleter
• dosage forms include instructions for the use of such compositions.
• parenteral application particularly are injectable, sterile solutions, preferably oily or aqueous solutions, as well as suspensions, emulsions, or implants, including suppositories.
• Ampules, vials, and injector cartridges are convenient unit dosages.
• "Unit dosage form" shall mean single administration entity. By way of example, a single tablet, capsule, dragee, or trochee, suppository, or syringe.
• Sustained or direct release compositions can be formulated, e.g., liposomes or those wherein the active component is protected with differentially degradable coatings, e.g ., by microencapsulation, multiple coatings, etc. It is also possible to freeze-dry the new compositions and use the lyophilizates obtained, for example, for the preparation of products for injection.
• a 63 year-old male presents with early signs of Alzheimer's disease. He is orally administered a pharmaceutical composition containing 30 mg ANAVEX2-73 according to an intermittent dosing regimen where each cycle includes daily administration for 10 days (dosing period) followed by 10 days of no administration (resting period). The patient is administered 30 mg ANAVEX2-73 according to the intermittent dosing regimen for 6 months. His loss of cognitive function stabilizes during that period.
• a 58 year-old male presents with signs of early onset Alzheimer's disease. He is orally administered a pharmaceutical composition containing 50 mg ANAVEX2-73 according to an intermittent dosing regimen where each cycle includes daily administration for 10 days (dosing period) followed by 20 days of no administration (resting period). His loss of cognitive function stabilizes during that period.
• a 60 year-old female presents with signs of early onset Alzheimer's disease. She is administered 3 mg of ANAVEX2-73 intravenously according to an intermittent dosing regimen where each cycle includes daily administration for 5 days (dosing period) followed by 20 days of no administration (resting period) for one year. Her loss of cognitive function stabilizes during that period.
• a 55 year-old male presents with signs of early onset Alzheimer's disease. He is administered 5 mg of ANAVEX2-73 intravenously according to an intermittent dosing regimen where each cycle includes daily administration for 14 days (dosing period) followed by 7 days of no administration (resting period) for one year. His loss of cognitive function stabilizes during that period.
• a 64 year-old female presents with early signs of Alzheimer's disease. She is orally administered a pharmaceutical composition containing 50 mg ANAVEX2-73 according to an intermittent dosing regimen where each cycle includes daily administration for 14 days (dosing period) followed by 7 days of no administration (resting period). The patient is administered 50 mg ANAVEX2-73 according to the intermittent dosing regimen for 6 months. Her loss of cognitive function is stabilized during that period.

Landscapes

• Health & Medical Sciences (AREA)
• Chemical & Material Sciences (AREA)
• Medicinal Chemistry (AREA)
• Pharmacology & Pharmacy (AREA)
• Life Sciences & Earth Sciences (AREA)
• Animal Behavior & Ethology (AREA)
• General Health & Medical Sciences (AREA)
• Public Health (AREA)
• Veterinary Medicine (AREA)
• Epidemiology (AREA)
• Bioinformatics & Cheminformatics (AREA)
• Neurology (AREA)
• Engineering & Computer Science (AREA)
• Biomedical Technology (AREA)
• Neurosurgery (AREA)
• Psychiatry (AREA)
• Hospice & Palliative Care (AREA)
• Emergency Medicine (AREA)
• Chemical Kinetics & Catalysis (AREA)
• General Chemical & Material Sciences (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• Organic Chemistry (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
• Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
• Medicinal Preparation (AREA)

Applications Claiming Priority (1)

Publications (1)

Family

ID=59270129

Family Applications (1)

Country Status (6)

Families Citing this family (2)

Family Cites Families (3)

• 2017
  • 2017-06-14 EP EP17734901.6A patent/EP3638225A1/de active Pending
  • 2017-06-14 AU AU2017418247A patent/AU2017418247B2/en active Active
  • 2017-06-14 WO PCT/US2017/037436 patent/WO2018231216A1/en active Application Filing
  • 2017-06-14 CN CN201780093392.2A patent/CN111315375A/zh active Pending
  • 2017-06-14 JP JP2020519659A patent/JP2020523417A/ja active Pending
  • 2017-06-14 CA CA3010480A patent/CA3010480A1/en active Pending
• 2022
  • 2022-01-07 JP JP2022001498A patent/JP2022050553A/ja active Pending
• 2023
  • 2023-09-19 JP JP2023151737A patent/JP2023164615A/ja active Pending
• 2024
  • 2024-03-14 AU AU2024201661A patent/AU2024201661A1/en active Pending

Also Published As

Similar Documents

Legal Events