Aripiprazole Dosing Strategy

Abstract

To provide an improved method of delivering antipsychotics to improve the patient compliance and maximize the pharmacological profile of an active agent.SOLUTION: The present invention relates to methods of treating schizophrenia using a combination of aripiprazole, aripiprazole lauroxil, and a nanoparticle dispersion of aripiprazole lauroxil.SELECTED DRAWING: None

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Provisional Patent Application No. 62 / 638,587, filed March 5, 2018, the entire contents of which are incorporated herein by reference. [Background technology]

[0002] Schizophrenia is a severe neuropsychiatric illness with onset in late adolescence or early adulthood. It is a devastating and relatively common disorder characterized by distorted perception of reality (hallucinations and delusions), social deficits, disorganized language and behavior, and mild cognitive impairment, affecting approximately 1% of the world's population.

[0003] Patients with schizophrenia require long-term antipsychotic therapy, and one limitation of long-acting injectable (LAI) antipsychotic therapy is that some LAI regimens require an oral induction (initiation) regimen lasting 2-3 weeks to achieve initial therapeutic concentrations. See, for example, Brissos, S. et al. Therapeutic Advances in Psychopharmacology, 2014, 4(5), 198-219;Citrome, L. Expert Review of Neurotherapeutics, 2017, 17(10), 1029-1043. These oral induction regimens can be challenging for patients who do not want to take pills, or when patients begin LAI therapy in the hospital but need to continue oral induction for some time after discharge. [Prior art documents] [Patent documents]

[0004] [Patent Document 1] U.S. Patent No. 4,734,416 [Patent Document 2] U.S. Patent No. 5,006,528 [Patent Document 3] U.S. Patent No. 8,431,576 [Patent Document 4] U.S. Patent No. 8,796,276 [Patent Document 5] U.S. Patent No. 9,034,867 [Patent Document 6] U.S. Patent No. 9,193,685 [Patent Document 7] U.S. Patent No. 9,452,131 [Patent Document 8] U.S. Patent No. 9,526,726 [Patent Document 9] U.S. Patent No. 10,016,415 [Non-patent literature]

[0005] [Non-Patent Document 1] Brissos, S. et al. Therapeutic Advances in Psychopharmacology, 2014, 4(5), 198~219 [Non-Patent Document 2] Citrome, L. Expert Review of Neurotherapeutics, 2017, 17(10), 1029~1043 [Non-Patent Document 3] Meltzer, HY et al., J. Clin. Psychiatry, 2015, 76(8), 1085~1090 [Non-Patent Document 4] McEvoy, JP et al., J. Clin. Psychiatry, 2017, 78(8), 1103-1109 Summary of the Invention [Problem to be solved by the invention]

[0006] Thus, there is a need for improved methods of delivering antipsychotic drugs that improve patient compliance and maximize the pharmacological profile of the active agent. [Means for solving the problem]

[0007] A method for treating schizophrenia in a subject in need thereof, comprising administering to said subject a nanoparticulate dispersion of aripiprazole, aripiprazole lauroxyl (ALPHA). NCD Provided herein are methods comprising administering to a subject a combination of an LAI of aripiprazole lauroxyl and aripiprazole lauroxyl. Conventional administration of an LAI of aripiprazole lauroxyl requires a 21-day oral induction (initiation) of aripiprazole. In contrast, the combination described herein requires only a 1-3 day oral induction period of aripiprazole. This minimized induction period has several advantages, including increased patient compliance.

[0008] Thus, in one aspect, there is provided a method of treating schizophrenia in a subject in need thereof, comprising: a first ingredient containing about 5-50 mg of aripiprazole; Approximately 629-695mg of AL NCD and a second component comprising: a third ingredient comprising a therapeutically effective amount of aripiprazole lauroxyl; In one embodiment, a method is provided herein that includes administering to a subject in any order.

[0009] In one embodiment, the components of the present invention may be administered in any order.

[0010] In one embodiment, all components are pharmaceutical compositions comprising the active ingredients listed above and a pharma- ceutically acceptable carrier.

[0011] In one embodiment, AL NCD comprises polysorbate 20, sodium citrate, sodium chloride, an aqueous buffer, and a population of particles of aripiprazole lauroxyl. In another embodiment, the population of particles of aripiprazole lauroxyl has a volume-based particle distribution diameter (Dv50) of less than about 1000 nm. In one embodiment, the population of particles of aripiprazole lauroxyl has a volume-based particle distribution diameter (Dv50) of between about 175 nm and about 350 nm. In one embodiment, the population of particles of aripiprazole lauroxyl has a volume-based particle distribution diameter (Dv50) of between about 175 nm and about 350 nm. NCDhas a particle to polysorbate 20 ratio of about 0.1:1 to about 40:1. NCD has a particle to polysorbate 20 ratio of 17:1. NCD about 26% by weight of aripiprazole lauroxyl particles, about 1.53% by weight of polysorbate 20, about 0.76% by weight of sodium citrate, 0.31% by weight of sodium chloride, and an aqueous buffer; and the aripiprazole lauroxyl particles have a volume-based particle distribution diameter (Dv50) of between about 175 nm and about 350 nm.

[0012] In one embodiment, the first component is administered at a dosage of about 30 mg of aripiprazole. In another embodiment, the first component is administered at a dosage of about 15 mg of aripiprazole. In yet another embodiment, the second component is administered at a dosage of about 675 mg of aripiprazole lauroxyl. In another embodiment, the second component is administered at a dosage of about 677 mg of aripiprazole lauroxyl. In yet another embodiment, the third component is administered at a dosage of about 300 to 1500 mg of aripiprazole lauroxyl. In one embodiment, the third component is administered at a dosage of 441, 662, 882, or 1064 mg.

[0013] The components can be administered substantially simultaneously (i.e., typically within minutes of each other, or within the time it would take a person skilled in the medical or pharmaceutical arts to administer the components). In one embodiment, all components of the method are administered substantially simultaneously. In another embodiment, the method includes a regimen in which the first, second, and third components are administered substantially simultaneously, with the first component not being administered again within 21 days of the first administration. In yet another embodiment, the method includes a regimen in which the first, second, and third components are administered substantially simultaneously, with the second administration of the components occurring 21 days or later after the first treatment. In yet another embodiment, the method includes a regimen in which the first, second, and third components are administered substantially simultaneously, with the second administration of the components occurring 21 days or later after the first treatment. In one embodiment, the second treatment of any or all of the components occurs 21 days or later after the first treatment. In one embodiment, the first component is administered only once during the treatment period. In one embodiment, the first component is not administered again within 21 days after the first treatment.

[0014] In one embodiment, the method includes a regimen in which the first component is administered only on the first and / or second days of treatment, the second component is administered only on the first day of treatment, and the third component is administered only once within the first 10 days of treatment. In another embodiment, the regimen further includes a second administration of only the third component. In yet another embodiment, the third component is administered on the first day of treatment. In yet another embodiment, the third component is administered on the second day of treatment. In one embodiment, the third component is administered 7-10 days after the start of the treatment regimen. In another embodiment, the third component is administered 3-6 days after the start of the treatment regimen. In yet another embodiment, the first component is administered only on the first and second days of treatment. In yet another embodiment, the first component is administered only on the first day of treatment.

[0015] In one embodiment, the first component is administered orally. In one embodiment, the second component is administered intramuscularly. In one embodiment, the second component is administered intramuscularly to the deltoid or gluteal muscles. In one embodiment, the second component is administered intramuscularly to the deltoid muscle. In one embodiment, the third component is administered intramuscularly. In one embodiment, the third component is administered intramuscularly to the deltoid or gluteal muscles.

[0016] In another aspect, there is provided a method of treating schizophrenia in a subject in need thereof, comprising: a first ingredient comprising aripiprazole; AL NCD and a second component comprising: Aripiprazole with a third ingredient, lauroxyl administering to a subject the combined dosage of the first, second and third components is sufficient to maintain a therapeutically effective mean plasma level of aripiprazole in the subject; A method is provided herein. Figure 8 shows the mean plasma levels obtained using this method.

[0017] In one embodiment, the therapeutically effective mean plasma level of aripiprazole is between about 102 and 435 ng / mL at steady state plasma levels. In one embodiment, the therapeutically effective mean plasma level of aripiprazole is greater than about 102 ng / mL at steady state plasma levels. In one embodiment, the therapeutically effective mean plasma level of aripiprazole is less than about 435 ng / mL at steady state plasma levels. In one embodiment, the therapeutically effective mean plasma level of aripiprazole is between about 102 ng / mL and about 435 ng / mL at steady state plasma levels. In one embodiment, the therapeutically effective mean plasma level of aripiprazole is reached within 24 hours of the first treatment. In one embodiment, the therapeutically effective mean plasma level of aripiprazole is maintained for 21 days or more.

[0018] In another aspect, a kit for treating schizophrenia is provided, comprising a therapeutically effective amount of a first ingredient comprising aripiprazole; AL NCD and a second component comprising: Aripiprazole with a third ingredient, lauroxyl Including, Provided herein is a kit further comprising instructions for administration, the instructions specifying oral administration of the first component, intramuscular administration of the second component, and intramuscular administration of the third component. [Brief description of the drawings]

[0019] [Figure 1] FIG. 1 shows the study design from Example 1. [Diagram 2] FIG. 1 shows mean (SD) aripiprazole concentrations over time (28 days) following initiation of treatment with oral aripiprazole (15 mg / day for 21 days) or ALNCD plus a single dose of oral aripiprazole (30 mg on day 1). [Diagram 3] FIG. 13 is a box plot of AUC0-28 for aripiprazole by starting AL dose / starting regimen. [Figure 4] Scatter plots of aripiprazole concentrations (log scale) for patients receiving the 21-day initiation regimen in the Phase 1 study (plus signs) and the Phase 3 efficacy study (circle signs) for the combined 441 mg and 882 mg AL dose groups. [Diagram 5] Scatter plots (log scale) of aripiprazole concentrations for patients receiving the daily initiation regimen in the Phase 1 study (plus signs) and the Phase 3 efficacy study (circle signs) for the combined 441 mg and 882 mg AL dose groups. [Figure 6A] FIG. 1 shows mean aripiprazole concentrations following a single injection of ALNCD at a 441 mg dose relative to minimum and maximum thresholds established by the FDA. [Figure 6B] FIG. 1 shows mean aripiprazole concentrations following a single injection of ALNCD at a 662 mg dose relative to minimum and maximum thresholds established by the FDA. [Figure 6C] FIG. 1 shows mean aripiprazole concentrations following a single injection of ALNCD at an 882 mg dose relative to minimum and maximum thresholds established by the FDA. [Figure 7A] FIG. 1 is a scatter plot of aripiprazole concentrations following a single injection of ALNCD at a 441 mg dose against minimum and maximum threshold values ​​established by the FDA. [Figure 7B] FIG. 1 is a scatter plot of aripiprazole concentrations following a single injection of ALNCD at a 662 mg dose against minimum and maximum threshold values ​​established by the FDA. [Figure 7C] FIG. 1 is a scatter plot of aripiprazole concentrations following a single injection of ALNCD at an 882 mg dose against minimum and maximum threshold values ​​established by the FDA. [Figure 8] FIG. 1 shows simulated aripiprazole concentrations following a single injection of ALNCD at the doses provided in the legend, along with a 50 mg IM dose of aripiprazole. The 662 mg dose provides sufficient coverage to maintain concentrations above the minimum threshold. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0020] Aripiprazole lauroxyl (AL), a prodrug of the atypical antipsychotic aripiprazole, is available as a long-acting intramuscular (IM) injection indicated to treat schizophrenia. See, e.g., Meltzer, HY, et al., J. Clin. Psychiatry, 2015, 76(8), 1085-1090. Treatment with AL can be initiated in patients at any of the four available doses: 441 mg, 662 mg, 882 mg, or 1064 mg. The dissolution properties of AL allow for extended dosing intervals. For example, there is a 1064 mg AL dose that is specifically indicated as a 2-month dosing interval option. The slow dissolution of AL results in an initial delay between the first AL injection and the attainment of effective concentrations of aripiprazole. Currently, 21 days of oral aripiprazole supplementation is required for the first AL dose to provide sufficient antipsychotic coverage between treatment initiation.

[0021] The 21-day oral requirement poses the challenge that, as an oral medication, it may be stopped prematurely. In the context of initiating AL, premature discontinuation of oral aripiprazole supplementation at initiation may result in a decline to subtherapeutic plasma levels of aripiprazole. Therefore, there is a need to provide an alternative initiation regimen for AL that does not require continued oral supplementation.

[0022] The combination and dosing strategies described herein address this need. A Phase 1 pharmacokinetic (PK) study demonstrated that AL on Day 1 (day 1 start regimen) NCD and a single 30 mg oral aripiprazole tablet results in similar aripiprazole plasma concentrations as a 21-day starting regimen when starting with AL 441 or 882 mg. Thus, a method for treating schizophrenia in a subject in need thereof, comprising administering to the subject a first component comprising aripiprazole; NCD A method is provided herein that includes administering to a subject a second component comprising: and a third component comprising a therapeutically effective amount of aripiprazole lauroxyl. In one embodiment, the first component is administered at a dosage of about 30 mg, the second component is administered at a dosage of about 675 mg, and the third component is administered at a dosage of 441, 662, 882, or 1064 mg. In yet another embodiment, the first component is administered at a dosage of about 30 mg, the second component is administered at a dosage of about 677 mg, and the third component is administered at a dosage of 441, 662, 882, or 1064 mg. In another embodiment, the combined dosage of the first, second, and third components is sufficient to maintain a therapeutically effective mean plasma level of aripiprazole in the subject. The threshold for the therapeutically effective mean plasma level of aripiprazole is about 102 ng / mL. Figure 8 shows the effect of aripiprazole in combination with aripiprazole and aripiprazole lauroxyl. NCD The results show that the 662 and 882 mg doses of 100 mg produced mean plasma levels above the threshold.

[0023] The FDA has also established a maximum threshold for acceptable mean plasma levels of 435 ng / mL. Figures 7A, 7B, and 7C show the AL at doses of 441 mg (Figure 7A), 662 mg (Figure 7B), and 882 mg (Figure 7C). NCD 1 shows a scatter plot of the mean plasma levels of aripiprazole after injection of AL alone. NCD An 882 mg dose of results in average plasma levels above the maximum levels recommended by the FDA.

[0024] definition Listed below are definitions of various terms used in this specification. These definitions apply to the terms as they are used throughout the specification and claims, unless limited in specific instances, either individually or as part of a larger group.

[0025] Unless otherwise defined, all technical and scientific terms used herein generally have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Generally, the nomenclature used herein and the laboratory procedures of cell culture, molecular genetics, organic chemistry, and peptide chemistry are those well known and commonly used in the art.

[0026] As used herein, the articles "a" and "an" refer to one or to more than one (i.e., to at least one) of the grammatical object of the article. By way of example, "an element" means one element or more than one element. Furthermore, use of the term "including" as well as other forms such as "include," "includes," and "included" are not limiting.

[0027] As used herein, the term "about" is understood by those of skill in the art and will vary to some extent depending on the context in which it is used. As used herein, when referring to a measurable value, such as an amount, duration of time, etc., the term "about" is intended to encompass ±20% or ±10% variation from the specified value, including ±5%, ±1%, and ±0.1%, when such variation is appropriate for performing the disclosed methods.

[0028] As used in the specification and claims, the term "comprising" can include the embodiments "consisting of" and "consisting essentially of." The terms "comprise(s)," "include(s)," "having," "has," "may," "contain(s)," and variations thereof, as used herein, are intended to be open-ended transitional phrases, terms, or words that require the presence of the recited components / steps and allow for the presence of other components / steps. However, such descriptions should also be construed as describing compositions or methods as "consisting of" and "consisting essentially of" the recited compounds, allowing for the presence of only the recited compounds and any pharma- ceutically acceptable carriers, and excluding other compounds.

[0029] As used herein, the terms "treat," "treated," "treating," or "treatment" include the attenuation or alleviation of at least one symptom associated with or caused by the condition, disorder, or disease being treated. For example, treatment can be the attenuation of one or several symptoms of the disorder.

[0030] As used herein, the term "prevent" or "prevention" refers to the absence of a disorder or disease occurring if none has occurred, or the absence of further development of a disorder or disease if a disorder or disease has already occurred. The ability to prevent some or all of the symptoms associated with a disorder or disease is also considered.

[0031] As used herein, the term "use" includes each of any one or more of the following embodiments of the invention: unless otherwise stated, use where appropriate and expedient in the treatment of schizophrenia, use for the manufacture of pharmaceutical compositions, e.g. in the manufacture of medicaments, for use in the treatment of these diseases; methods of using compounds of the invention in the treatment of these diseases; pharmaceutical preparations having compounds of the invention for treating these diseases; and compounds of the invention for use in the treatment of these diseases.

[0032] As used herein, the terms "patient," "individual," or "subject" are intended to include organisms, e.g., prokaryotic and eukaryotic organisms, that suffer from or may be afflicted by a disease, disorder, or condition associated with protein kinase activity. Examples of subjects include mammals, e.g., humans, dogs, cows, horses, pigs, sheep, goats, cats, mice, rabbits, rats, and transgenic non-human animals. In certain embodiments, the subject is a human, e.g., a human that suffers from, is at risk of suffering from, or may potentially suffer from, schizophrenia. In another embodiment, the subject is a cell.

[0033] As used in reference to the therapeutic / prophylactic methods and uses of the compounds and pharmaceutical compositions thereof described herein, an individual "in need thereof" may be an individual who has been diagnosed with the condition to be treated or has previously been treated for the condition to be treated. For prevention, an individual in need thereof may also be an individual at risk for the condition (e.g., family history of the condition, lifestyle factors indicative of risk for the condition, etc.). Typically, when a step of administering a compound of the invention is disclosed herein, the invention further contemplates a step of identifying an individual or subject in need of the particular treatment to be administered or having the particular condition to be treated.

[0034] In some embodiments, the individual is a mammal, including but not limited to, a cow, a horse, a cat, a rabbit, a dog, a rodent, or a primate. In some embodiments, the mammal is a primate. In some embodiments, the primate is a human. In some embodiments, the individual is a human, including adults, children, and premature infants. In some embodiments, the individual is a non-mammal. In some variations, the primate is a non-human primate, such as chimpanzees and other ape and monkey species. The term "individual" does not denote a particular age or sex.

[0035] As used herein, the terms "effective amount," "pharmacologically effective amount," and "therapeutically effective amount" refer to a nontoxic but sufficient amount of an agent to produce a desired biological result. This result may be a reduction or alleviation of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system. The appropriate therapeutic amount in any individual case may be determined by one of skill in the art using routine experimentation.

[0036] As used herein, the term "composition" or "pharmaceutical composition" refers to a mixture of at least one compound effective in the present invention and a pharma- ceutically acceptable carrier. The pharmaceutical composition facilitates administration of the compound to a patient or subject. Multiple techniques of administering the compound exist in the art, including, but not limited to, intravenous administration, oral administration, aerosol administration, parenteral administration, ocular administration, pulmonary administration, and topical administration.

[0037] The terms "combination," "therapeutic combination," or "pharmaceutical combination" as used herein refer to a fixed combination in one dosage unit form, or a non-fixed combination, or a kit-of-parts for combined administration, where two or more therapeutic agents are administered separately and independently, either simultaneously or within a time interval, particularly where these time intervals allow the combination partners to exhibit a cooperative, e.g., synergistic, effect.

[0038] As used herein, the term "weight percent" is intended to refer to the amount by weight of a compound and / or ingredient in a composition as a percentage of the total weight of the composition, as the amount by weight of a component of the composition. Weight percent can also be calculated by multiplying the mass fraction by 100. "Weight fraction" refers to the ratio of the mass m1 of a substance to the total mass m of the composition. T The ratio of mass percent to mass is (m1 / m T ) * The result is 100.

[0039] "Aqueous buffer" refers to an aqueous solution that resists changes in hydronium ion and hydroxide ion concentration (and resulting pH) upon addition of small amounts of acid or base or upon dilution. Buffer solutions consist of a weak acid and its conjugate base (more common) or a weak base and its conjugate acid (less common). Buffers can be prepared by methods well known in the art using an appropriate buffering agent that produces the desired pH value. Examples of suitable buffering agents include hydrochloric acid, lactic acid, acetic acid, citric acid, malic acid, maleic acid, pyruvic acid, succinic acid, tris-hydroxymethylaminomethane, sodium hydroxide, sodium bicarbonate, phosphoric acid, sodium phosphate, and other biologically acceptable buffering agents. Aqueous buffers are readily available commercially and can be used in the preparation of the compositions of the present invention without further processing.

[0040] As used herein, the "mean plasma level" of a substance refers to the average level of the substance found in multiple plasma samples. The mean plasma level is obtained by summing the concentrations of the substance found in the plasma samples and then dividing the sum by the number of plasma samples.

[0041] As used herein, "steady-state plasma level" is intended to indicate the total exposure over one dosing interval (at steady state) divided by the time of the dosing interval. Therefore, even if the concentration rises and falls during the dosing interval at steady state, the average concentration does not change. Once at steady state, all doses give the same maximum serum concentration (Cmax), minimum serum concentration (Cmin), area under the curve (AUC) and steady-state concentration (Css), resulting in Css=AUC / dosing interval.

[0042] Pharmaceutical Compositions Disclosed herein is a method and dosing regimen for treating schizophrenia in a subject in need thereof, comprising administering to the subject a first component comprising aripiprazole.U.S. Patent Nos. 4,734,416 and 5,006,528 disclose aripiprazole, 7-{4-[4-(2,3-dichlorophenyl)-1-piperazinyl]butoxy}-3,4-dihydro-2(1H)-quinolinone or 7-{4-[4-(2,3-dichlorophenyl)-1-piperazinyl]butoxy}-3,4-dihydrocarbostyril as atypical antipsychotics useful for treating schizophrenia, bipolar disorder, depression and other CNS disorders.These documents are incorporated herein by reference in their entirety.Aripiprazole has the following chemical structure:

[0043] [ka]

[0044] Aripiprazole is sold under the trade name ABILIFY®. It also acts as a dopamine D2 partial agonist, a serotonin 5-HT1A receptor agonist, and an antagonist of the serotonin 5-HT2A receptor. ABILIFY® is currently administered orally on a once-daily dosing schedule in ABILIFY® (aripiprazole) tablets, ABILIFY DISCMELT® (aripiprazole) orally disintegrating tablets, and ABILIFY® (aripiprazole) oral solution. In one embodiment, the aripiprazole component is a pharmaceutical composition comprising aripiprazole and a pharma- ceutical acceptable carrier.

[0045] The method and dosing regimen also include the component aripiprazole lauroxyl. U.S. Patent Nos. 8,431,576, 8,796,276, 9,034,867, 9,193,685, 9,452,131 and 9,526,726 disclose aripiprazole lauroxyl, (7-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)butoxy)-2-oxo-3,4-dihydroquinolin-1(2H)-yl)methyl dodecanoate, as an extended release prodrug of aripiprazole useful for treating schizophrenia, bipolar disorder, depression and other CNS disorders. These documents are incorporated herein by reference in their entirety. Aripiprazole lauroxyl has the following chemical structure:

[0046] [ka]

[0047] Aripiprazole lauroxyl is sold under the trade name ARISTADA® and is currently administered intramuscularly.

[0048] In one embodiment, the aripiprazole lauroxyl component is a pharmaceutical composition comprising the aripiprazole lauroxyl component and a pharma- ceutically acceptable carrier.In one embodiment, the aripiprazole lauroxyl component is a pharmaceutical composition comprising aripiprazole lauroxyl, sorbitan laurate, polysorbate 20, and an aqueous vehicle.

[0049] The methods and dosing regimens also include nanoparticulate dispersions of aripiprazole lauroxyl (ALPHA). NCD ) is a component of U.S. Patent No. 10,016,415. NCD AL NCD is a pharmaceutical composition comprising polysorbate 20, sodium citrate, sodium chloride, an aqueous buffer and a population of particles of aripiprazole lauroxyl useful for the treatment of schizophrenia, bipolar disorder, depression and other CNS disorders.

[0050] The particle size of nanoparticle dispersions can be measured using techniques such as light scattering, using water or a dilute surface stabilizer solution as diluent. Measurements can be verified using microscopy. Particle size distribution can be determined as a wet suspension using a Horiba 950 particle size analyzer. Volume-based particle size (Dv50) is expressed herein in terms of the average volume diameter of the particles. Particle size measurements can also be performed using PCS (dynamic light scattering measurements).

[0051] In one embodiment, AL NCD In one embodiment, the population of aripiprazole lauroxyl particles in the AL has a volume-based particle distribution diameter (Dv50) of less than about 1000 nm. NCD The population of particles of aripiprazole lauroxyl therein has a volume-based particle distribution diameter (Dv50) between about 175 nm and about 350 nm.

[0052] In one embodiment, AL NCD has a particle to polysorbate 20 ratio of between about 0.1:1 and about 40:1. NCD has a particle to polysorbate 20 ratio of 17:1.

[0053] In one embodiment, AL NCD comprises about 20-30% by weight of aripiprazole lauroxyl, about 1-2% by weight of polysorbate 20, about 0.5-1% by weight of sodium citrate, 0.1-0.5% by weight of sodium chloride, and an aqueous buffer solution. NCD about 26% by weight of aripiprazole lauroxyl, about 1.53% by weight of polysorbate 20, about 0.76% by weight of sodium citrate, 0.31% by weight of sodium chloride, and an aqueous buffer solution.

[0054] In one embodiment, AL NCD about 26% by weight aripiprazole lauroxyl particles, about 1.53% by weight polysorbate 20, about 0.76% by weight sodium citrate, 0.31% by weight sodium citrate, and an aqueous buffer; and the aripiprazole lauroxyl particles have a volume-based particle distribution diameter (Dv50) of between about 175 nm and about 350 nm.

[0055] Treatment method The methods and dosing regimens provided herein can be used to treat a variety of disorders in subjects in need thereof. For example, the pharmaceutical compositions described herein can be used to treat subjects with depression, schizophrenia, and bipolar disorder.

[0056] In one aspect, a method of treating these disorders, e.g., schizophrenia, in a subject in need thereof, comprising: a first ingredient comprising aripiprazole; AL NCD and a second component comprising: a third ingredient comprising a therapeutically effective amount of aripiprazole lauroxyl; Provided herein are methods comprising administering to a subject.

[0057] In one aspect, there is provided a method of treating schizophrenia in a subject in need thereof, comprising: a first ingredient containing about 5-50 mg of aripiprazole; Approximately 629-695mg of AL NCD and a second component comprising: a third ingredient comprising a therapeutically effective amount of aripiprazole lauroxyl; Provided herein are methods comprising administering to a subject.

[0058] In another aspect, there is provided a method of treating schizophrenia in a subject in need thereof, comprising: a first ingredient comprising aripiprazole; AL NCD and a second component comprising: Aripiprazole with a third ingredient, lauroxyl administering to a subject the combined dosage of the first, second and third components is sufficient to maintain a therapeutically effective mean plasma level of aripiprazole in the subject; Methods are provided herein.

[0059] In one embodiment, the therapeutically effective mean plasma level of aripiprazole is between about 102 and 435 ng / mL at steady state plasma levels. In another embodiment, the therapeutically effective mean plasma level of aripiprazole is greater than about 102 ng / mL at steady state plasma levels. In another embodiment, the therapeutically effective mean plasma level of aripiprazole is less than about 435 ng / mL at steady state plasma levels. In another embodiment, the therapeutically effective mean plasma level of aripiprazole is reached within 24 hours of the first treatment. In another embodiment, the therapeutically effective mean plasma level of aripiprazole is maintained for 21 days or more.

[0060] In one aspect, a kit for treating schizophrenia is provided, comprising a therapeutically effective amount of a first ingredient comprising aripiprazole; AL NCD and a second component comprising: Aripiprazole with a third ingredient, lauroxyl Including, Provided herein is a kit further comprising instructions for administration, the instructions specifying oral administration of the first component, intramuscular administration of the second component, and intramuscular administration of the third component.

[0061] In one embodiment, a therapeutically effective amount of the drug is given to a subject using the pharmaceutical composition provided herein. The term "therapeutically effective amount" is further intended to define an amount that causes an improvement in any parameter or clinical symptoms. The actual dose varies with each patient and does not necessarily indicate the complete elimination of all disease symptoms. In the case of antipsychotic drugs, the management of the worsening of psychiatric symptoms and the maintenance of remission are the main goals of therapy, and the selection of the appropriate drug and dosage in a particular disease balances these goals with the minimization of adverse events caused by the drug.

[0062] The therapeutically effective amount of the compound used in the treatment described herein can be easily determined by the attending diagnostician as a person skilled in the art by using conventional techniques and observing the results obtained under similar circumstances. When determining a therapeutically effective dose, several factors are taken into consideration by the attending diagnostician, including, but not limited to, the species of mammal; its size, age and general health; the specific disease involved; the extent or comorbidity or severity of the disease; the response of the individual patient; the specific compound administered; the mode of administration; the bioavailability characteristics of the administered preparation; the selected dosing regimen; the use of concomitant medications; and other relevant circumstances.

[0063] Administration / Dosage The actual dosage levels of the components of the methods and administration regimens provided herein can be varied to obtain an amount of the active ingredients effective to achieve the desired therapeutic response, composition and mode of administration for a particular patient, without being toxic to the patient.

[0064] In particular, the selected dosage level will depend on a variety of factors, including the activity of the particular compound used, the time of administration, the rate of excretion of the compound, the duration of treatment, other drugs, compounds or substances used in combination with the compound, the age, sex, weight, condition, general health and prior medical history of the patient being treated, and similar factors well known in the medical arts.

[0065] A medical practitioner, e.g., a physician or veterinarian, having the skills of one of ordinary skill in the art, can readily determine and prescribe the effective amount of the pharmaceutical composition required. For example, the physician or veterinarian could begin administration of the pharmaceutical composition to administer a level of the disclosed compound lower than required to achieve the desired therapeutic effect, and gradually increase the dosage until the desired effect is achieved.

[0066] The compounds of the methods and dosing regimens provided herein can be orally administered in an amount of about 10 mg to about 2000 mg (e.g., including about 10 mg to about 500 mg) per day, in single or multiple doses. Thus, in one embodiment of the methods of treatment provided herein, the first component (aripiprazole) is administered at a dosage of about 5 to 50 mg per day. In a further embodiment, the first component (aripiprazole) is administered at a dosage of about 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, or 100 mg per day. In a further embodiment, the first component (aripiprazole) is administered at a dosage of about 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, or 30 mg per day. In a further embodiment, the first component (aripiprazole) is administered at a dosage of about 30 mg / day. In yet another embodiment, the first component (aripiprazole) is administered at a dosage of about 15 mg / day for two days. In yet another embodiment, the first component (aripiprazole) is administered at a dosage of about 10 mg / day for three days.

[0067] The compounds of the methods and dosing regimens provided herein can be administered intramuscularly in an amount of about 10 mg to about 2000 mg (including, for example, about 10 mg to about 500 mg) per day, in single or multiple doses. Thus, in one embodiment of the methods of treatment provided herein, the second component (AL NCD ) is administered at a dose of about 629-695 mg / day. In a further embodiment, the second component (AL NCD) is administered at a dosage of about 630 mg, 640 mg, 650 mg, 660 mg, 662 mg, 670 mg, 675 mg, 677 mg, 680 mg, 690 mg or 700 mg per day. In a further embodiment, the second component (AL NCD In another embodiment, the second component (AL) is administered at a dose of about 675 mg / day. NCD ) is administered at a dose of approximately 677 mg / day.

[0068] The compounds of the methods and dosing regimens provided herein can be administered intramuscularly in an amount of about 10 mg to about 2000 mg (e.g., including about 300 mg to about 1500 mg or about 629 to about 695 mg) per day, in single or multiple doses. Thus, in one embodiment of the methods of treatment provided herein, the third component (aripiprazole lauroxyl) is administered at a dosage of about 300 to 1500 mg per day. In further embodiments, the third component (aripiprazole lauroxyl) is administered at a dosage of about 441 mg, 662 mg, 882 mg, or 1064 mg per day.

[0069] In certain embodiments, it is particularly advantageous to formulate the compound into dosage unit form for ease of administration and uniformity of dosage.Dosage unit form as used herein refers to a physically discrete unit suitable as a unitary dosage for the patient to be treated; each unit contains a predetermined amount of the disclosed compound calculated to produce a desired therapeutic effect together with the required pharmaceutical vehicle.The dosage unit form of the present invention is determined by and directly depends on (a) the unique properties of the disclosed compound and the specific therapeutic effect to be achieved, and (b) the limitations inherent in the art of compounding / formulating such disclosed compounds to treat anxiety, depression, bipolar disorder, autism-related irritability and psychotic conditions (including acute mania, schizophrenia and schizophreniform disorder) in patients.

[0070] In one embodiment, the components of the methods and dosing regimens provided herein are formulated using one or more pharma- ceutically acceptable excipients or carriers. In one embodiment, the pharmaceutical composition of the present invention comprises a therapeutically effective amount of a disclosed compound and a pharma- ceutically acceptable carrier.

[0071] As used herein, references to "dose" or "administration" refer to the dose of an active agent. For example, "about 629 to 695 mg of AL NCD The second ingredient contains 629-695 mg of aripiprazole lauroxyl. NCD As discussed above, the aripiprazole and / or aripiprazole lauroxyl component may be a pharmaceutical composition comprising an active agent and a pharma- ceutically acceptable carrier. Any reference to a "dose" or "dosage" of these components refers to a dose or dosage of the active agent (aripiprazole and / or aripiprazole lauroxyl, regardless of the pharma- ceutically acceptable carrier).

[0072] In one embodiment, the active agent in the first component is aripiprazole. In another embodiment, the active agent in the second component is aripiprazole lauroxyl. In yet another embodiment, the active agent in the third component is aripiprazole.

[0073] Various dosage regimens can be used to treat schizophrenia. In some embodiments, a daily dosage, such as any of the exemplary dosages described above, is administered once, twice, three or four times a day for 3, 4, 5, 6, 7, 8, 9 or 10 days. In one embodiment, the method includes a regimen in which the first, second and third components are administered substantially simultaneously.

[0074] In one embodiment, a dose of the first component is administered over the first three days of treatment. In one embodiment, the first component is administered over the first two days of treatment. In one embodiment, the first component is administered only on the first day of treatment. In one embodiment, the first component is administered only once during the treatment period. In one embodiment, the first component is not administered again within 21 days after the initial treatment.

[0075] In one embodiment, the first, second and third components are administered substantially simultaneously, and the first component is not administered again within 21 days of the first administration.

[0076] In one embodiment, the first, second and third components are administered substantially simultaneously, followed by a second treatment comprising administration of only the third component.

[0077] In one embodiment, the second treatment is administered no later than 21 days after the first treatment.

[0078] In one embodiment, the method includes a regimen in which the first component is administered only on the first and / or second days of treatment, the second component is administered only on the first day of treatment, and the third component is administered once within the first 10 days of treatment. In another embodiment, the regimen further includes a second administration of only the third component. In yet another embodiment, the third component is administered on the first day of treatment. In yet another embodiment, the third component is administered on the second day of treatment. In one embodiment, the third component is administered 7-10 days after the initiation of the treatment regimen. In one embodiment, the third component is administered 3-6 days after the initiation of the treatment regimen. In another embodiment, the first component is administered only on the first and second days of treatment. In yet another embodiment, the first component is administered only on the first day of treatment.

[0079] In one embodiment, the method comprises a regimen in which a first component is administered at a dosage of 15 mg / day only on days 1 and 2 of treatment, a second component is administered only on day 1 of treatment, and a third component is administered on day 2 of treatment.

[0080] In one embodiment, the method includes a regimen in which the first component is administered only on day 1 of treatment, the second component is administered only on day 1 of treatment, and the third component is administered 7-10 days after initiation of the treatment regimen. In yet another embodiment, the third component is administered 7, 8, 9, or 10 days after initiation of the treatment regimen. In yet another embodiment, the third component is administered 7 days after initiation of the treatment regimen. In yet another embodiment, the third component is administered 8 days after initiation of the treatment regimen. In one embodiment, the third component is administered 9 days after initiation of the treatment regimen. In another embodiment, the third component is administered 10 days after initiation of the treatment regimen.

[0081] In one embodiment, the method includes a regimen in which the first component is administered only on day 1 of treatment, the second component is administered only on day 1 of treatment, and the third component is administered 3-6 days after initiation of the treatment regimen. In yet another embodiment, the third component is administered 3, 4, 5, or 6 days after initiation of the treatment regimen. In yet another embodiment, the third component is administered 3 days after initiation of the treatment regimen. In yet another embodiment, the third component is administered 4 days after initiation of the treatment regimen. In one embodiment, the third component is administered 5 days after initiation of the treatment regimen. In another embodiment, the third component is administered 6 days after initiation of the treatment regimen.

[0082] Routes of administration of any of the compositions of the invention include oral, nasal, rectal, intravaginal, parenteral, buccal, sublingual, or topical. Compounds for use in the methods and dosing regimens provided herein may be formulated for administration by any suitable route, such as oral or parenteral, for example, transdermal, transmucosal (e.g., sublingual, lingual, (trans)buccal, (trans)urethral, ​​vaginal (e.g., vaginal and perivaginal), (intram)nasal and (trans)rectal), intravesical, intrapulmonary, intraduodenal, intragastric, intrathecal, subcutaneous, intramuscular, intradermal, intraarterial, intravenous, intrabronchial, inhalation, and topical administration.

[0083] In one embodiment, the preferred route of administration for the first ingredient (aripiprazole) is oral.

[0084] In one embodiment, the second component (ALNCD In a further embodiment, the preferred route of administration for the second component (AL) is intramuscular. NCD A preferred route of administration for the second component (AL) is intramuscularly into the deltoid or gluteal muscles. In a further embodiment, the second component (AL) is NCD The preferred route of administration for is intramuscularly into the deltoid muscle.

[0085] In one embodiment, the preferred route of administration for the third component (aripiprazole lauroxyl) is intramuscular. In a further embodiment, the preferred route of administration for the third component (aripiprazole lauroxyl) is intramuscular into the deltoid or gluteal muscles.

[0086] In one embodiment, the route of administration for the first component (aripiprazole) is oral and the route of administration for the second component (AL NCD ) is intramuscular and the route of administration for the third ingredient (aripiprazole lauroxyl) is intramuscular.

[0087] Suitable compositions and dosage forms include, for example, tablets, capsules, caplets, pills, gel caps, troches, dispersions, suspensions, solutions, syrups, granules, beads, transdermal patches, gels, powders, pellets, magmas, lozenges, creams, pastes, plasters, lotions, discs, suppositories, liquid sprays for nasal or oral administration, dry powder or aerosolized formulations for inhalation, compositions and formulations for intravesical administration, etc. It should be understood that the formulations and compositions that would be useful in the present invention are not limited to the specific formulations and compositions described herein.

[0088] For oral application, tablets, dragees, liquids, drops, suppositories or capsules, caplets and gelcaps are particularly suitable. Compositions intended for oral use can be prepared according to any method known in the art, and such compositions may contain one or more agents selected from the group consisting of inert, non-toxic pharmaceutical excipients suitable for the manufacture of tablets. Such excipients include, for example, inert diluents such as lactose; granulating and disintegrating agents such as cornstarch; binding agents such as starch; and lubricants such as magnesium stearate. Tablets may be uncoated or may be coated by known techniques for elegance or to delay the release of the active ingredient. Formulations for oral use may also be provided as hard gelatin capsules in which the active ingredient is mixed with an inert diluent.

[0089] For parenteral administration, the disclosed compounds can be formulated for injection or infusion, e.g., intravenous, intramuscular or subcutaneous injection or infusion, or administration by bolus or continuous infusion. Suspensions, solutions or emulsions in oily or aqueous vehicles, optionally containing other formulatory agents such as suspending, stabilizing or dispersing agents, can be used.

[0090] Those skilled in the art will recognize or be able to ascertain, using no more than routine experimentation, numerous equivalents to the specific procedures, embodiments, claims and examples described herein. Such equivalents are considered to be within the scope of the present invention and were covered by the appended claims. For example, modifications of reaction conditions, including but not limited to reaction times, reaction sizes / volumes, and experimental reagents, such as solvents, catalysts, pressure, atmospheric conditions, such as nitrogen atmosphere, and reducing / oxidizing agents, using art-recognized substitutions and no more than routine experimentation, should be understood to be within the scope of this application.

[0091] Whenever values ​​and ranges are provided herein, it should be understood that all values ​​and ranges encompassed within these values ​​and ranges are intended to be encompassed within the scope of the present invention. Moreover, all values ​​falling within these ranges, as well as the upper or lower limits of the range of values, are also contemplated by the present application. The following examples further illustrate aspects of the present invention. However, they are in no way a limitation of the teachings or disclosure of the present invention as presented. EXAMPLES

[0092] Example 1 Study Design and Treatment Regimens The study was conducted in accordance with the Declaration of Helsinki and Good Clinical Practice guidelines agreed upon by the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use in 1997. The study protocol, amendments, and informed consent forms were approved by independent ethical committees / institutional review boards at each site. All patients provided written informed consent prior to study entry.

[0093] As used herein, AL NCD refers to a pharmaceutical composition comprising about 26% by mass of aripiprazole lauroxyl particles, about 1.53% by mass of polysorbate 20, about 0.76% by mass of sodium citrate, 0.31% by mass of sodium chloride, and an aqueous buffer solution, wherein the aripiprazole lauroxyl particles have a volume-based particle distribution diameter (Dv50) of about 175 nm to about 350 nm.

[0094] This was a Phase 1, double-blind, placebo-controlled study to evaluate the PK, safety, and tolerability of two initiation regimens for initiating treatment with AL in patients with schizophrenia. The first regimen consisted of a single 662 mg AL combined with a single dose of 30 mg oral aripiprazole. NCDThe first regimen was a daily start-up regimen that included dosing with AL441 or 882 mg of AL441 per day. The second regimen was a 21-day oral start-up regimen based on the regimen used in the pivotal 12-week Phase 3 study of AL. This Phase 1 study compared the daily start-up regimen with the 21-day start-up regimen (starting with AL441 or 882 mg of AL441 per day with dosing with oral aripiprazole for 21 days).

[0095] The study duration was approximately 6 months and consisted of screening, inpatient administration, outpatient, and follow-up periods (Figure 1). Patients in the prospective study were evaluated during a pre-administration 30-day screening period during which aripiprazole-naive patients received a 5 mg test dose 30 and 29 days prior to study entry. A total of 160 patients were planned to be enrolled and randomized 1:1:1:1 to one of four treatment arms, as follows: a daily start regimen arm (30 mg oral aripiprazole + AL NCD , +AL441 or 882 mg [day 1] followed by 20 days of oral placebo), or a 21-day starting regimen group (15 mg oral aripiprazole + placebo IM, +AL441 or 882 mg [day 1] followed by 20 days of oral aripiprazole 15 mg / day). For all study groups, the order of dosing on day 1 was as follows: first, oral aripiprazole; second, AL441 or 882 mg [day 1] followed by 20 days of oral placebo. NCD or IM injection of placebo (administered within 15 minutes after oral aripiprazole); third, IM injection of AL (AL NCD or placebo IM injection). NCD or placebo was administered as an IM injection into the gluteal muscle. For AL administration, a single 441 mg dose was given in the deltoid muscle or AL NCD (or placebo) was given as a single 882 mg dose in the gluteus muscle contralateral to the injection.

[0096] Patients were admitted as inpatients one day prior to their first scheduled dose and remained as inpatients for the first 15 days. After discharge, patients returned for 17 outpatient follow-up assessments, with the final assessment on day 141. PK samples were collected daily on days 1-15, every other day on days 17-25, weekly on days 28 and 31, 35-85, and on days 113 and 114. On days 1 and 21, samples were collected at multiple time points (detailed in Example 3).

[0097] Example 2 Study population Eligible patients were adults aged 18-65 years with a diagnosis of chronic schizophrenia or schizoaffective disorder according to the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) and a documented history of tolerability to aripiprazole or demonstrated tolerability to the test dose during screening. The study required patients to be clinically stable, as defined as no hospitalization for acute psychiatric exacerbations within 3 months prior to screening, and a Clinical Global Impression-Severity (CGI-S) score of 3 or less at screening and study entry. Patients were on a stable oral antipsychotic medication regimen (excluding aripiprazole and clozapine) for at least 2 months prior to screening, without any medication changes between screening and randomization.

[0098] Key exclusion criteria included patients who had received oral aripiprazole within 28 days prior to randomization or other LAI antipsychotics within 3 months prior to admission, and patients currently participating or having participated within 3 months prior to admission in a clinical trial involving an investigational drug. Patients who had received AL or IM depot aripiprazole within 6 months prior to admission were also excluded. History of major psychopathology other than schizophrenia or schizoaffective disorder at screening or admission, CYP2D6 poor metabolizer status, or positive tests for illicit drug use were not allowed.

[0099] Example 3 Test evaluation Blood samples for liquid chromatography-tandem mass spectrometry were collected to analyze aripiprazole plasma concentrations. Samples were collected on Day 1 within 1 hour pre-dose and 1, 2, 3, 4, 5, 6, and 8 hours (±15 minutes) post-dose. On Days 2-20 after initiation, a single sample was collected before oral aripiprazole (or oral placebo) administration. As on Day 1, additional samples were collected 1, 2, 3, 4, 5, 6, and 8 hours (±15 minutes) post-dose after collection of the pre-dose sample on Day 21. On Days 23-85, a single sample was collected within ±2 hours of the time of oral dosing on Day 1, or as close to that time frame as possible. On Days 113 and 141, a single PK sample was collected.

[0100] All safety analyses were performed using observational data from the safety population, and measures included adverse events (AEs), vital sign measures, weight, laboratory test results, ECG findings, Columbia-Suicide Severity Rating Scale (C-SSRS) response, movement disorder measures, CGI-S response, and injection site assessments.

[0101] AEs were assessed daily on days 1-15, every other day on days 17-25, once a week on days 28 and 31, 35-85, and on days 113 and 114. Injection site evaluations were performed daily on days 1-15, every other day on days 17-25, and on day 28. The injection sites and surrounding areas were examined for each injection (AL NCD or placebo injection and AL sites separately). Observed injection site reactions were followed until resolution.

[0102] Example 4 statistical analysis The study population consisted of a safety population (all patients who received study drug) and a PK population (all patients who received study drug and had one or more measurable concentrations of aripiprazole).

[0103] AUC calculated from days 0 to 28 (AUC 0~28) were calculated using the linear trapezoidal method and included only oral pre-dose concentrations collected on days 1 and 21. Actual time since dosing was used to estimate individual parameters. In addition, the proportion of patients who achieved known therapeutic concentrations of aripiprazole within 4 days after starting AL was calculated. The daily initiation regimen was designed to achieve therapeutic concentrations within 4 days, consistent with the oral initiation regimen indicated in the AL prescribing information. Aripiprazole concentrations and AUC 0~28 were summarized descriptively.

[0104] A post-hoc evaluation was performed comparing aripiprazole concentration results from this study with concentrations observed from a 12-week Phase 3 efficacy study (using a 21-day oral regimen).

[0105] Safety and tolerability parameters were estimated in the safety population. Descriptive statistics were used to determine the association between the first dose of study drug (AL NCD and new-emerging or worsening AEs during treatment with a single 30 mg oral aripiprazole dose or placebo injection and 21 days of oral aripiprazole 15 mg, +AL441, or 882 mg) were summarized.

[0106] Example 5 Patient and baseline characteristics In total, 161 patients were enrolled, received one of the starting regimens, and were included in the PK and safety populations (Table 1). Patients were randomized to receive either the 1-day starting regimen (n=80) or the 21-day starting regimen (n=81) with an AL starting dose of 441 or 882 mg. In total, 39 patients were enrolled in the AL 441 mg / day starting group and 41 patients were enrolled in the AL 881 mg / day starting group. Of the patients enrolled in the 21-day starting regimen group, 40 patients were assigned to the AL 441 mg / 21-day starting group and 41 patients were assigned to the AL 882 mg / 21-day starting group.

[0107] A total of 133 (82.6%) patients completed the study. Among the 28 patients (17.4%) who did not complete the study, reasons for discontinuation included loss to follow-up and patient withdrawal (n=10, 6.2%, respectively), AEs (n=5, 3.1%), protocol deviations (n=2, 1.2%), and noncompliance with medication (n=1, 0.6%).

[0108] Patient demographics are summarized in Table 1. The mean age and BMI of the patients were 44 years and 29.5 kg / m2, respectively. 2 Overall, the treatment groups were generally well balanced with regard to demographics and baseline characteristics.

[0109] [Table 1]

[0110] Example 6 Pharmacokinetic results Results from the 1-day start regimen group showed mean plasma aripiprazole concentrations and exposures within the first month comparable to the 21-day start regimen group (Figure 2). In the first 24 hours after initiation, higher aripiprazole concentrations were observed in the 1-day start regimen group compared to the 21-day start regimen group due to the higher dose of aripiprazole administered on day 1 with the 1-day start regimen (30 mg vs. 15 mg). Since the 1-day start regimen was designed to replicate the 21-day start regimen in achieving therapeutic aripiprazole concentrations within 4 days after the first AL administration, plasma concentrations on day 4 after initiation were of particular interest. As shown in Figure 2, the 1-day start regimen results in the achievement of therapeutic levels of aripiprazole similar to the 21-day start regimen within 4 days.

[0111] As can be seen in FIG. 2, the mean concentrations appear visibly lower in the 1-day start regimen group than in the 21-day start regimen group from approximately day 4 to day 14, and the error bars around the plasma concentration means show a perfect overlap of the range of concentrations across treatment groups. As expected for the 21-day oral start regimen group, aripiprazole concentrations declined after day 21 upon discontinuation of active oral medication. In contrast, for the 1-day start regimen group, plasma aripiprazole concentrations did not show any meaningful change until after day 30 post-start, when the mean aripiprazole concentrations began to decline (FIG. 6A, FIG. 6B, FIG. 6C). This indicates that the 1-day start regimen provides a continuous coverage over a longer period of time compared to the 21-day start regimen.

[0112] AUC 0~28 Values ​​were comparable across the four treatment groups (Figure 3, Table 2). Comparison of the range of values ​​across groups indicated similar exposure within the first month of treatment regardless of the initiation regimen used.

[0113] [Table 2]

[0114] Post-hoc comparison of aripiprazole concentrations from this study to those observed in the 12-week Phase 3 efficacy study demonstrated consistent and reproducible results across studies using 21-day oral aripiprazole initiation regimens (Figure 4). Importantly, the 1-day initiation regimen from this study resulted in aripiprazole concentrations that were within the range of concentrations observed with 21-day oral aripiprazole supplementation used in the Phase 3 efficacy study (Figure 5).

[0115] Example 7 Adverse events Small and similar mean changes (≦0.1) in CGI-S scores from baseline (score 3.0; mild) were seen in each starting regimen group at all time points throughout the study, indicating no change in disease severity. All patients had a score of 0 (no suicidal behavior or ideation) on the C-SSRS throughout the study.

[0116] In the AL 441 mg / day and AL 882 mg / day initiation groups, 26 patients (66.7%) and 28 patients (68.3%) experienced AEs, respectively, and 24 patients (60.0%) in the AL 441 mg / 21 day initiation group and 28 patients (68.3%) in the AL 882 mg / 21 day initiation group experienced AEs (Table 4). The majority of AEs were mild or moderate in intensity. Serious AEs were reported in six patients, three in the 1-day initiation regimen (traffic accident, status epilepticus, psychosis, and schizoaffective disorder) and three in the 21-day initiation regimen groups (upper gastrointestinal bleeding, cellulitis, traffic accident, and accidental overdose). Of these, schizoaffective disorder and status epilepticus were assessed as "probably related" to treatment. A total of five patients discontinued the study due to AEs: three in the 1-day start regimen (traffic accident, extrapyramidal disorder, and status epilepticus) and two in the 21-day start regimen (traffic accident and nausea). One patient in the 21-day start regimen group died as a result of injuries sustained in a traffic accident (not believed to be related to study drug). Overall, the most common AEs reported were injection site pain (23.0%), headache (9.9%), weight gain (7.5%), insomnia (6.2%), dyspepsia (5.6%), and anxiety (5.0%). All other AEs occurred with an overall incidence of less than 5%.

[0117] ISR and akathisia are considered AEs of particular interest because they have been associated with the onset of AL in previous studies (see, e.g., Meltzer, HY et al., J. Clin. Psychiatry, 2015, 76(8), 1085-1090; McEvoy, JP et al., J. Clin. Psychiatry, 2017, 78(8), 1103-1109).

[0118] Overall, A.L. NCD All injection site reactions (ISRs) associated with placebo IM, AL 441 mg, and AL 882 mg injections were mild to moderate in severity.

[0119] In total, 14 of 80 (17.5%) patients had AL compared with 5 of 81 (6.2%) patients who received a placebo injection. NCD 10 (3.1%) of 81 patients who received placebo IM injections experienced an ISR related to the injection (Table 3). The most common explanation for ISR was injection site pain, which occurred in 4 of 81 (4.9%) patients who received placebo IM injections compared with 10 (3.1%) of 81 patients who received placebo IM injections. NCD AL was reported in 12 of 80 (15.0%) patients who received an injection, whether the patient received an AL injection in the deltoid (AL 441 mg; n = 7, 17.5%) or the contralateral gluteal muscle (AL 882 mg; n = 5, 12.5%). NCD The incidence of injection site pain associated with

[0120] In total, 18 of 79 (22.8%) patients receiving AL 441 mg in the deltoid and 15 of 82 (18.3%) patients receiving AL 882 mg in the gluteal muscle experienced an ISR (Table 2). The most common explanation for ISR was injection site pain, which was reported in 16 of 79 (20.3%) patients receiving AL 441 mg and 15 of 82 (18.3%) patients receiving AL 882 mg, respectively.

[0121] [Table 3]

[0122] The overall incidence of akathisia was low in all groups, with an overall AE rate of 6 of 140 patients (3.7%). Among patients treated with the 1-day start regimen, akathisia was reported in 4 of 80 patients (5%). Two of these patients reported mild akathisia during the first week of treatment, one of the patients rated as having mild akathisia was probably not related to the study drug, and the other rated as having mild akathisia was definitely related to the study drug. Two other patients experienced akathisia during the third week of treatment; one of these was rated as mild and the other as moderate in severity, rated as "probably related" and "definitely related" to treatment, respectively. Among patients treated with the 21-day oral regimen, mild akathisia was reported in 2 of 81 patients (2.5%). One experienced a first akathisia event in the second week and the other in the third week of treatment, rated as "possibly" and "probably" related to treatment, respectively.

[0123] [Table 4]

[0124] Example 8 Population Pharmacokinetic (PK) Model Three of them are being developed as formulations and starting regimens for AL (Hard et al. CNS Drugs, submitted; Wehr et al. in preparation). NCDA PopPK model for aripiprazole was developed using data from four Phase 1 studies that are important for the feasibility of using ALK9072-1, ALK9072-B102, and ALK9072-B103. These studies (ALK9072-1, ALK9072-B102, and ALK9072-B103) are referred to herein as Study 1, Study 2, and Study 3, respectively. The fourth study was a pre-Phase 1 study of AL administered alone (ALKS9072-A105, referred to as Study 4). All studies enrolled adult patients with schizophrenia or schizoaffective disorder who were stable on first-line antipsychotic medication (except aripiprazole); all patients with sufficient data on dosing, actual sampling times, and aripiprazole concentration data were included in the PopPK analysis.

[0125] The mean patient age was 45.2 ± 10.8 years; 73% were male; 78% were black or African American, and the mean body weight was 89.1 ± 17.9 kg (Table 1). A total of 12,768 plasma aripiprazole concentrations (including 351 [3%] records below the lower limit of quantification) from 343 patients were included in the analysis. The dataset consisted of 2,536 administration records (1,742 oral aripiprazole, 626 AL, and 168 AL). NCD The drug contained the following:

[0126] Models were developed using nonlinear mixed-effects modeling with the NONMEM® program version 7.3.0, and PDx-Pop version 5.1 was used as the NONMEM interface (full details of the development of the PopPK models are provided in the supplementary material). NCD The doses were 75, 150, 300, 450, 600, and 724 mg of aripiprazole equivalents (110, 221, 441, 662, 882, and 1064 mg of aripiprazole equivalents, respectively). NCD A previously developed model for AL that includes an oral input function served as a starting point for model development, which was used to calculate the AL dose. NCD We have expanded it to include input functions for AL NCDA base model was first selected that adequately described the time course of aripiprazole plasma concentrations in Study 1, accounting for IM absorption of and conversion to aripiprazole. The initial base model was then expanded following the inclusion of final data from Study 3 (completed before Study 2) and used to re-estimate model parameters. Once final data from Study 2 were received, the model was updated, existing parameters were re-estimated, and a full covariate analysis was performed.

[0127] Covariates available for evaluation included: age at baseline (years), and body weight (WT) at baseline (kg) for continuous covariates, and injection site (gluteal or deltoid), formulation, CYP2D6 genotype, ethnicity, sex, and race for categorical covariates. Body weight, formulation, and CYP2D6 genotype were evaluated as part of the initial base model development in Study 1. After receiving data from Study 3 and Study 2, the covariate models were re-evaluated. The effect of body weight on the clearance (CL) and volume (V) terms was incorporated using fixed allometric exponents of 0.75 and 1, respectively, and rescaled to 70 kg (7). Background removal was performed to evaluate the relative impact of each covariate by adding all relevant covariates to the model (full model) and removing the background from the full model on an individual basis until a final model was identified.

[0128] Data from study 4 were then added (to include data from AL-only administration) and the parameters of the final model were updated based on data from all four studies. Models were assessed using goodness-of-fit analysis and by generating predictor-corrected visual posterior predictive performance scores (pcVPCs).

[0129] Initial simulations for oral aripiprazole administered at 15 mg for 21 days suggested that the final PopPK model may overpredict exposure to aripiprazole with multiple oral doses. Investigations showed that variability in aripiprazole concentrations associated with the 21-day oral regimen in Study 2 was high but consistent with that previously observed in a pivotal Phase 3 study, and that there appeared to be a subpopulation of individuals whose profile reflected lower exposure following multiple oral doses of aripiprazole. A mixture model was evaluated for oral aripiprazole to see if the subpopulations could be formally identified.

[0130] Monte Carlo simulations were performed using Pharsight Trial Simulator version 2.2.2 (Certara USA, Inc, Princeton, NJ) with the final PopPK model and mixture model appropriate for oral aripiprazole. A total of 500 individual concentration-time profiles were simulated for each scenario without incorporating residuals from the final PopPK model. Simulations were performed for: To evaluate the effect on aripiprazole concentrations when a single-day start regimen is coadministered with AL on the same day compared with administering AL several days later. NCD and a single 30 mg dose of oral aripiprazole) were simulated for all five approved AL dose strengths and dosing intervals (441, 662, and 882 mg q4w, 882 mg q6w, and 1064 mg q8w). In addition, AL (all approved doses) was simulated to be administered 1, 3, 7, 10, or 14 days after the daily initiation regimen. AL treatment was continued for the given dosing intervals from the time of the first dose. AL as an alternative to the current recommendation of daily oral aripiprazole supplementation to re-establish therapeutic aripiprazole plasma concentrations after a missed dose of AL NCD To evaluate the use of the "re-establishment" regimen (AL NCD or 1-day starting regimen) was started at the same time as the subsequent dose. ALNCD Simulations were performed to predict likely aripiprazole concentration-time profiles following a multiple dosing scenario to determine the likely effect of subsequent AL administration, with and without supplementation with aripiprazole. Five dosing regimens were simulated at steady state (441, 662, and 882 mg q4wk, 882 mg q6wk, and 1064 mg q8wk). Fixed doses of AL were administered alone or in combination with 7 days of oral aripiprazole or AL. NCD was administered 1, 2, 3, 4 or 6 weeks later.

[0131] AL NCD A base model was parameterized to describe aripiprazole after a single IM dose of , a single IM dose of AL, and oral aripiprazole doses from Studies 1, 2, and 3. The model contained central and peripheral compartments for aripiprazole and 16 structural parameters.

[0132] Previous PopPK models for aripiprazole following administration of AL and oral aripiprazole included covariate terms describing the increase in VC / F for body weight alongside the decrease in CL / F for CYP2D6 poor metabolizers (power model fixed with allometric exponent of 1.0). However, the present data set did not contain any poor metabolizers; as a result, CYP2D6 phenotype was not evaluated for this data set. Based on eta vs covariate plots, WT was tested with VC / F for AL (power model fixed with allometric exponent of 1.0), CL / F, D, and ALAG. Additionally, age vs CL / F, AL vs FRAC. NCD Injection site and potential effect of AL injection site on D and ALAG. For injection site effects, parameter changes after administration in the deltoid were estimated with the buttock used as reference. Ethnicity was not included in the covariate analysis due to the limited number of Hispanic or Latino patients (5%). Race and sex were not included due to no clear differences in model parameter estimates.

[0133] The base model was updated to include eight covariate effects to form a full covariate model. Parameters related to AL administration were consistent with previous analyses. Of the eight effects in the model, two of the estimated injection site effects contained null values ​​(AL in FRAC). NCD The following covariates were removed: age in CL / F, WT in ALAG, WT in input D, AL injection site in D, and WT in CL / F. Removal of age in CL / F, WT in ALAG, WT in input D, AL injection site in D, and WT in CL / F resulted in small changes in OFV. Thus, the model resulting from backward elimination contained only the single covariate effect of VC / F, which was increased by WT.

[0134] The final PopPK model was developed by adding data from Study 4 (to include data from AL dosing only). A two-compartment model with central and peripheral compartments for aripiprazole was used, with the conversion of IM AL to aripiprazole described by a zero-order process with an estimated conversion of D and a first-order absorption of aripiprazole from the dosing depot defined as 1 / D1. In addition, there was an ALAG from the IM AL depot to the appearance of aripiprazole in the central compartment. A first-order process described the absorption of aripiprazole after oral dosing and the transport between the central and peripheral compartments, all as in the previous model. However, the previous model was updated here to include a zero-order process for IM AL NCD IM AL NCD A double Weibull function was included to describe the conversion to aripiprazole in plasma after dosing.

[0135] Goodness-of-fit analysis demonstrated that the observed concentrations were well described by the model predictions with no obvious study, route of administration, or observed dose-effect bias. pcVPC plots were generated by study and regimen within Study 2 and Study 4. pcVPC showed that the majority of observed concentrations were contained within the final PopPK model predicted 90% PI within and across studies for Study 1 and Study 3, and by regimen within Study 2 and Study 4. The final PopPK model was deemed sufficient to perform simulations evaluating various dosing and administration scenarios.

[0136] The mixed model was applied to patients who received the 21-day start regimen in Study 2 to account for a subgroup of patients with lower exposure after multiple doses of oral aripiprazole over the first 28 days of dosing. The mixed model estimated that there was a subpopulation of patients in the 21-day start regimen arm of Study 2 (37.4%; 95% CI 22.3% to 55.4%) who had a 44.6% lower FPO (95% CI: 40.9 to 48.3%). These estimates of the reduction in FPO, n, from the mixed model and the proportion of patients in the subpopulation were applied to the final PopPK model in a formal simulation.

[0137] Observed results from Study 2 demonstrated that coadministration of a daily start regimen with AL 441 mg and 882 mg achieved therapeutic concentrations of aripiprazole within 4 days similar to those achieved with a 21-day start regimen administered in conjunction with the first AL dose (Hard et al. CNS Drugs, submitted; Aristada USPI, 2017). Simulations were performed for all approved AL dose strengths and dosing intervals (441, 662, and 882 mg q4w, 882 mg q6w, and 1064 mg q8w) with the daily start regimen given on the same day as the AL start dose. In all cases, same-day administration of the AL and the daily start regimen was predicted to provide rapid and sustained levels of aripiprazole within 4 days of treatment initiation for all regimens. Aripiprazole concentrations remained comparable for all five AL doses over the first 2 weeks. After the first 2 weeks, AL dose-related differences in aripiprazole concentrations begin to become evident as expected.

[0138] Simulations were performed to evaluate whether the daily start regimen could be administered prior to and on a different day from the first dose of AL. As before, all five AL dosing regimens were simulated (441, 662 and 882 mg q4wk, 882 mg q6wk, and 1064 mg q8wk). For all scenarios, the daily start regimen was administered on day 1, and the first AL dose was given on the same day as the daily start regimen, or 1, 3, 7, 10 or 14 days after the daily start regimen (i.e., AL was started on days 2, 4, 8, 11 and 15). The AL was then continued at the given dosing interval from the previous time point.

[0139] Delaying the initiation of AL relative to the start of the daily start regimen reduced the median aripiprazole concentrations over the first two dosing intervals of AL compared with simultaneous treatment initiation, with the magnitude of this effect determined by the length of the delay. When AL was administered 1 or 3 days after the daily start regimen, negligible decreases in aripiprazole concentrations were observed at the end of the AL dosing interval (Ct) compared with when AL was administered on the same day as the daily start regimen. Delays in the first AL injection of 1 week or more from the daily start regimen were also evaluated. When AL was administered 7, 10, or 14 days later, Ct was significantly lower. T The median values ​​were 8%-16%, 9%-23%, and 14%-31% lower, respectively, compared with administration on the same day as the 1-day start regimen. T was reduced by 23% or less compared to when both were administered on day 1.

[0140] AL as an alternative to the current recommendation of using oral replacement for 7 days after a missed AL injection NCD Simulations were performed to evaluate the use of AL. At steady state, all approved AL dosing regimens were simulated (441, 662, and 882 mg q4wk, 882 mg q6wk, and 1064 mg q8wk). Fixed doses of AL were administered alone, with 7 days of supplemental oral aripiprazole, or as single-injection AL. NCD (without a single oral aripiprazole dose) 1, 2, 3, 4 or 6 weeks later (depending on the dosing regimen).

[0141] Simulated median aripiprazole concentrations for selected later dosing scenarios for five approved AL regimens (with and without re-establishment regimens) currently require 7 days of oral aripiprazole supplementation with a later dose to restore therapeutic aripiprazole concentrations (Aristada US PI 2017). In these simulations, later dosing of AL resulted in lower predicted median concentrations after later dosing than if AL dosing was not delayed. AL NCDWhen used in combination with AL after a missed dose, aripiprazole concentrations increased to achieve similar C achieved with 7 days of oral aripiprazole. max values ​​and spans the maximum concentration range associated with the approved dosing range for AL.

[0142] If no AL dose was missed, aripiprazole C max The C-values ​​for AL ranged from 153 to 310 ng / mL. Both reestablishment regimens were max C in the range comparable to max These simulations demonstrated that missed AL doses were sufficient to restore concentrations to therapeutic levels after 7 days of oral aripiprazole or AL. NCD It is demonstrated that aripiprazole concentrations can be returned to the therapeutic range using

[0143] Therefore, A.L. NCD is a suitable alternative to daily oral aripiprazole replacement to restore aripiprazole concentrations after a missed AL dose. Further simulations showed that a longer delay (which requires 21 days of oral aripiprazole replacement according to the current prescribing information [Aristada PI, 2017]) was sufficient to restore aripiprazole concentrations after a missed AL dose. NCD It was shown that resumption of AL treatment with a combination of 30 mg oral aripiprazole was necessary.

[0144] The disclosed subject matter is not intended to be limited in scope by the specific embodiments and examples described herein. Indeed, various modifications of the present disclosure in addition to those described will become apparent to those skilled in the art from the description and accompanying drawings. Such modifications are intended to fall within the scope of the appended claims.

[0145] All references (e.g., publications or patents or patent applications) cited herein are incorporated by reference in their entirety for all purposes to the same extent as if each individual reference (e.g., publication or patent or patent application) was specifically and individually indicated to be incorporated by reference in its entirety for all purposes. Other embodiments are within the scope of the following claims.

Claims

1. For use in a method for treating schizophrenia, The first component contains approximately 5 to 50 mg of aripiprazole. A composition comprising: A composition, wherein the method comprises oral administration of the first component, intramuscular administration of a second component comprising about 629-695 mg of AL NCD, and intramuscular administration of a third component comprising a therapeutically effective amount of aripiprazole lauroxyl.

2. For use in a method for treating schizophrenia. a second component comprising about 629-695 mg of AL NCD; and / or a third ingredient comprising a therapeutically effective amount of aripiprazole lauroxyl A composition comprising: A composition, wherein the method comprises oral administration of a first component comprising about 5-50 mg of aripiprazole, intramuscular administration of the second component, and intramuscular administration of the third component.

3. The composition described in claim 2, comprising the second component and the third component.

4. AL NCD 4. The composition of claim 1, comprising a population of particles of polysorbate 20, sodium citrate, sodium chloride, an aqueous buffer and aripiprazole lauroxyl.

5. The composition of any one of claims 1 to 4, wherein the population of particles of aripiprazole lauroxyl has a volume-based particle distribution diameter (Dv50) between about 175 nm and about 350 nm.

6. AL NCD 6. The composition of claim 1, wherein the ratio of polysorbate 20 to particles is 17:

1.

7. 7. The composition of claim 1, wherein the first component is administered in a dosage of about 30 mg.

8. 7. The composition of claim 1, wherein the first component is administered in a dosage of about 15 mg.

9. 9. The composition of any one of claims 1 to 8, wherein the second component is administered in a dosage of about 675 mg of active ingredient.

10. The composition of any one of claims 1 to 9, wherein the third component is administered in a dosage of about 300 to 1500 mg.

11. 11. The composition of any one of claims 1 to 10, wherein the third component is administered in a dosage of 441, 662, 882 or 1064 mg.

12. The method of any one of claims 1 to 11, wherein all components of the method are administered substantially simultaneously.

13. 12. The composition of any one of claims 1 to 11, wherein the method comprises a regimen in which the first, second and third components are administered substantially simultaneously, and the first component is not administered again within 21 days of the first administration.

14. 12. The composition of any one of claims 1 to 11, wherein the method comprises a regimen in which the first, second and third components are administered substantially simultaneously, with the second administration of the components occurring no later than 21 days after the initial treatment.

15. 13. The composition of any one of claims 1 to 12, wherein the method comprises a regimen in which the first, second and third components are administered substantially simultaneously, followed by a second treatment comprising administering only the third component.

16. The method of claim 13, wherein the second treatment is administered no later than 21 days after the first treatment.

17. 15. The composition of any one of claims 1 to 14, wherein the first component is administered only once during the treatment period.

18. 16. The composition of any one of claims 1 to 15, wherein the first component is not administered again within 21 days after the initial treatment.

19. 10. The composition of any one of claims 1 to 9, wherein the method comprises a regimen in which the first component is administered only on the first and / or second days of treatment, the second component is administered only on the first day of treatment, and the third component is administered only once within the first 10 days of treatment.

20. 20. The composition of claim 17, wherein the regimen further comprises a second administration of only the third component.

21. 18. The composition of claim 17, wherein the third component is administered on day 1 of treatment.

22. 18. The composition of claim 17, wherein the third component is administered on the second day of treatment.

23. The composition of claim 17, wherein the third component is administered 7 to 10 days after the initiation of the treatment regimen.

24. 22. The composition of any one of claims 17 to 21, wherein the first component is administered only on days 1 and 2 of treatment.

25. 22. The composition of any one of claims 17 to 21, wherein the first component is administered only on the first day of treatment.

26. 26. The composition of any one of claims 1 to 25, wherein the second component is administered intramuscularly in the deltoid or gluteus muscle.

27. 27. The composition of any one of claims 1 to 26, wherein the second component is administered intramuscularly in the deltoid muscle.

28. 28. The composition of any one of claims 1 to 27, wherein the third component is administered intramuscularly to the deltoid or gluteal muscle.

Images