Dosing regimens associated with extended-release paliperidone injectable formulations

Abstract

The present invention provides a method of treating a patient with a long-acting injectable paliperidone palmitate formulation.

Description

[Technical Field]

[0001] (CROSS-REFERENCE TO RELATED APPLICATIONS) This application claims the benefit of U.S. Provisional Patent Application No. 63 / 119,382, filed November 30, 2020, the disclosure of which is incorporated herein by reference.

[0002] FIELD OF THE INVENTION The present invention relates to a method of treating psychiatric patients in need of treatment with a long-acting injectable paliperidone palmitate formulation.

[0003] BACKGROUND OF THE INVENTION Antipsychotic drug therapy is the mainstay of treatment for schizophrenia, schizoaffective disorder, and schizophreniform disorders. Antipsychotic drugs were first introduced in the mid-1950s. These typical or first-generation drugs are usually effective in controlling the positive symptoms of schizophrenia, but are less effective in alleviating the negative symptoms or cognitive impairment associated with the disease. Atypical antipsychotics or second-generation drugs, represented by risperidone and olanzapine, were developed in the 1990s and are generally characterized by their effectiveness against both the positive and negative symptoms associated with schizophrenia.

[0004] Paliperidone palmitate is the palmitate ester of paliperidone (9-hydroxy-risperidone), a monoaminergic antagonist that exhibits the dopamine D2 and serotonin (5-hydroxytryptamine type 2A) antagonism characteristic of second-generation atypical antipsychotics. Paliperidone (9-OH risperidone) is the primary active metabolite of risperidone. Extended-release (ER) osmotic controlled-release oral delivery (OROS) paliperidone is marketed in the United States as a tablet for the treatment and maintenance of schizophrenia.

[0005] Paliperidone palmitate is being developed as a long-acting, intramuscular (i.m.) injectable aqueous nanosuspension for the treatment of schizophrenia and other related disorders that are typically treated with antipsychotics. Due to very low water solubility, paliperidone esters such as paliperidone palmitate dissolve slowly after i.m. injection before being hydrolyzed to paliperidone and becoming available to the systemic circulation.

[0006] Many patients with psychiatric disorders achieve symptom stability with available oral antipsychotics. However, it is estimated that up to 75% have difficulty following daily oral treatment regimens, i.e., have adherence problems. Adherence problems often result in worsening symptoms, suboptimal treatment responses, frequent relapses and rehospitalizations, and failure to benefit from rehabilitation and psychosocial therapies. A once-monthly paliperidone palmitate injection has been developed to provide sustained plasma concentrations of paliperidone, which can greatly enhance administration compliance. Paliperidone palmitate formulated as an aqueous nanosuspension is described in U.S. Patent Nos. 6,077,843 and 6,555,544, each of which is incorporated herein by reference. Additionally, dosing regimens of paliperidone palmitate for treating patients are disclosed in U.S. Patent Nos. 9,439,906 and 10,143,693, each of which is incorporated herein by reference.

[0007] Paliperidone palmitate is an atypical antipsychotic administered by intramuscular injection. The prototype formulation of paliperidone palmitate is a once-monthly antipsychotic approved in many countries for the treatment of schizophrenia in adults. The acute and sustained efficacy and tolerability profile of once-monthly paliperidone palmitate have been demonstrated in clinical trials totaling over 3,800 patients. Patients who initially responded to paliperidone palmitate for acute symptom exacerbations experienced an approximately fourfold reduction in relapse risk when continued treatment with once-monthly paliperidone palmitate compared with patients randomized to placebo. A later-developed 3-month formulation offered a substantially longer dosing interval, with injections administered once every 3 months. This sustained dosing interval is expected to reduce the opportunity for nonadherence compared with previously available long-acting injectable formulations, thereby reducing the risk of relapse as a result of subtherapeutic plasma concentrations and their associated negative consequences in patients with schizophrenia.

[0008] Paliperidone is currently available in three formulations: an oral extended-release formulation (also referred to as INVEGA® extended-release (ER) tablets and INVEGA® prolonged-release (PR) tablets) and two long-acting injectable (LAI) formulations (paliperidone palmitate 1-month injection (INVEGA SUSTENNA® or XEPLION®) and paliperidone palmitate 3-month injection (INVEGA TRINZA® or TREVICTA®). As disclosed herein, to further improve compliance and convenience, a separate paliperidone palmitate product intended for administration once every 6 months (paliperidone palmitate 6-month injection) is being developed.

[0009] Patients who do not take their medication regularly can suffer many consequences, most notably relapse of schizophrenia. For oral antipsychotics, a one-day gap in dosing can double the risk of rehospitalization. This typically results in worsening psychiatric comorbidities, loss of employment, interrupted education, and impaired family relationships. Biological consequences include loss of synaptic plasticity in neurons, particularly in the frontal lobe. Functional schizophrenia relapse is associated with pruning at the level of synaptic neuronal junctions. Overall, this can be measured radiologically by widespread shrinkage of the brain's gray matter, accompanied by enlargement of the ventricles. These changes can be seen on CT / MRI scans of the brain. With each subsequent relapse, further progressive changes to the brain are typically observed. Currently, there is no known cure for schizophrenia, and the only proven way to treat this disease is through long-term administration of antipsychotic medications along with social and behavioral interventions. The strongest predictor of schizophrenia relapse is antipsychotic medication adherence.

[0010] Paliperidone palmitate products, intended to be given once every six months, present a challenge for patients remembering to come in for treatment at exactly six months. This is exacerbated by the fact that the length of a month varies between 28 and 31 days. Because injections are intended to be given by a healthcare professional and not self-administered, allowing patients the flexibility to schedule clinic visits and receive injections is an important consideration. Most other antipsychotic regimens (oral and LAI) are typically given over a monthly cycle, with patients returning to the clinic to either refill their prescription or receive injections. The six-month dosing interval presents unique challenges for ensuring compliance.

[0011] Patients may also skip doses of the drug, resulting in the need to restart the dosing regimen for patients who have missed their regularly scheduled dose.

[0012] Moreover, weight gain is a very common phenomenon in the treatment of patients requiring antipsychotics. During long-term treatment with antipsychotics in patients with schizophrenia or schizoaffective disorder or any other psychotic disorder, obesity and other cardiovascular risk factors increase, almost adversely affecting the patient's long-term morbidity and even mortality. Patients with severe mental disorders also face stigma and reduced quality of life due to treatment side effects such as weight gain, especially in young patients in the early stages of the disease. Avoiding or stabilizing weight gain can help these patients maintain their social lives, reduce stigma, and improve quality of life. Either the possibility of weight loss or stabilizing current weight would be beneficial for patients who require long-term symptom protection and are treated with risperidone or paliperidone.

[0013] (Summary of the Invention) In one embodiment, the present disclosure provides a method for administering paliperidone palmitate to a patient in need thereof who has been administered a first dose of paliperidone palmitate extended-release injectable suspension, the method comprising administering a second dose of paliperidone palmitate extended-release injectable suspension to the patient's deltoid or gluteal muscle up to two weeks before or up to three weeks after administration of the first dose, at a time six months after administration of the first dose, wherein there is no intervening dose of paliperidone palmitate between the first and second doses.

[0014] In other embodiments, the present disclosure provides a restart dosing regimen for patients who have missed their regularly scheduled drug dose, where the regimen depends on the time elapsed since the patient's last dose. For example, the present disclosure provides a method for administering paliperidone palmitate to a patient in need thereof who has been administered a first dose of a first paliperidone palmitate sustained-release injectable suspension (first suspension), the method comprising administering a restart loading dose of a second paliperidone palmitate sustained-release injectable suspension (second suspension) to the patient's deltoid muscle more than 6 months and 3 weeks after administration of the first dose of the first suspension, but less than 8 months after administration of the first dose of the first suspension, and administering a maintenance dose of the first suspension to the patient's deltoid or gluteal muscle about 1 month (±7 days) after administration of the restart loading dose of the second suspension.

[0015] Another reinstatement regimen involves administering paliperidone palmitate to a patient in need of paliperidone palmitate who has received a first dose of a first paliperidone palmitate extended-release injectable suspension (first suspension), such administration comprising a first reinstatement of 156 mg of paliperidone palmitate in a second paliperidone palmitate extended-release injectable suspension (second suspension) at 8 to 11 months after administration of the first dose of the first suspension. administering a first re-loading dose of the second suspension to the patient's deltoid muscle; administering a second re-loading dose of 156 mg of paliperidone palmitate of the second suspension to the patient's deltoid muscle about 8 days (± 4 days) after administering the first re-loading dose of the second suspension; and administering a maintenance dose of about 1092 mg to about 1560 mg of paliperidone palmitate of the first suspension to the patient's deltoid or gluteal muscle about 1 month (± 7 days) after administering the second re-loading dose of the second suspension.

[0016] Another resumption regimen includes administering paliperidone palmitate to a patient in need of paliperidone palmitate who has received a first dose of a first paliperidone palmitate extended-release injectable suspension (first suspension), comprising: (1) administering a first resumption loading dose of 234 mg of paliperidone palmitate of a second paliperidone palmitate extended-release injectable suspension (second suspension) into the patient's deltoid muscle at a time greater than 11 months after administration of the first dose of the first suspension; (2) administering a second resumption loading dose of 156 mg of paliperidone palmitate of the second suspension into the patient's deltoid muscle about 8 days (±4 days) after administration of the first resumption loading dose of the second suspension; and (3) administering a second resumption loading dose of 39 mg of paliperidone palmitate of the second suspension about 1 month (±7 days) after administration of the second resumption loading dose. (4) about one month (±7 days) after administering the first resumption maintenance dose of the second suspension, administering a second resumption maintenance dose of about 39 mg to about 234 mg of paliperidone palmitate of the second suspension to the patient's deltoid or gluteal muscles; (5) about one month (±7 days) after administering the second resumption maintenance dose of the second suspension, administering a third resumption maintenance dose of about 39 mg to about 234 mg of paliperidone palmitate of the second suspension to the patient's deltoid or gluteal muscles; and (6) about one month (±7 days) after administering the third resumption maintenance dose of the second suspension, administering a maintenance dose of about 1092 mg to about 1560 mg of paliperidone palmitate of the first suspension to the patient's deltoid or gluteal muscles. Additional resumption maintenance doses may be administered before the maintenance dose of the first suspension (e.g., a fourth resumption maintenance dose, a fifth resumption maintenance dose, etc.). In certain embodiments, the resumption maintenance dose of paliperidone palmitate is about 156 to about 234 mg.

[0017] The present disclosure also provides a method for stabilizing or reducing weight in a patient who has been treated with paliperidone palmitate extended-release injectable suspension at either one-month intervals (PP1M) or three-month intervals (PP3M), comprising administering a final dose of PP1M or PP3M, followed by administering an initial dose of paliperidone palmitate extended-release injectable suspension having a six-month dosing interval (PP6M). [Brief explanation of the drawings]

[0018] [Figure 1] 1 shows a flow chart of a double-blind, randomized, active-controlled, parallel-group study of a 6-month formulation of paliperidone palmitate. [Figure 2] Kaplan-Meier plot of time to relapse during the double-blind period up to 12 months is shown. [Figure 3] Forest plot of the estimated percentage (95% CI) of subjects who remained relapse-free at 12 months is shown. [Figure 4] 1 shows the median plasma concentration time profiles of paliperidone following administration of PP3M (350 mg eq or 525 mg eq) and PP6M (700 mg eq or 1000 mg eq) in a double-blind study. [Figure 5] Comparison of PK plasma concentrations and clinical efficacy (median time to relapse) across paliperidone formulations is shown. [Figure 6] Skipped dose simulations are shown for >6 months and 3 weeks and up to 8 months after the last steady-state 1000 mg equivalent PP6M injection (7 and 7.5 months after the last PP6M dose). [Figure 7] Skipped dose simulations are shown for cases 8 to 11 months after the last 1000 mg equivalent PP6M injection (8, 10, and 11 months after the last PP6M administration). [Figure 8] Skipped dose simulations are shown for cases where more than 11 months have passed since the last 1000 mg equivalent PP6M injection (12, 15, and 18 months after the last PP6M administration). [Figure 9]1 shows bar graphs depicting mean and abnormal weight change from double-blind baseline for patients who have been treated with PP6M. [Figure 10] 1 shows a bar graph showing the mean weight change in patients of different weight classes (normal, overweight, and obese) treated with PP6M. [Figure 11] 1 shows a bar graph showing the mean weight change of patients in various age groups treated with PP6M.

[0019] (Detailed description) The inventive subject matter disclosed herein may be more readily understood by reference to the following detailed description taken in conjunction with the accompanying examples, which form a part of this disclosure. It is to be understood that the present invention is not limited to the specific formulations, methods, or parameters described and / or illustrated herein, and that the terminology used herein is for the purpose of describing specific embodiments by way of example only, and is not intended to limit the claimed invention.

[0020] When values ​​are expressed as approximations, by use of the descriptors "about" or "substantially," it is understood that the particular value forms another embodiment. In general, use of the terms "about" or "substantially" indicates approximations that can vary depending on the desired properties sought to be obtained by the disclosed subject matter, but should be interpreted in the particular context in which it is used based on its function.

[0021] It is understood that certain features of the invention that are, for clarity, described herein in the context of separate embodiments, may also be provided in combination in a single embodiment. That is, unless expressly incompatible or excluded, each separate embodiment is deemed to be compatible with any other embodiment, and such combinations are considered to be separate embodiments. Conversely, different features of the invention that are, for brevity, described in the context of a single embodiment, may also be provided separately or in any subcombination.

[0022] Where present, all ranges are inclusive and combinable. For example, when a range of "1 to 5" is recited, the recited range should be interpreted as optionally including ranges such as "1 to 4," "1 to 3," "1 to 2," "1 to 2 and 4 to 5," "1 to 3 and 5," etc. In addition, when a list of alternatives is explicitly provided, such a list may also include embodiments in which any of the alternatives may be excluded. For example, when a range of "1 to 5" is recited, such a recitation may support a situation in which any of 1, 2, 3, 4, or 5 is excluded. Thus, a recitation of "1 to 5" may support "1 and 3 to 5, but not 2," or simply "2 is not included."

[0023] As used herein, "PP1M" refers to a paliperidone palmitate sustained-release injectable suspension or other type of formulation having an amount of paliperidone palmitate suitable for a dosing interval of about one month. Commercially available examples include INVEGA SUSTENNA® or XEPLION®. See also U.S. Pat. No. 9,439,906, incorporated herein by reference.

[0024] As used herein, "PP3M" refers to a paliperidone palmitate sustained-release injectable suspension or other type of formulation having an amount of paliperidone palmitate suitable for a dosing interval of about 3 months. Commercially available examples include INVEGA TRINZA® or TREVICTA®. See also U.S. Pat. No. 10,143,693, incorporated herein by reference.

[0025] As used herein, "PP6M" refers to a paliperidone palmitate extended-release injectable suspension or other type of formulation having an amount of paliperidone palmitate suitable for a dosing interval of about 6 months.

[0026] Paliperidone is effective in treating psychosis and has been used to treat schizophrenia and schizoaffective disorder. Therefore, PP6M is suitable for the treatment of psychotic disorders, including but not limited to schizophrenia and / or schizoaffective disorder or bipolar disorder.

[0027] PP6M is typically administered to patients who have been adequately treated with PP1M (e.g., INVEGA SUSTENNA®) for several months, and in certain embodiments, for at least four months, at a PP1M dose of about 156 mg or about 234 mg of paliperidone palmitate. More preferably, the final two doses of PP1M are at the same dosage strength as before initiation of PP6M. Alternatively, PP6M is administered to patients who have been adequately treated with PP3M (e.g., INVEGA TRINZA®) for at least one three-month cycle, at a PP3M dose of about 546 mg or about 819 mg of paliperidone palmitate.

[0028] PP6M is typically provided in doses ranging from about 1000 mg to about 1600 mg of paliperidone palmitate to provide sustained therapeutic concentrations of paliperidone over a 6-month dosing interval. Preferably, PP6M is provided in dosage strengths of about 1092 mg or about 1560 mg of paliperidone palmitate. The formulation hydrolyzes to the active moiety, paliperidone, to yield dosage strengths of about 700 mg equivalent or about 1000 mg equivalent of paliperidone, respectively.

[0029] PP6M is preferably provided in a pre-filled syringe (cyclic olefin copolymer) pre-filled with either 700 mg equivalent (3.5 mL) or 1000 mg equivalent (5.0 mL) of paliperidone (1092 mg or 1560 mg as paliperidone palmitate, respectively) with a plunger stopper, plunger rod, and tip cap (bromobutyl rubber), backstop, and needle, preferably a thin-walled 20 gauge (G), 1 1 / 2 inch safety needle.

[0030] PP6M is intended for intramuscular use. Administration by any other route is not recommended. Care should be taken to prevent inadvertent intravascular injection. The dose is preferably administered in a single injection. For example, split injections may change the release profile. Otherwise, it is preferable to slowly inject the drug into the patient's muscle, particularly the deep deltoid or gluteal muscles. Typically, PP6M is administered into the gluteal muscles, taking into account the injection volume.

[0031] Intramuscular injection Typically, regardless of patient weight, PP6M is administered intramuscularly into the deltoid or gluteal muscles using a thin-walled syringe, e.g., a 20-gauge, 1.5-inch needle. To the extent administered into the deltoid muscle, paliperidone palmitate is typically administered into the center of the deltoid muscle, preferably alternating between the two deltoid muscles per injection (i.e., the opposite deltoid muscle is used at the next scheduled dosing interval). For PP6M, intramuscular gluteal administration is preferred. For example, PP6M can be administered into the upper outer quadrant of the gluteal muscle. It is also preferred that gluteal injections should alternate between the two gluteal muscles per injection (i.e., the opposite gluteal muscle is used at the next scheduled dosing interval).

[0032] Incomplete administration PP6M is typically a highly concentrated product. As a result, an important consideration is ensuring complete suspension / resuspension of the product before administration. To avoid incomplete dosing, the syringe is shaken and / or mechanically agitated to achieve a uniform dispersion of the suspension. For example, the syringe is preferably quickly shaken for at least 15 seconds with the syringe tip cap facing up. A short rest period may be allowed, and then the syringe may, and preferably is, shaken again for another 15 seconds. Injection is then preferably performed immediately or within 5 minutes of the final shaking to ensure resuspension and prevent clogging of the needle during injection.

[0033] Due to the slow-release characteristics of PP6M, this product is not intended for use in patients immediately transitioning from oral to LAI antipsychotic therapy. Rather, PP6M is intended for use in patients who are adequately treated with either PP1M or PP3M at the time of initiation of PP6M. The determination of adequate treatment is typically left to the judgment of the prescribing clinician. Typically, PP6M administration is initiated A) one month after adequate treatment with PP1M (e.g., INVEGA SUSTENNA®) for at least four months, or B) three months after a PP3M (e.g., INVEGA TRINZA®) dose has been established as adequate treatment. PP6M may be administered one month (±7 days) after the last PP1M injection or three months (±14 days) after the last PP3M injection.

[0034] After the initial PP6M injection, PP6M should be administered every six months. If necessary, dose adjustments can be made every six months, increasing the dose of paliperidone palmitate within the range of 1092 mg to 1560 mg, based on individual patient tolerability and / or efficacy. Typically, the dosage is adjusted to approximately 1092 mg or approximately 1560 mg of paliperidone palmitate. Due to the long-acting nature of PP6M, a patient's response to the adjusted dose may not be apparent for several months.

[0035] Administration period As described herein, non-adherence is a major problem in the treatment of psychiatric patients, especially those with schizophrenia, who often abruptly discontinue medication without consulting their general practitioner or caregiver. Lack of adherence has been identified as the strongest predictor of relapse, which typically results in worsening psychiatric comorbidities, loss of employment, interruption of education, and impaired family relationships. For oral antipsychotics, a dosing interval of just one day can double the risk of rehospitalization. Long-acting injectable (LAI) antipsychotics have been developed to address this issue and ensure timely intervention for non-adherent patients to prevent relapse and hospitalization.

[0036] However, a common difficulty encountered in clinical practice is that the subject needs to return to the clinic on a specific date after receiving a previous maintenance injection of LAI antipsychotics.Having a window in which injections can be given will give prescribers, patients, and caregivers greater flexibility.This window is often prescribed by medical professionals and / or set by regulatory agencies.

[0037] Previously, for PP1M, a dosing window of ±1 week around the target injection date (the planned injection date based on the dosing interval) was established. For PP3M, this window was expanded to ±2 weeks around the target injection date. It was now discovered that dosing windows of up to 2 weeks before and up to 3 weeks after the target injection date for PP6M can be used, providing further dosing flexibility.

[0038] Dosing recommendations have historically targeted paliperidone plasma concentrations above a threshold of 7.5 ng / mL. This threshold is associated with 60% central dopamine type 2 (D2) receptor occupancy, although receptor occupancy in the range of 60% to 80% is believed to be necessary for a satisfactory antipsychotic response. As reflected in the Examples section (see Example 7), simulations were performed to evaluate the relationship between the median time to relapse and the point at which the median paliperidone concentration fell below 7.5 ng / mL. A clear delay, lasting several weeks to several months, was observed between the time at which the median plasma paliperidone concentration decreased to 7.5 ng / mL and the median time to relapse, i.e., the point at which half of the subjects experienced a relapse while the other half relapsed later or did not relapse during the study. Thus, the treatment effect was extended beyond that predicted based on the 7.5 ng / mL threshold, and the relapse protection window appears to be further sustained in a positive direction.

[0039] In one embodiment, a dosing window of up to two weeks before and up to three weeks after the target injection date of PP6M (i.e., the scheduled six-month time point) is used. Accordingly, the present disclosure includes a method for administering paliperidone palmitate to a patient in need thereof who has received a first dose of paliperidone palmitate extended-release injectable suspension, comprising administering a second dose of paliperidone palmitate extended-release injectable suspension to the patient's deltoid or gluteal muscle, preferably the gluteal muscle, up to two weeks before or three weeks after the six-month time point following administration of the first dose, wherein there is no intervening dose of paliperidone palmitate between the first and second doses. It should be appreciated that the first and second doses are doses within the sequence of the described method, but do not necessarily refer to the exact first (initial) or second dose administered to the patient.

[0040] Unless otherwise indicated, as used herein, "month" refers to a Gregorian calendar month, which can vary from as little as 28 days (e.g., February) to as many as 31 days (e.g., October), e.g., 28, 29, 30, or 31 days. A six-month time point reflects six consecutive calendar months. As shown herein, certain studies reflected in the examples, including simulations, were based on 30 days used for one month. "Week" refers to 7 days.

[0041] In some embodiments, other dosing windows may be considered. For example, a dosing window of up to 1 week before and up to 2 weeks after, or up to 1 week before and up to 3 weeks after, or up to 2 weeks before and up to 2 weeks after the target injection date of PP6M. In still other embodiments, the second dose is administered as part of the dosing window up to 4 weeks or up to 5 weeks after the time that is 6 months after administration of the first dose. Any combination of these periods before and after the time that is 6 months after administration of the first dose may be utilized. In certain embodiments, the dosing window applies to patients who have reached a steady-state plasma concentration of paliperidone.

[0042] The first dose and the second dose are independently typically about 1000 mg to about 1600 mg of paliperidone palmitate. In particular, the first dose and the second dose are independently about 1092 mg or about 1560 mg of paliperidone palmitate. In another embodiment, the first dose and the second dose are each about 1092 mg of paliperidone palmitate. In another embodiment, the first dose and the second dose are each about 1560 mg of paliperidone palmitate.

[0043] Typically, the patient's plasma concentration of paliperidone is about 5 to about 50 ng / mL at the time of administration of the second dose, or about 10 to about 40 ng / mL at the time of administration of the second dose. For example, if the first dose is 1092 mg of paliperidone palmitate, the patient's plasma concentration of paliperidone is about 5 to about 30 ng / mL, or about 10 to about 25 ng / mL at the time of administration of the second dose. If the first dose is 1560 mg of paliperidone palmitate, the patient's plasma concentration of paliperidone is about 9 to about 40 ng / mL, or about 20 to about 30 ng / mL at the time of administration of the second dose. In this context, "time of the second dose" refers to the concentration level immediately prior to the second dose, typically C トラフ Represents a value.

[0044] In other embodiments, the patient's plasma concentration of paliperidone reaches a peak of about 10 to about 150 ng / mL after administration of the second dose, or about 35 ng / mL to about 125 ng / mL after administration of the second dose. For example, if the first dose is 1092 mg of paliperidone palmitate, the patient's plasma concentration of paliperidone reaches a peak of about 10 to about 125 ng / mL, or about 50 to about 90 ng / mL after administration of the second dose. If the first dose is 1560 mg of paliperidone palmitate, the patient's plasma concentration of paliperidone reaches a peak of about 35 to about 145 ng / mL, or about 70 to about 110 ng / mL after administration of the second dose.

[0045] In certain embodiments, PP3M and PP6M may have the same formulation. In such embodiments, the pharmacokinetic properties of PP6M are similar to those of PP3M, but such PP6M would be expected to have a higher peak and a lower trough given the larger drug dose and longer dosing frequency. As shown in Example 6, absolute drug plasma concentrations were lower for PP6M at its target interval compared to PP3M at its target interval. Given that PP3M established a dosing window of ±2 weeks around the target injection date, it was not suggested to extend the dosing window in a positive direction for a formulation that results in lower drug plasma concentrations at the target interval. However, as reflected herein, it was discovered that the therapeutic effect was longer than predicted based on the pharmacokinetic data, thus allowing the dosing window to be further maintained in a positive direction.

[0046] Missing dose Patients receiving LAI antipsychotics return to their healthcare provider periodically to receive injections of the drug. The timing of these doses is typically carefully prescribed. As described herein, for any given antipsychotic, an optimal dosing cycle is recommended, along with a dosing window (±) during which the drug can be tolerated without any adverse side effects or loss of efficacy. In the present disclosure, after the initial dose of PP6M, PP6M should be administered every six months. Skipping doses of PP6M should be avoided, but injections given within the prescribed dosing window would not be considered skipped doses. If necessary, dose adjustments can be made every six months between 1092 mg and 1560 mg of paliperidone palmitate dose levels based on individual patient tolerability and / or efficacy.

[0047] However, despite this, schizophrenia patients frequently become noncompliant at some point during their illness. Therefore, based on population pharmacokinetic simulations, guidelines are provided for skipping doses of PP6M beyond the dosing window.

[0048] The present disclosure provides a mechanism by which patients can resume treatment with PP6M if they become completely or partially non-compliant. Because PP6M administration relies on patients being initially stabilized with PP1M / PP3M, this will reduce the need for patients to start anew. In addition, because the therapeutic effect was found to be longer than expected based on pharmacokinetic data, patients who received at least one PP6M injection are expected to remain relapse-free for a longer period of time. This demonstrates the positive effect of PP6M on preventing relapse, even in the setting of non-compliance.

[0049] The present disclosure provides resumption dosing regimens for patients who have missed their regularly scheduled drug doses, i.e., are outside the prescribed dosing window, and the regimen depends on the time elapsed since the patient's last dose. In some embodiments, the missed doses span six months and three weeks, but less than seven to nine months, e.g., less than eight months, after the last injection.

[0050] For example, so long as the dosing window is up to two weeks before and up to three weeks after the target injection date, the present disclosure provides a method for administering paliperidone palmitate to a patient in need thereof who has been administered a first dose of a first paliperidone palmitate sustained-release injectable suspension (first suspension), the method comprising administering a restart loading dose of a second paliperidone palmitate sustained-release injectable suspension (second suspension) to the patient's deltoid muscle more than six months and three weeks after administration of the first dose of the first suspension, but less than seven to nine months, e.g., less than eight months, after administration of the first dose of the first suspension, and administering a maintenance dose of the first suspension to the patient's deltoid or gluteal muscle about one month (±7 days) after administration of the restart loading dose of the second suspension. In one embodiment, the restart loading dose of the second suspension and the maintenance dose of the first suspension are selected based on the first dose of the first suspension as shown in Table 1 below, and the administration of the first suspension is preferably in the patient's gluteal muscles.

[0051] [Table 1]

[0052] To the extent a different dosing window is prescribed, the same restart dosing regimen described above may be implemented, but may be adjusted based on the outer dosing window parameters. For example, if the dosing window is up to 1 week before and up to 2 weeks after the target injection date, the restart loading dose of the second suspension may be administered more than 6 months and 2 weeks after the administration of the first dose of the first suspension, but less than 7 to 9 months, e.g., less than 8 months, after the administration of the first dose of the first suspension.

[0053] Other restart regimens are based on missed doses 7 to 9 months and 10 to 14 months after the last injection. For example, the present disclosure includes administering paliperidone palmitate to a patient in need of paliperidone palmitate who has been administered a first dose of a first paliperidone palmitate extended-release injectable suspension (first suspension), and administering 156 mg of paliperidone palmitate of a second paliperidone palmitate extended-release injectable suspension (second suspension) 7 to 9 months, e.g., 8 months up to 10 to 14 months, e.g., up to 11 months, after administration of the first dose of the first suspension. The method includes administering a first loading dose of paliperidone to the patient's deltoid muscle, administering a second loading dose of 156 mg of paliperidone palmitate of the second suspension to the patient's deltoid muscle about 8 days (±4 days) after administering the first loading dose of the second suspension, and administering a maintenance dose of about 1092 mg to about 1560 mg of paliperidone palmitate of the first suspension to the patient's deltoid or gluteal muscle about 1 month (±7 days) after administering the second loading dose of the second suspension. In one embodiment, the first dose of the first suspension is about 1092 mg of paliperidone palmitate, and the maintenance dose of the first suspension is about 1092 mg of paliperidone palmitate. In another embodiment, the first dose of the first suspension is about 1560 mg of paliperidone palmitate and the maintenance dose of the first suspension is about 1560 mg of paliperidone palmitate. In a preferred embodiment, the administration of the first suspension is to the gluteal muscle of the patient.

[0054] Other restart regimens are based on doses skipped >10–14 months after the last injection. For example, the disclosure includes administering paliperidone palmitate to a patient in need of paliperidone palmitate who has been administered a first dose of a first paliperidone palmitate extended-release injectable suspension (first suspension), by: (1) administering a first loading dose of 234 mg of paliperidone palmitate of a second paliperidone palmitate extended-release injectable suspension (second suspension) to the patient's deltoid muscle at 10 to 14 months or more, e.g., 11 months or more, after administration of the first dose of the first suspension; (2) administering a second loading dose of 156 mg of paliperidone palmitate of the second suspension to the patient's deltoid muscle about 8 days (±4 days) after administration of the first loading dose of the second suspension; and (3) administering a second loading dose of 356 mg of paliperidone palmitate of the second suspension to the patient's deltoid muscle about 1 month (±7 days) after administration of the second loading dose. (4) about one month (±7 days) after administering the first resumption maintenance dose of the second suspension, administering a second resumption maintenance dose of about 39 mg to about 234 mg of paliperidone palmitate of the second suspension to the patient's deltoid or gluteal muscles; (5) about one month (±7 days) after administering the second resumption maintenance dose of the second suspension, administering a third resumption maintenance dose of about 39 mg to about 234 mg of paliperidone palmitate of the second suspension to the patient's deltoid or gluteal muscles; and (6) about one month (±7 days) after administering the third resumption maintenance dose of the second suspension, administering a maintenance dose of about 1092 mg to about 1560 mg of paliperidone palmitate of the first suspension to the patient's deltoid or gluteal muscles. Preferably, the first suspension is administered to the gluteal muscle. In one embodiment, the first dose of the first suspension is about 1092 mg of paliperidone palmitate, and the maintenance dose of the first suspension is about 1092 mg of paliperidone palmitate. In another embodiment, the first dose of the first suspension is about 1560 mg of paliperidone palmitate, and the maintenance dose of the first suspension is about 1560 mg of paliperidone palmitate. In other embodiments, the second and third resumption maintenance doses of the second suspension are the same.Additional resumption maintenance doses may be administered at monthly (±7 day) intervals prior to the first suspension maintenance dose (e.g., a fourth resumption maintenance dose, a fifth resumption maintenance dose, etc.). In certain embodiments, the resumption maintenance dose of paliperidone palmitate is about 156 to about 234 mg. For any of the resumption regimens, after administration of the first suspension maintenance dose, the first suspension is typically administered at six-month intervals as described herein.

[0055] In a specific embodiment, the first suspension is PP6M and the second suspension is PP1M. Exemplary resumption regimens based on PP1M and PP6M are further disclosed in Example 8. The goal of the resumption regimen is to achieve a rapid return to paliperidone plasma concentrations as before the skipped dose without overshoot due to the applied resumption regimen. It should be recognized that the present method does not contemplate intervening doses of paliperidone palmitate between the recited doses of the skipped dosing regimen described herein, e.g., between the first dose and the resumption loading dose.

[0056] Another aspect of the present disclosure is the observed effect of longer-acting paliperidone palmitate treatment on stabilizing or reducing weight in patient populations where most treatments cause weight gain. In particular, it has been found that transitioning patients who have been well treated with PP1M or PP3M to PP6M can reduce, halt, or potentially partially reverse paliperidone-induced weight gain while maintaining good pharmacological efficacy and relapse prevention.

[0057] As a result, the present disclosure fulfills an unmet medical need for overweight patients treated with risperidone or paliperidone who require long-term symptom protection and thus antipsychotic therapy, but who cannot tolerate continued weight gain. Weight gain during long-term treatment has metabolic effects that increase risk factors for higher morbidity and mortality (e.g., from cardiovascular disease). In addition, weight gain can affect a patient's mobility and functionality, significantly reducing their quality of life. The PP6M formulations and regimens disclosed herein enable weight-neutral or weight-loss treatment for patients while providing the same efficacy as other paliperidone or paliperidone palmitate formulations (e.g., PP1M or PP3M).

[0058] In one embodiment, the present disclosure provides a method for stabilizing or reducing weight in a patient who has been treated with paliperidone palmitate extended-release injectable suspension at either a one-month interval (PP1M) or a three-month interval (PP3M), comprising administering a final dose of PP1M or PP3M and then administering an initial dose of paliperidone palmitate extended-release injectable suspension having a six-month dosing interval (PP6M). In certain embodiments, the patient has been treated with PP1M for at least four months, at least five months, or at least six months. In other embodiments, the patient has been treated with PP3M for at least one three-month interval, at least two three-month intervals, or at least three three-month intervals.

[0059] In embodiments where the patient is being treated with PP1M, the first dose of PP6M is administered about 1 month (±7 days) after the last dose of PP1M is administered. Typically, if the last dose of PP1M is about 156 mg paliperidone palmitate, the first dose of PP6M is about 1092 mg paliperidone palmitate. In other embodiments, if the last dose of PP1M is about 234 mg paliperidone palmitate, the first dose of PP6M is about 1560 mg paliperidone palmitate.

[0060] In embodiments where the patient is being treated with PP3M, the first dose of PP6M is administered about 3 months (±14 days) after the last dose of PP1M is administered. Typically, if the last dose of PP3M is about 546 mg paliperidone palmitate, the first dose of PP6M is about 1092 mg paliperidone palmitate. In other embodiments, if the last dose of PP3M is about 819 mg paliperidone palmitate, the first dose of PP6M is about 1560 mg paliperidone palmitate.

[0061] After the initial dose of PP6M, PP6M is administered at six-month intervals as described herein.

[0062] Further analysis of the data showed particular benefit in overweight patients (body mass index (BMI) of about 25 and less than about 30) and younger patients (about 18 to about 25 years old).

[0063] In certain embodiments, the patient has a body mass index (BMI) of about 25 to less than about 30 at the time of the final dose of PP1M or PP3M.

[0064] In another embodiment, the patient is about 18 to about 25 years of age at the time of the final dose of PP1M or PP3M.

[0065] Typically, weight stabilization refers to a BMI change of about -1 to about +1, or about -0.5 to about +0.5, from the time of transition to PP6M (from the time of the first dose of PP6M). Preferably, the BMI change is about 0. With respect to weight loss, a negative weight change from the time of transition to PP6M can be viewed as weight loss. Such stabilization or weight loss can occur within about 12 months from the time of transition to PP6M.

[0066] In other embodiments, the patient's weight is assessed or determined at the time of the last dose of PP1M or PP3M, at the time of the first administration of PP6M, at a later time point after transitioning to PP6M, or a combination thereof.

[0067] Paliperidone palmitate preparations Paliperidone ester is an antipsychotic drug belonging to the chemical class of benzisoxazole derivatives, containing a racemic mixture of (+)- and (-)-paliperidone, and is described in U.S. Patent No. 5,254,556 (incorporated herein by reference). The chemical name of paliperidone palmitate is (±)-3-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl]-6,7,8,9-tetrahydro-2-methyl-4-oxo-4H-pyrido[1,2-c]pyrimidin-9-yl hexadecanoate. The structural formula is:

[0068] [ka]

[0069] Paliperidone esters can be formulated into injectable dosage forms with pharmaceutical excipients as described in U.S. Patent Nos. 5,254,556 and 6,077,843, both of which are incorporated herein by reference. Injectable formulations can be formulated in an aqueous carrier.

[0070] As described in U.S. Patent No. 9,439,906, incorporated herein by reference, the one-month aqueous formulation is a nanoparticle suspension in which the nanoparticles have an average size of less than about 2,000 nm to about 100 nm. For example, the nanoparticles have an average particle size (d50) of about 1,600 nm to about 400 nm, or about 1,400 nm to about 900 nm. The d90 is less than about 5,000 nm, or less than about 4,400 nm. The d10 is about 300 nm to about 600 nm. As used herein, d10 is the percentage of particles having a diameter smaller than this value (10%), d50 is the percentage of particles having a diameter smaller than this value (50%), and d90 is the percentage of particles having a diameter smaller than this value (90%), as measured by conventional techniques known in the art, such as sedimentation field flow fractionation, photon correlation spectroscopy, or disk centrifugation.

[0071] In certain embodiments, the 3-month (PP3M) formulation has an average particle size of less than about 20 μm to about 1 μm. In other embodiments, the particles have an average particle size (d50) of about 5 μm to about 15 μm, about 3 μm to about 10 μm, or about 5 μm to about 9 μm. The d90 is about 50 μm, about 10 μm to about 30 μm, or about 10 μm to about 20 μm. The d10 is about 1 μm to about 10 μm, or about 1 μm to about 5 μm.

[0072] In certain embodiments, the 6-month (PP6M) formulation has an average particle size of less than about 30 μm to about 1 μm, or about 20 μm to about 1 μm. In other embodiments, the particles have an average particle size (d50) of about 3 μm to about 25 μm, about 5 μm to about 15 μm, about 3 μm to about 10 μm, or about 5 μm to about 9 μm. The d90 is 60 μm, or about 50 μm, about 10 μm to about 30 μm, or about 10 μm to about 20 μm. The d10 is about 1 μm to about 15 μm, about 1 μm to about 10 μm, or about 1 μm to about 5 μm.

[0073] Suitable aqueous nanoparticle formulations are described in U.S. Patent No. 6,555,544, which is incorporated herein by reference. In some embodiments, the formulation includes microparticles, a surfactant, a suspending agent, and any one or more additional components selected from the group consisting of a preservative, a buffer, and a tonicity agent.

[0074] Useful surface modifiers for paliperidone palmitate formulations are believed to include those that physically adhere to the surface of the active agent but do not chemically bond thereto. Suitable surface modifiers may preferably be selected from known organic and inorganic pharmaceutical excipients. Such excipients include various polymers, low molecular weight oligomers, natural products, and surfactants. Preferred surface modifiers include nonionic and anionic surfactants. Representative examples of excipients include gelatin, casein, lecithin (phosphatide), gum arabic, cholesterol, tragacanth, stearic acid, benzalkonium chloride, calcium stearate, glyceryl monostearate, cetostearyl alcohol, cetomacrogol emulsifying wax, sorbitan ester, polyoxyethylene alkyl ether (e.g., macrogol ether such as cetomacrogol 1000), polyoxyethylene castor oil derivative, polyoxyethylene sorbitan fatty acid ester (e.g., commercially available TWEENS®), polyethylene glycol, polyoxyethylene stearate, colloidal silicon dioxide, phosphate, sodium dodecyl sulfate, carboxymethylcellulose calcium, carboxymethylcellulose sodium, methylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose phthalate, amorphous cellulose, magnesium aluminosilicate, triethanolamine, polyvinyl alcohol (polyvinyl alcohol), and the like. Surface modifiers include hydroxypropyl alcohol (PVA), poloxamer, tyloxapol, and polyvinylpyrrolidone (PVP). Most of these excipients are described in detail in the Handbook of Pharmaceutical Excipients, the Pharmaceutical Press, 1986, jointly published by the American Pharmaceutical Association and the Pharmaceutical Society of Great Britain. Surface modifiers are commercially available and / or can be prepared by techniques known in the art. Two or more surface modifiers can be used in combination.

[0075] Particularly preferred surface modifiers include polyvinylpyrrolidone, tyloxapol, poloxamers (e.g., PLURONIC™ F68, F108, and F127, block copolymers of ethylene oxide and propylene oxide, available from BASF), poloxamines (e.g., TETRONIC™ 908 (T908), a tetrafunctional block copolymer derived from the sequential addition of ethylene oxide and propylene oxide to ethylenediamine, available from BASF), dextran, lecithin, Aerosol OT™ (AOT), a dioctyl ester of sodium sulfosuccinate, available from Cytec Industries, DUPONOL™ P, a sodium lauryl sulfate, available from DuPont, TRITON™ X-200, an alkylaryl polyether sulfonate, available from Rohm and Haas, TWEEN™ 20, 40, 60, and 80 (ICI Specialty Chemicals, Inc.), and the like. Other examples of suitable sorbitan fatty acid esters include polyoxyethylene sorbitan fatty acid esters available from Croda Chemicals, SPAN™ 20, 40, 60, and 80 (sorbitan esters of fatty acids), ARLACEL™ 20, 40, 60, and 80 (sorbitan esters of fatty acids available from Hercules, Inc.), CARBOWAX™ 3550 and 934 (polyethylene glycols available from Union Carbide), CRODESTA™ F110 (a mixture of sucrose stearate and sucrose distearate available from Croda, Inc.), CRODESTA™ SL-40 (available from Croda, Inc.), hexyldecyl trimethyl ammonium chloride (CTAC), bovine serum albumin, and SA90HCO(C 18 H 17CH2(CON(CH3)CH2(CHOH)4CH2OH)2). Surface modifiers that have been found to be particularly useful include tyloxapol and poloxamers, preferably Pluronic™ F108 and Pluronic™ F68.

[0076] Pluronic™ F108 corresponds to poloxamer 338 and has the formula HO[CHCHO] where the average values ​​of x, y, and z are 128, 54, and 128, respectively. x [CH(CH3)CH2O] y [CH2CH2O] z H. Other commercial names for poloxamer 338 are Hodag NONIONIC™ 1108-F, available from Hodag, and SYNPERONIC™ PE / F108, available from ICI Americas.

[0077] The optimal relative amounts of paliperidone palmitate and surface modifier depend on various parameters. The optimal amount of surface modifier may depend, for example, on the particular surface modifier selected, the critical micelle concentration of the surface modifier if the surface modifier forms micelles, the surface area of ​​the antipsychotic, etc. The particular surface modifier is preferably present in an amount of about 0.1 to about 1 mg per square meter of surface area of ​​paliperidone palmitate. In the case of paliperidone palmitate (9-hydroxyrisperidone palmitate), PLURONIC™ F108 is preferably used as the surface modifier, with a relative amount (w / w) of both components of about 6:1 being preferred.

[0078] The particles of the present invention can be prepared by a process comprising dispersing paliperidone palmitate in a liquid dispersion medium and applying mechanical means to reduce the particle size of the antipsychotic to an effective average particle size in the presence of a grinding medium. The particles can be reduced in size in the presence of a surface modifier. Alternatively, the particles can be contacted with a surface modifier after attrition.

[0079] A general procedure for preparing the particles described herein includes: (a) obtaining paliperidone palmitate; (b) adding the paliperidone palmitate to a liquid medium to form a premix; and (c) subjecting the premix to mechanical means in the presence of grinding media to reduce the particle size to an effective average particle size.

[0080] Paliperidone palmitate can be prepared using techniques known in the art. Preferably, the particle size of paliperidone palmitate is less than about 100 μm, as determined by sieve analysis. If the particle size of paliperidone palmitate is greater than about 100 μm, then, preferably, the particles of paliperidone palmitate are reduced to a size less than 100 μm.

[0081] Paliperidone palmitate can then be added to the liquid medium in which it is essentially insoluble to form a premix. The concentration of paliperidone palmitate (weight by weight percentage) in the liquid medium can vary widely and depends on the surface modifier selected and other factors. Suitable concentrations of paliperidone palmitate in the composition range from about 0.1 to about 60%, preferably from about 0.5 to about 30%, and more preferably about 7% (w / v). For PP1M, it is currently preferred to use a concentration of about 100 mg equivalents of paliperidone per mL, or about 156 mg of paliperidone palmitate per mL. For PP3M, it is preferred to use a concentration of about 200 mg equivalents of paliperidone per mL, or about 312 mg of paliperidone palmitate per mL. For PP6M, it is preferred to use a concentration of about 200 mg equivalent of paliperidone per mL, or about 312 mg of paliperidone palmitate per mL.

[0082] A more preferred procedure involves adding a surface modifying agent to the premix before subjecting it to mechanical means to reduce the effective average particle size. The concentration of the surface modifying agent (weight by weight percentage) can range from about 0.1% to about 90%, preferably from about 0.5% to about 80%, and more preferably is about 7% (w / v).

[0083] The premix can be used directly by subjecting it to mechanical means to reduce the effective average particle size within the dispersion to the desired particle size. When a ball mill is used for attrition, it is preferable to use the premix directly. Alternatively, the antipsychotic drug and, optionally, the surface modifier, can be dispersed in a liquid medium using suitable agitation, such as, for example, a roller mill or a Coles-type mixer, until a homogeneous dispersion is achieved.

[0084] The mechanical means applied to reduce the effective average particle size of the antipsychotic agent can conveniently take the form of a dispersion mill. Suitable dispersion mills include media mills, such as ball mills, attritor mills, vibratory mills, planetary mills, sand mills, and bead mills. Media mills are preferred due to the relatively short milling times required to provide the desired reduction in particle size. For media milling, in some embodiments, the apparent viscosity of the premix is ​​preferably from about 0.1 Pa·s to about 1 Pa·s. In some embodiments, for ball milling, the apparent viscosity of the premix is ​​preferably from about 1 mPa·s to about 100 mPa·s.

[0085] The grinding media for the particle size reduction step can be selected from spherical or granular hard media, preferably having an average size of less than about 3 mm, more preferably less than about 1 mm. Such media can desirably provide the particles of the present invention in a shorter processing time and impart less wear to the grinding equipment. The choice of material for the grinding media is not believed to be critical. However, about 95% ZrO stabilized with magnesia, zirconium silicate, and glass grinding media provide particles acceptable for the preparation of pharmaceutical compositions. Additionally, other media such as polymer beads, stainless steel, titania, alumina, and about 95% ZrO stabilized with yttrium are useful. A preferred grinding media is about 2.5 g / cm. 3 It has a density exceeding 1000 MPa and contains approximately 95% ZrO stabilized with magnesia and polymer beads.

[0086] Attrition times can vary widely and depend primarily on the particular mechanical means and processing conditions selected. For rolling mills, processing times of up to 2 days or more can be required for small sized particles.

[0087] The particles are typically reduced in size at a temperature that does not significantly degrade the antipsychotic. Processing temperatures of less than about 30°C to about 40°C are generally preferred. If necessary, the processing equipment can be cooled with conventional cooling equipment. The process is conventionally carried out under ambient temperature conditions and processing pressures that are safe and effective for the milling process.

[0088] If the surface modifier is not present in the premix, it must typically be added to the dispersion after attrition, for example, in the amount described above for the premix.The dispersion can then be mixed, for example, by vigorously shaking.Optionally, the dispersion can be subjected to a dispersion step, for example, using an ultrasonic power supply.

[0089] Aqueous compositions according to the present invention advantageously further comprise one or more of a suspending agent and a buffering agent, and optionally a preservative and an isotonicity agent. A particular component may function as two or more of these agents simultaneously, for example, acting as both a preservative and a buffering agent, or as both a buffering agent and an isotonicity agent.

[0090] Suitable suspending agents (also called physical stabilizers) for use in aqueous suspensions according to the invention are cellulose derivatives such as methylcellulose, sodium carboxymethylcellulose and hydroxypropylmethylcellulose, polyvinylpyrrolidone, alginic acid, chitosan, dextran, gelatin, polyethylene glycol, polyoxyethylene, and polyoxypropylene ether. Preferably, sodium carboxymethylcellulose is used at a concentration of about 0.5 to about 2%, most preferably about 1% (w / v).

[0091] Preferred wetting agents selected from the surfactants described for use in aqueous suspensions according to the present invention are polyoxyethylene derivatives of sorbitan esters, such as polysorbate 20 and polysorbate 80, lecithin, polyoxyethylene and polyoxypropylene ethers, and sodium deoxycholate. Preferably, polysorbate 20 is used at a concentration of about 0.5 to about 3%, more preferably about 0.5 to about 2%, and most preferably about 1.1% (w / v).

[0092] Suitable buffers are salts of weak acids and should be used in an amount sufficient to render the dispersion basic, from about pH 6.0. Preferably, the pH is within the range of about 6.0 to about 9.0, or about 6.0 to about 8.0, or about 6.5 to about 7.5. For example, the pH is within the range of about 6.0 to about 6.5, or about 6.5 to about 7.0, or about 7.0 to about 7.5, or about 7.5 to about 8.0, or about 8.0 to about 8.5, or about 8.5 to about 9.0. The use of a mixture of disodium hydrogen phosphate (anhydrous) (typically about 0.9% (w / v)) and sodium dihydrogen phosphate monohydrate (typically about 0.6% (w / v)) is particularly preferred. This buffer renders the dispersion isotonic and, in addition, reduces the tendency of the ester suspended therein to aggregate.

[0093] The preservative is an antimicrobial and antioxidant agent that can be selected from the group consisting of benzoic acid, benzyl alcohol, butylated hydroxyanisole, butylated hydroxytoluene, chlorobutol, gallates, hydroxybenzoates, EDTA, phenol, chlorocresol, metacresol, benzethonium chloride, myristyl-gamma-picolinium chloride, phenylacetate nitrate, and thimerosal. In particular, it is benzyl alcohol, which can be used at a concentration of up to about 2% (w / v), preferably up to about 1.5% (w / v).

[0094] Examples of isotonicity agents include sodium chloride, dextrose, mannitol, sorbitol, lactose, and sodium sulfate. The suspension conveniently contains about 0% to about 10% (w / v) of an isotonicity agent. Mannitol can be used at a concentration of about 0% to about 7%, but more preferably, about 1% to about 3% (w / v), particularly about 1.5% to about 2% (w / v), of one or more electrolytes are used to make the suspension isotonic, presumably because the ions help prevent aggregation of the suspended ester. In particular, the electrolytes of the buffer function as isotonicity agents.

[0095] A particularly desirable characteristic of an injectable formulation relates to the ease with which it can be administered. In particular, such injection should be feasible in as short a time as possible and using as thin a needle as possible. This can be achieved with the aqueous suspensions of the present invention by maintaining a particular viscosity that allows them to be easily drawn into a syringe (e.g., from a vial) and injected through a thin needle. For example, PP1M has a viscosity of less than about 75 mPa·s or less than about 60 mPa·s at room temperature, and a 23G, 1-inch needle or a 22G, 1 1 / 2-inch needle is typically used. For PP3M, a 22G, 1 1 / 2-inch needle or a 22G, 1-inch needle is typically used. And for PP6M, a 20G, 1 1 / 2-inch needle is typically used.

[0096] Ideally, the aqueous suspensions according to the present invention contain as much paliperidone palmitate as can be tolerated and as few other ingredients as possible to keep the injection volume to a minimum.

[0097] Specifically, for PP3M or PP6M, the composition comprises or consists essentially of (a) about 200 to about 500 mg / mL paliperidone palmitate, (b) about 2 to about 25 mg / mL wetting agent, (c) about 2.5 to about 50 mg / mL one or more buffering agents, (d) about 25 to about 150 mg / mL suspending agent, (e) optionally, up to about 2% (w / v) preservative, and (f) water, qs.s. PP3M or PP6M compositions typically have a pH of about 6.0 to about 8.0, preferably about 6.5 to about 7.5.

[0098] In another embodiment, for PP3M or PP6M, the composition comprises or consists essentially of: (a) about 250 to about 400 mg / mL of paliperidone palmitate; (b) about 5 to about 20 mg / mL of a wetting agent; (c) about 5 to about 25 mg / mL of one or more buffering agents; (d) about 50 to about 100 mg / mL of a suspending agent; (e) optionally, up to about 2% (w / v) of a preservative; and (f) water, qs.s. to 100%.

[0099] In another embodiment, for PP3M or PP6M, the composition comprises or consists essentially of: (a) about 280 to about 350 mg / mL paliperidone palmitate; (b) about 8 to about 12 mg / mL wetting agent; (c) about 5 to about 15 mg / mL one or more buffering agents; (d) about 65 to about 85 mg / mL suspending agent; (e) optionally, up to about 2% (w / v) preservative; and (f) water, qs.s. to 100%.

[0100] In certain embodiments, the active ingredient in PP3M or PP6M is paliperidone palmitate (about 312 mg / mL). In certain embodiments, the inactive ingredients in PP3M or PP6M are polysorbate 20 (about 10 mg / mL), polyethylene glycol 4000 (about 75 mg / mL), citric acid monohydrate (about 7.5 mg / mL), sodium phosphate monobasic monohydrate (about 6 mg / mL), sodium hydroxide (about 5.4 mg / mL), and water for injection. An exemplary PP3M is disclosed in Example 2. An exemplary PP6M is disclosed in Example 3.

[0101] In particular, compositions for PP1M comprise or consist essentially of, by weight based on the total volume of the composition, (a) about 1% to 50% (w / v) paliperidone palmitate, (b) about 0.1% to 5% (w / v) humectant, (c) one or more buffering agents, (d) about 0.1% to about 5% (w / v) suspending agent, (e) optionally, up to about 2% (w / v) preservative, and (f) water, qs.s. PP1M compositions typically have a pH of about 6.0 to about 8.0, preferably about 6.5 to about 7.5.

[0102] Composition PP1M preferably comprises or is essentially consisting of, by weight based on the total volume of the composition, (a) about 2% to 40% (w / v) paliperidone palmitate, (b) about 0.25% to 3% (w / v) humectant, (c) one or more buffering agents, (d) about 0.25% to about 3% (w / v) suspending agent, (e) optionally, up to about 2% (w / v) preservative, and (f) water, qs to 100%.

[0103] The composition for PP1M more preferably comprises or consists essentially of, by weight based on the total volume of the composition, (a) about 3% to 20% (w / v) paliperidone palmitate, (b) about 0.5% to 2% (w / v) humectant, (c) one or more buffering agents, (d) about 0.5% to about 2% (w / v) suspending agent, (e) optionally, up to about 2% (w / v) preservative, and (f) water, qs.s.l.

[0104] Specifically for PP1M, the composition comprises or consists essentially of: (a) about 50 to about 250 mg / mL paliperidone palmitate; (b) about 2 to about 25 mg / mL wetting agent; (c) about 2.5 to about 50 mg / mL one or more buffering agents; (d) about 5 to about 75 mg / mL suspending agent; (e) optionally, up to about 2% (w / v) preservative; and (f) water, qs.s. to 100%.

[0105] In another embodiment, for PP1M, the composition comprises or consists essentially of: (a) about 100 to about 200 mg / mL paliperidone palmitate; (b) about 5 to about 20 mg / mL wetting agent; (c) about 5 to about 25 mg / mL one or more buffering agents; (d) about 10 to about 50 mg / mL suspending agent; (e) up to about 2% (w / v) preservative; and (f) water, qs to 100%.

[0106] In another embodiment, for PP1M, the composition comprises or consists essentially of: (a) about 140 to about 180 mg / mL paliperidone palmitate; (b) about 8 to about 16 mg / mL wetting agent; (c) about 5 to about 15 mg / mL one or more buffering agents; (d) about 20 to about 40 mg / mL suspending agent; (e) optionally, up to about 2% (w / v) preservative; and (f) water, qs to 100%.

[0107] Most preferably, the active ingredient in PP1M is paliperidone palmitate (about 156 mg / mL). Most preferably, the inactive ingredients in PP1M are polysorbate 20 (about 12 mg / mL), polyethylene glycol 4000 (about 30 mg / mL), citric acid monohydrate (about 5 mg / mL), sodium dihydrogen phosphate monohydrate (about 2.5 mg / mL), disodium hydrogen phosphate anhydrous (about 5 mg / mL), sodium hydroxide (about 2.84 mg / mL), and water for injection. An exemplary PP1M is disclosed in Example 1.

[0108] Preferably, the aqueous suspension is made under sterile conditions and preservatives are not used. A suitable method for preparing paliperidone palmitate aseptically is described in WO 2006 / 114384, which is incorporated herein by reference.

[0109] A preferred aqueous dosage form contains the following inactive ingredients: polysorbate 20, polyethylene glycol 4000, citric acid monohydrate, disodium hydrogen phosphate anhydrous, sodium dihydrogen phosphate monohydrate, sodium hydroxide, and water for injection.

[0110] Doses or administration are typically expressed in milligrams (mg) of paliperidone palmitate.

[0111] For six-month dosing intervals, paliperidone palmitate doses may be expressed in milligram equivalents (mg eq) of paliperidone, with approximately 1092 and 1560 mg of paliperidone palmitate corresponding to approximately 700 and 1000 mg eq of paliperidone, respectively. For six-month dosing, patients are preferably administered between about 700 mg eq and about 1000 mg eq of paliperidone or between about 1092 mg and about 1560 mg of paliperidone palmitate.

[0112] For administration at three-month intervals, paliperidone palmitate doses may be expressed in mg equivalents (mg eq) of paliperidone, with approximately 273, 410, 546, and 819 mg of paliperidone palmitate corresponding to approximately 175, 263, 350, and 525 mg eq of paliperidone, respectively. For three-month administration, patients are preferably administered between about 175 mg eq and about 525 mg eq of paliperidone or between about 273 mg and about 819 mg of paliperidone palmitate.

[0113] For monthly administration, paliperidone palmitate doses may be expressed in mg equivalents (mg eq) of paliperidone, with approximately 39, 78, 117, 156, and 234 mg of paliperidone palmitate corresponding to approximately 25, 50, 75, 100, and 150 mg eq of paliperidone, respectively. For monthly administration, patients are preferably administered approximately 25 mg eq to approximately 150 mg eq of paliperidone, or approximately 39 mg to approximately 234 mg of paliperidone palmitate, or approximately 100 mg eq to approximately 150 mg eq of paliperidone, or approximately 156 mg to approximately 234 mg of paliperidone palmitate, e.g., approximately 156 mg of paliperidone palmitate or approximately 234 mg of paliperidone palmitate.

[0114] As used herein, the term "antipsychotic" or "antipsychotic medication" means any medication used to reduce or ameliorate psychotic symptoms in patients with a psychotic disorder.

[0115] As used herein, the term "psychiatric patient" refers to a human being who is the subject of treatment or experimentation for a "psychiatric disorder," and "psychiatric disorders" refer to those provided in the Diagnostic and Statistical Manual, Fifth Edition (DSM-5) of the American Psychiatric Association (APA). Those skilled in the art will appreciate that paliperidone esters (e.g., paliperidone palmitate) can be administered to psychiatric patients for all known uses of risperidone. These psychiatric disorders include, but are not limited to, schizophrenia; bipolar disorder; or other conditions manifesting psychosis, aggressive behavior, anxiety, or depression. As described in DSM-5, schizophrenia refers to conditions characterized by schizophrenia, schizoaffective disorder, and schizophreniform disorder. Bipolar disorder refers to conditions characterized by bipolar disorder, including bipolar disorder I and bipolar disorder II. The DSM was developed by the Task Force on Nomenclature and Statistics of the American Psychiatric Association and provides clear descriptions of diagnostic classifications. Pathological mental conditions that may be psychotic or associated with psychotic traits include, but are not limited to, the following disorders characterized in the DSM: See Diagnostic and Statistical Manual of Mental Disorders, Revised, 5th Ed. (2013). Those skilled in the art will recognize that alternative nomenclatures, nosologies, and classification systems for pathological mental conditions exist and that these systems evolve with scientific advances in medicine. Examples of pathological mental conditions that may be treated include mild intellectual disability, moderate intellectual disability, severe intellectual disability, profound intellectual disability, intellectual disability severity not otherwise specified, autistic disorder, Rett's disorder, childhood disintegrative disorder, Asperger's disorder, pervasive developmental disorder not otherwise specified, attention-deficit / hyperactivity disorder combined type, attention-deficit / hyperactivity disorder predominantly inattentive type, attention-deficit / hyperactivity disorder predominantly impulsive type, attention-deficit / hyperactivity disorder NOS,Conduct disorder (childhood-onset childhood-onset and adolescent type, oppositional defiant disorder, disruptive behavior disorder not otherwise specified, isolated aggressive type, conduct disorder, undifferentiated type, Tourette's disorder, chronic motor or vocal tic disorder, transient tic disorder, tic disorder NOS, alcohol-induced delirium, alcohol-withdrawal delirium, alcohol-induced persistent dementia, alcohol-induced psychotic disorder with delusions, alcohol-induced psychotic disorder with hallucinations, amphetamine or similar sympathomimetic intoxication, amphetamine or similar sympathomimetic delirium, amphetamine with delusions amphetamine or similarly acting sympathomimetic drug-induced psychosis, amphetamine or similarly acting sympathomimetic drug-induced psychosis with hallucinations, cannabis-induced psychotic disorder with delusions, cannabis-induced psychotic disorder with hallucinations, cocaine intoxication, cocaine-toxic delirium, cocaine-induced psychotic disorder with delusions, cocaine-induced psychotic disorder with hallucinations, hallucinogen intoxication, hallucinogen-toxic delirium, hallucinogen-induced psychotic disorder with delusions, hallucinogen-induced psychotic disorder with delusions, hallucinogen-induced mood disorder, hallucinogen opioid-induced anxiety disorder, hallucinogen-related disorder not otherwise specified, inhalant poisoning, inhalant poisoning delirium, inhalant-induced persistent dementia, inhalant-induced psychotic disorder with delusions, inhalant-induced psychosis with hallucinations, inhalant-induced mood disorder, inhalant-induced anxiety disorder, inhalant-related disorder not otherwise specified, opioid poisoning delirium, opioid-induced psychotic disorder with delusions, opioid poisoning delirium, opioid-induced psychotic disorder with hallucinations, opioid-induced mood disorder, phencyclidine (PCP) or similarly acting arylcyclohexylamine phencyclidine (PCP) or similarly acting arylcyclohexylamine toxic delirium, phencyclidine (PCP) or similarly acting arylcyclohexylamine induced psychotic disorder with delusions, phencyclidine (PCP) or similarly acting arylcyclohexylamine induced psychotic disorder with hallucinations, phencyclidine (PCP) or similarly acting arylcyclohexylamine induced mood disorder, phencyclidine (PCP) or similarly acting arylcyclohexylamine induced anxiety disorder,Phencyclidine (PCP) or similarly acting arylcyclohexylamine-related disorders, unspecified, sedative, hypnotic, or anxiolytic intoxication, sedative, hypnotic, or anxiolytic toxic delirium, sedative, hypnotic, or anxiolytic withdrawal delirium, sedative, hypnotic, or anxiolytic-induced persistent dementia, sedative, hypnotic, or anxiolytic-induced psychotic disorder with delusions, sedative, hypnotic, or anxiolytic-induced psychotic disorder with hallucinations, sedative, hypnotic, or anxiolytic-induced delirium Other (or unknown) drug-induced mood disorder, sedative-, hypnotic-, or anxiolytic-induced anxiety disorder, other (or unknown) drug intoxication, other (or unknown) drug-induced delirium, other (or unknown) drug-induced persistent dementia, other (or unknown) drug-induced psychotic disorder with delusions, other (or unknown) drug-induced psychotic disorder with hallucinations, other (or unknown) drug-induced mood disorder, other (or unknown) drug-induced anxiety disorder, other (or unknown) drug disorder unspecified, obsessive-compulsive disorder, post-traumatic stress disorder, generalized anxiety disorder, unspecified anxiety disorder, body dysmorphic disorder Harm, hypochondriasis (or hypochondriasis), somatization disorder, unspecified somatoform disorder, somatoform disorder not otherwise specified, intermittent explosive disorder, kleptomania, pathological gambling, pyromania, trichotillomania, and impulse control disorder NOS, schizophreniform disorder, schizoaffective disorder, delusional disorder, brief psychotic disorder, shared psychotic disorder, psychotic disorder due to generalized illness with delusions, psychotic disorder due to generalized illness with hallucinations, psychotic disorder not otherwise specified, major depression, single episode, severe, without psychotic features, major depression, recurrent, severe, without psychotic features Bipolar disorder includes, but is not limited to, bipolar disorder, mixed, severe, without psychotic features, bipolar disorder, mixed, severe, with psychotic features, bipolar disorder, manic, severe, without psychotic features, bipolar disorder, manic, severe, with psychotic features, bipolar disorder, depressive, severe, without psychotic features, bipolar disorder, depressive, severe, with psychotic features, bipolar II disorder, bipolar disorder not otherwise specified, personality disorder, paranoia, personality disorder, schizophrenia, personality disorder, schizophrenic, personality disorder, antisocial, and personality disorder, borderline.

[0116] As used herein, the term "therapeutically effective amount" means that amount of an active compound or pharmaceutical agent that elicits the biological or medicinal response in humans that is sought by a researcher, physician, or other clinician, including alleviation of the symptoms of the disease or disorder being treated.

[0117] Those skilled in the art of treating diseases can determine the effective amount of paliperidone to be administered for the treatment of the diseases listed above. For example, an effective amount of paliperidone for the treatment of psychiatric disorders is about 0.01 mg / kg to about 2 mg / kg of body weight per day. For twice-yearly administration, patients are preferably administered about 700 mg equivalent to about 1000 mg equivalent of paliperidone or about 1092 mg to about 1560 mg of paliperidone palmitate. The amount of paliperidone palmitate is provided in an amount sufficient to provide an equivalent dose of paliperidone after the palmitic acid moiety is removed from the ester (e.g., 1560 mg is equivalent to 1000 mg of paliperidone). For six-month administration, patients are preferably administered about 700 mg equivalent to about 1000 mg equivalent of paliperidone or about 1092 mg to about 1560 mg of paliperidone palmitate.

[0118] The following examples are provided to illustrate some of the concepts described within this disclosure. The examples are considered to describe specific embodiments, but should not be considered to limit the more general embodiments described herein. The following non-limiting examples are provided to further illustrate the invention. Unless otherwise specified, references to PP1M, PP3M, and PP6M in Examples 4-9 refer to the formulations described in Example 1 (PP1M), Example 2 (PP3M), and Example 3 (PP6M).

[0119] Example 1: One-month sustained release formulation (PP1M) Table 2 below contains an exemplary one-month sustained release formulation (PP1M) of paliperidone equivalent to 100 mg / mL suitable for intramuscular (IM) injection.

[0120] [Table 2] 1 Equivalent to PEG400 or MacroGol4000

[0121] PP1M can be provided in pre-filled syringes with dosage strengths ranging from 25 mg equivalent to 150 mg equivalent, obtained by filling the syringes with different volumes of the 100 mg / mL equivalent bulk suspension. Table 3 shows the different dosage strengths, including syringe sizes and nominal fill volumes.

[0122] [Table 3]

[0123] Table 4 lists the syringe components used to package PP1M.

[0124] [Table 4]

[0125] Example 2: Three-month sustained release formulation (PP3M) Table 5 below contains exemplary 3-month sustained release formulations (PP3M) of paliperidone equivalent to 200 mg / mL suitable for intramuscular (IM) injection.

[0126] [Table 5]

[0127] PP3M can be provided in pre-filled syringes with dosage strengths ranging from 175 mg equivalent to 525 mg equivalent, obtained by filling the syringes with different volumes of the 200 mg / mL equivalent bulk suspension. Table 6 shows the different dosage strengths, including syringe sizes and nominal fill volumes.

[0128] [Table 6]

[0129] Table 7 lists the syringe components used to package PP3M.

[0130] [Table 7]

[0131] Example 3: Six-month sustained release formulation (PP6M) Table 8 below contains an exemplary 6-month sustained release formulation (PP6M) of paliperidone palmitate equivalent to 200 mg / mL suitable for intramuscular (IM) injection.

[0132] [Table 8]

[0133] PP6M can be provided in pre-filled syringes with dosage strengths ranging from 700 mg equivalent to 1000 mg equivalent, obtained by filling the syringes with different volumes of the 200 mg / mL equivalent bulk suspension. Table 9 shows the different dosage strengths, including syringe sizes and nominal fill volumes.

[0134] [Table 9]

[0135] Table 10 lists the syringe components used to package the 6-month extended release formulation.

[0136] [Table 10]

[0137] Example 4: A double-blind, randomized, active-controlled, parallel-group study of a 6-month formulation of paliperidone palmitate Test Plan This was a randomized, double-blind, active-controlled, multicenter, interventional, parallel-group, non-inferiority trial. Figure 1 shows a flowchart of the study design. All eligible subjects who progressed without relapse participated in a screening phase (up to 28 days), a maintenance phase including one injection cycle with either PP1M or PP3M (resulting in a phase duration of 1 or 3 months, accordingly), and a double-blind phase (12 months). The double-blind phase was designed to include four injection cycles of PP3M (active control) or two injection cycles of PP6M (study drug alternating with placebo).

[0138] Prior to the maintenance phase, some subjects participated in a transition phase with 1 to 5 injections of oral antipsychotics, injectable risperidone, or PP1M if they entered the study previously initiated but not yet stabilized on PP1M. The combination of the transition and maintenance phases is hereafter referred to as the open-label phase.

[0139] Randomization: 702 subjects were randomized 1:2 to either the PP3M (n=224) or PP6M (n=478) treatment groups. Randomization was stratified by study center and maintenance dose level (intermediate or high).

[0140] Primary Analysis Population for Efficacy: Double-blind Intent-to-Treat (DB ITT) analysis set, defined as all randomized subjects who received at least one dose of double-blind study medication.

[0141] Primary efficacy variable: Percentage of subjects who are relapse-free at the end of the 12-month double-blind phase, based on Kaplan-Meier cumulative estimates of survival.

[0142] Additional Analysis Population for Efficacy: Per-protocol analysis set defined as all randomized subjects who received at least one dose of double-blind study drug and had no major protocol violations that could affect efficacy, i.e., violation of the intended study population, treatment assignment error, or use of excluded medication.

[0143] Safety analysis population: Same as DB ITT.

[0144] Planned sample size: The sample size for the double-blind portion of the study was 549 randomized subjects, based on a determination that would provide a minimum of 80% power for the primary endpoint. The sample size determination included the assumption that the expected survival rate (percentage of subjects remaining recurrence-free at 12 months) in the PP3M group was 85% and the one-sided significance level should be 2.5%. Given these assumptions, 549 subjects randomized in a 1:2 ratio (PP3M:PP6M) were required to demonstrate with 80% power that PP6M was no worse than PP3M with a 10% non-inferiority margin for the percentage of subjects remaining recurrence-free at 12 months.

[0145] Main purpose The primary efficacy objective is to demonstrate that an injection cycle consisting of a single dose of PP6M (700 or 1000 mg equivalent) is more effective than two consecutive injections of PP3M (350 or 525 mg equivalent) in preventing relapse in subjects with schizophrenia who were previously stabilized on corresponding doses of PP1M (100 or 150 mg equivalent) or PP3M (350 or 525 mg equivalent).

[0146] Subject and Treatment Information This study enrolled 841 subjects across 20 countries and 126 centers. Of these, 702 subjects were randomized to one of two treatment groups in a 1:2 ratio (224 to PP3M and 478 to PP6M). Of the 702 subjects in the DB ITT population, 23 subjects were excluded from the per-protocol population, leaving 217 and 462 subjects in the per-protocol analysis sets for the PP3M and PP6M treatment groups, respectively. In the DB ITT analysis population, 521 (74.2%) of the subjects were Caucasian, and 480 (68.4%) were male. The mean (SD) age was 40.8 (11.53) years, ranging from 18 to 69 years.

[0147] Of the 702 randomized subjects, 571 (81.3%) subjects completed the 12-month double-blind period without a recurrent event, and 47 (6.7%) subjects completed the double-blind period with a recurrent event. The most common reason for withdrawal was "subject-initiated withdrawal" by 54 (7.7%) subjects.

[0148] Effectiveness The primary efficacy endpoint was the percentage of subjects who were relapse-free at the end of the 12-month double-blind phase, based on the Kaplan-Meier 12-month cumulative estimate of survival. Statistical analysis tests were performed at a two-sided 0.05 significance level.

[0149] Primary Efficacy Endpoint In the DB ITT population, 11 (4.9%) subjects in the PP3M group and 36 (7.5%) subjects in the PP6M group experienced a relapse event during the 12-month double-blind phase. The estimated difference (95% CI) between treatment groups (PP6M-PP3M) in the percentage of subjects who remained relapse-free was -2.9% (-6.8%, 1.1%). The lower limit of the 95% confidence interval was greater than the prespecified noninferiority margin of -10%, and therefore, PP6M can be declared noninferior to PP3M (Figure 2).

[0150] In the per-protocol analysis population, 10 (4.6%) subjects in the PP3M group and 35 (7.6%) subjects in the PP6M group experienced a recurrent event during the double-blind phase, results similar to those obtained for the DB ITT analysis population, further confirming the non-inferiority of PP6M to PP3M (Figure 3).

[0151] A supplemental analysis was performed for the primary efficacy analysis by including data collected during the follow-up period for subjects who withdrew from the double-blind period. The results are consistent with the primary efficacy analysis.

[0152] For the DB ITT analysis population, the ratio (95% CI) of the instantaneous risk (hazard) of relapse for subjects in the PP6M-treated group during the double-blind phase to the risk for subjects in the PP3M-treated group during the double-blind phase was 1.57 (95% CI: 0.8, 3.08) based on a Cox proportional hazards model with treatment as the only factor. Thus, the hazard rate for PP6M subjects is 1.57 times the hazard rate for PP3M-treated subjects.

[0153] safety Overall, 297 / 478 (62.1%) subjects in the PP6M group and 131 / 224 (58.5%) in the PP3M group experienced at least one TEAE during the double-blind phase. The most common (≥5%) TEAEs during the double-blind phase were weight gain (8.4%), injection site pain (7.7%), headache (6.7%), and upper respiratory tract infection (5.0%) in the PP6M group and weight gain (7.6%), nasopharyngitis (5.8%), and headache (5.4%) in the PP3M group.

[0154] There were one and three deaths in the open-label (combined transition and maintenance) and double-blind periods, respectively. Of the three deaths in the double-blind period, one (0.2%) occurred in the PP6M group and two (0.9%) occurred in the PP3M group.

[0155] Thirty-nine subjects (24 [5.0%] in PP6M and 15 [6.7%] in PP3M) experienced serious TEAEs during the double-blind phase.

[0156] During the double-blind phase, study drug was permanently discontinued due to adverse events with the following incidence across treatment groups: 16 (3.3%) subjects in the PP6M group and 6 (2.7%) subjects in the PP3M group.

[0157] abbreviation DB: double-blind. OL: Open label. MA: Maintain. PANSS: Schizophrenia Positive and Negative Syndrome Scale. PP: Per Protocol. KM: Kaplan-Meier. ITT: intention to treat. SD: standard deviation. CI: confidence interval. TEAE: Treatment-emergent adverse event.

[0158] Example 5: Dosage Conversion The conversion of PP1M or PP3M doses to PP6M doses is set forth in Table 11 below.

[0159] [Table 11]

[0160] Patients who are adequately treated with either PP1M (after at least 4 months of treatment) or PP3M (at least one 3-month injection cycle) and do not require dose adjustment can switch to PP6M. PP6M should be initiated in place of the next scheduled dose of PP1M (±7 days) or PP3M (±14 days). The dose of PP6M should be based on the previous corresponding dose of PP3M or PP1M, as shown in Table 1 above. When transitioning from PP1M to PP6M, it is recommended that the final two doses of PP1M be at the same dosage strength as before starting PP6M to establish a consistent maintenance dose.

[0161] The pretreatment period with PP1M or PP3M ensures that paliperidone plasma concentrations are at or approaching steady state before transitioning to PP6M.

[0162] Model-based simulations suggest that subjects transitioning directly from PP1M (after at least 4 months of treatment) to PP6M have similar paliperidone exposure levels compared to subjects transitioning from PP3M (after at least one 3-month injection cycle) to PP6M. Consequently, subjects may transition directly from PP1M to PP6M without first transitioning to PP3M before initiating PP6M administration.

[0163] Example 6 - Pharmacokinetic profile of PP6M in subjects transitioning from PP1M or PP3M the purpose The objective of this study was to evaluate the pharmacokinetic (PK) profile of PP6M (700 or 1000 mg equivalents) administered into the gluteal muscle in subjects with schizophrenia who had transitioned from the corresponding dose of PP1M (100 or 150 mg equivalents) or PP3M (350 or 525 mg equivalents).

[0164] Subjects and methods This clinical trial was a randomized, double-blind, active-controlled, multicenter, interventional, parallel-group study. All eligible subjects who progressed without relapse participated in a screening phase (up to 28 days), a maintenance phase (resulting in a 1- or 3-month period duration) including one injection cycle of either paliperidone palmitate 1-month (PP1M) or paliperidone palmitate 3-month (PP3M)), and a double-blind phase (12 months). The double-blind phase was designed to include two injection cycles of paliperidone palmitate 6-month (PP6M) (study drug alternating with placebo) or four injection cycles of PP3M (active control). To determine the time course of paliperidone plasma concentrations, multiple pharmacokinetic blood samples were collected during the open-label (PP1M and PP3M) and double-blind (PP3M and PP6M) phases of the study. The objective of the PK evaluation was to characterize plasma paliperidone concentrations and the time course of PK parameters (e.g., maximum and minimum plasma concentrations and their associated timing). Thus, three PK samples were scheduled weekly near the expected peak of paliperidone approximately 1 month after PP6M administration, and six PK samples were scheduled weekly near the end of the 6-month dosing interval.

[0165] result Pharmacokinetics of paliperidone during the maintenance phase after PP1M and PP3M administration After administration of PP1M in the maintenance phase, median t after administration of a 100 mg equivalent dose max , is 8 days, and the median t of 7 days after administration of the 150 mg equivalent dose max After administration of 350 or 525 mg equivalent doses, the median t (PP3M) max Based on visual inspection, C トラフ , C max , and AUC 3M appeared to increase proportionally with dose for both PP1M and PP3M. Dose-normalized mean C トラフ , C max , and AUC 3M were comparable for PP1M and PP3M. The peak / trough ratio was also comparable for PP1M and PP3M.

[0166] Pharmacokinetics of paliperidone during the double-blind phase after administration of PP6M and PP3M. Mean dose-normalized trough concentrations were comparable for PP3M and PP6M on Day 1 (24.6 ng / mL and 25.0 ng / mL, respectively). At later time points, subjects receiving PP6M had approximately 25-28% lower trough concentrations (16.7 ng / mL on Day 183 and 17.3 ng / mL on Day 365) compared with subjects receiving PP3M (22.2 ng / mL on Day 183 and 24.1 ng / mL on Day 365). After the first dose of 350 or 525 mg equivalents of PP3M or 700 or 1000 mg equivalents of PP6M in the double-blind phase, the median t max was comparable for all treatments, i.e., approximately 28 days. Similarly, the median t max were comparable, ranging from 29 to 32 days. トラフ , C max , and AUC 6M appeared to increase dose-proportionally for PP6M (700 or 1000 mg equivalent) after administration of each of the first and second doses in the double-blind phase. Similarly, the PK exposure parameters (Cトラフ , C max , and AUC 6M ) appears to be dose-proportional after the first and third doses of PP3M (350 or 525 mg equivalent) in the double-blind phase. max was slightly higher (1.4-1.5-fold) for PP6M when compared with PP3M. Mean dose-normalized total paliperidone exposure (AUC 6M ) were comparable in the double-blind phase after administration of PP3M and PP6M. The results are summarized in Table 12 below and in Figure 4.

[0167] The median peak-to-trough ratios after PP3M administration in the maintenance and double-blind phases were comparable across doses, ranging from 1.85 to 1.92 and 1.66 to 2.11 in the maintenance and double-blind phases, respectively. The median peak-to-trough ratios after PP6M administration once every 6 months in the double-blind phase ranged from 2.71 to 3.41.

[0168] The median peak-to-trough ratio after PP6M administration during the double-blind phase was comparable across doses and slightly higher after the first dose (range 3.32–3.41) compared with the second dose (range 2.71–3.20).

[0169] After stratification by administration dose, maintenance product, maintenance injection site, sex, age, and creatinine clearance category for several groups, C max , AUC 6M No clinically significant differences were observed as the ranges overlapped due to high intersubject variability for the PP3M and PP6M subgroups.

[0170] Dose-normalized mean paliperidone exposure (C) after PP6M administration during the double-blind phase max , AUC 6M ) was comparable between the subgroups of subjects receiving PP1M or PP3M in the maintenance phase.

[0171] [Table 12] a n=92(C トラフ (AUC 3M and AUC 6M About b n=108(C トラフ About c n=182(C トラフ ) and n=215 (AUC 6M About d n=181(C トラフ ) and n=222 (AUC 6M About e n=82(C トラフ (AUC 3M and AUC 6M About f n=95(C トラフ About g n=160(C トラフ ) and n=185 (AUC 6M About h n=177(C トラフ ) and n=194 (AUC 6M About

[0172] Example 7 - Dosing window for PP6M maintenance treatment Group PK Simulation:C max and C トラフ Effect of prolonging or shortening the administration interval on The tolerability of the dosing windows 2 weeks before and 3 weeks after the regularly scheduled 6-month maintenance injections was assessed as follows. Using a medium dose strength of PP6M (700 mg equivalent), the dosing interval is maintained at a lower C トラフ As shown in Table 13, the median C for injections delayed by 1, 2, and 3 weeks relative to the scheduled 6-month injection after reaching PP6M steady state at 700 mg equiv. トラフdecreased from 15.8 ng / mL to 15.3 (-3.2%), 14.9 (-5.6%), and 14.4 (-8.9%) ng / mL, respectively. Using the highest dose strength of PP6M (1000 mg equivalent), the C max As shown in Table 13, reproduced below, the median C for injections administered 1 week and 2 weeks prior to the scheduled 6-month injection after reaching PP6M steady state at 1000 mg equiv. max increased from 76.1 ng / mL to 76.3 (+0.3%) and 76.6 (+0.7%), respectively.

[0173] [Table 13]

[0174] Duration of clinical response based on median time to relapse in relapse prevention trials PK simulations were performed to evaluate the relationship between the median time to relapse and the time when the median paliperidone concentration decreased to 7.5 ng / mL after administration of the final steady-state dose in each study (oral paliperidone ER 12 mg, PP1M 150 mg equivalent, PP3M 525 mg equivalent, and PP6M 1000 mg equivalent) before the double-blind phase, as shown in Figure 5. A clear delay, lasting several weeks to several months, was observed between the time when the median plasma paliperidone concentration decreased to 7.5 ng / mL and the median time to relapse, i.e., the time when half of the subjects experienced a relapse, while the other half either relapsed later or did not relapse during the study. Thus, the treatment effect was extended beyond that predicted based on the 7.5 ng / mL threshold, and the relapse protection window appears to have further persisted in a positive direction.

[0175] Regarding Figure 5, the simulation shows the decay of paliperidone plasma concentrations after cessation of steady-state dose administration of 1) 12 mg oral paliperidone ER, 2) 150 mg equivalents of PP1M, 3) 525 mg equivalents of PP3M, and 4) 1000 mg equivalents of PP6M, using the higher dose levels for each formulation as representative scenarios. Median time to relapse was calculated based on final Kaplan-Meier estimates from the placebo groups from the following studies: oral paliperidone ER (R076477SCH301), PP1M (R092670PSY3001), and PP3M (R092670PSY3012).

[0176] Thus, a dosing window of up to 2 weeks before and 3 weeks after the target 6-month date for maintenance treatment with PP6M is possible, providing scheduling flexibility and enhancing treatment adherence without loss of efficacy or worsening side effects.

[0177] Example 8: Skipped doses Based on population pharmacokinetic simulations, guidelines are provided for when a dose of PP6M is missed beyond the dosing window. If more than 6 months and less than 3 weeks to a maximum of 8 months have elapsed since the last injection of PP6M, the following restart regimen can be used:

[0178] [Table 14]

[0179] If 8 to 11 months have passed since the last PP6M injection, the following restart regimen can be used:

[0180] [Table 15]

[0181] If more than 11 months have passed since the last PP6M injection, resume treatment with PP1M as described in the PP1M product prescribing information. PP6M can then be resumed after the patient has been adequately treated with PP1M for at least 4 months. To establish a consistent maintenance dose, it is recommended that the final two doses of PP1M be the same dose strength as before resuming PP6M.

[0182] The timing of restarting the regimen after a missed dose and continuing the PP6M maintenance regimen depends on the time interval since the last PP6M dose. These recommendations are based on simulations performed to address missed dose scenarios in patients stabilized on PP6M treatment, as shown in Figures 6-8. The criterion was to achieve a rapid return to paliperidone plasma concentrations similar to those before the missed dose without overshoot due to the applied restart regimen.

[0183] Regarding Figure 6, the solid central line represents the median paliperidone concentration, and the shaded area between the lower and upper dotted lines represents the 90% predictive band. Standard 4-month PP1M treatment in the deltoid muscle (initial dose, followed by maintenance dose) was followed by PP6M administration. A delay in the final PP6M dose is shown, followed by resumption with a single dose of 150 mg equivalent PP1M into the deltoid muscle at the higher dose level. The lightly stippled area represents the range from trough to peak concentrations (defined by the 90% predictive band) before the PP6M administration interval was changed.

[0184] Regarding Figure 7, the solid central line represents the median paliperidone concentration, and the shaded area between the lower and upper dotted lines represents the 90% predictive band. Standard 4-month PP1M treatment in the deltoid muscle (initial dose, followed by a maintenance dose) was followed by PP6M administration. A delay in the final PP6M dose is shown, followed by resumption with two 100 mg equivalent doses of PP1M in the deltoid muscle. The lightly stippled area represents the range from trough to peak concentrations (defined by the 90% predictive band) before the PP6M dosing interval was changed.

[0185] Regarding Figure 8, the solid central line represents the median paliperidone concentration, and the shaded area between the lower and upper dotted lines represents the 90% predictive band. Standard 4-month PP1M treatment in the deltoid muscle (initial dose, followed by maintenance dose) followed by PP6M administration. A delay in the final PP6M dose is shown, followed by resumption as 4 months of intradeltoid PP1M treatment. The lightly stippled area represents the range from trough to peak concentrations (defined by the 90% predictive band) before the PP6M dosing interval was changed.

[0186] These guidelines provide a mechanism by which patients can resume treatment with PP6M if they become completely or partially non-compliant, thereby reducing the need to start treatment anew.

[0187] Example 9 - Weight changes associated with PP6M treatment Based on the findings of the study described in Example 4, patients with schizophrenia stabilized on short-acting paliperidone formulations (PP1M, PP3M) who were switched to a long-acting formulation (PP6M) showed substantially less overall weight gain and more weight loss during the double-blind period (12 months) compared to patients treated with PP3M (active control) during the 12-month double-blind period, as shown in Figure 9. For example, weight gain in the PP6M patient population was minimal (0.1 kg at 12 months, left graph in Figure 9), and a higher percentage of patients showed significant weight loss of more than 7% of their body weight (right graph in Figure 9).

[0188] Further analysis of the data revealed that overweight patients (BMI between 25 and <30) benefited from switching to PP6M (Figure 10), as did patients in the age group 18-25 (Figure 11). While demonstrating a beneficial effect on body weight, the study also demonstrated non-inferior efficacy of PP6M compared with PP3M for the primary endpoint of time to relapse at the end of the 12-month period in both the intention-to-treat and per-protocol analysis sets. The safety profile observed for PP6M was consistent with previous studies of PP1M and PP3M formulations, with no new safety signals emerging.

[0189] Most of the weight gain was reported at the double-blind baseline (Day 1) of the study, indicating that weight gain occurred during the open-label stabilization phase. No increase in weight gain was observed during the double-blind phase (12 months), suggesting a stabilizing effect on average weight gain with less frequent injections. Therefore, patients gaining weight could be switched to PP6M to help stabilize their weight or support weight loss.

[0190] Changes in weight, waist circumference, and BMI from baseline (DB) to the double-blind endpoint were numerically higher in the PP3M group compared with the PP6M group. The mean (SD) increase in weight from baseline (MA) to the double-blind endpoint was 0.10 (4.959) kg and 0.96 (5.103) kg for the PP6M and PP3M groups, respectively.

[0191] From DB baseline to double-blind endpoint, 10.6% of subjects in the PP6M group and 13.2% of subjects in the PP3M group experienced abnormal weight gain (≥7%). 9.1% of subjects in the PP6M group and 6.8% of subjects in the PP3M group experienced abnormal weight loss (≥7%) from DB baseline to double-blind endpoint.

[0192] With reference to Figure 10, the mean (SD) change by baseline (DB) BMI was 0.28 (3.404) kg in the PP6M group and 1.42 (4.456) kg in the PP3M group for subjects with a normal (<25) baseline BMI, -0.53 (4.386) kg in the PP6M group and 1.15 kg (4.814) kg in the PP3M group for overweight (BMI 25 to <30) subjects, and 0.71 (6.448) kg in the PP6M group and 0.30 (5.955) kg in the PP3M group for obese (BMI ≥ 30) subjects.

[0193] With reference to Figure 11, the mean (SD) changes with age were -0.65 (4.955) kg in the PP6M group and 4.33 (7.112) kg in the PP3M group for subjects in the 18-25 year old age group, 0.29 (4.878) kg in the PP6M group and 0.91 (4.600) kg in the PP3M group for subjects in the 25-50 year old group, -0.31 (5.247) kg in the PP6M group and -1.20 (4.763) kg in the PP3M group for subjects in the 51-65 year old group, and 1.76 (4.738) kg in the PP6M group and 5.47 (5.707) kg in the PP3M group for subjects over 65 years old. The invention described herein may include the following aspects. [1] A method for administering paliperidone palmitate to a patient in need of paliperidone palmitate who has received a first dose of paliperidone palmitate extended-release injectable suspension, comprising administering a second dose of the paliperidone palmitate extended-release injectable suspension into the deltoid or gluteal muscle of the patient up to two weeks before or up to three weeks after a time six months after administration of the first dose, wherein there is no intervening dose of paliperidone palmitate between the first and second doses. [2] The method according to [1] above, wherein the second dose is administered to the gluteal muscle. [3] The method according to [1] or [2] above, wherein the patient has a steady-state plasma concentration of paliperidone at the time of administration of the first dose. [4] The method according to any one of [1] to [3] above, wherein the patient requires treatment for psychosis, schizophrenia, schizoaffective disorder, schizophreniform disorder, or bipolar disorder. [5] The method according to [4] above, wherein the patient is in need of treatment for schizophrenia. [6] The method according to any one of [1] to [5] above, wherein the first dose comprises about 1092 mg of paliperidone palmitate or about 1560 mg of paliperidone palmitate. [7] The method according to any one of [1] to [6] above, wherein the second dose comprises about 1092 mg of paliperidone palmitate or about 1560 mg of paliperidone palmitate. [8] The method according to any one of [1] to [7] above, wherein the first dose and the second dose each contain approximately 1092 mg of paliperidone palmitate. [9] The method according to any one of [1] to [7] above, wherein the first dose and the second dose each contain approximately 1560 mg of paliperidone palmitate.

[10] The method according to any one of [1] to [9] above, wherein the plasma concentration of paliperidone in the patient is about 5 to about 50 ng / mL upon administration of the second dose.

[11] The method according to

[10] above, wherein when the first dose contains 1092 mg of paliperidone palmitate, the plasma concentration of paliperidone in the patient is about 5 to about 30 ng / mL upon administration of the second dose.

[12] The method according to

[10] above, wherein when the first dose contains 1560 mg of paliperidone palmitate, the plasma concentration of paliperidone in the patient is about 9 to about 40 ng / mL upon administration of the second dose.

[13] The method according to any one of [1] to

[12] above, wherein the plasma concentration of paliperidone reaches a peak of about 10 to about 150 ng / mL after administration of the second dose.

[14] The method according to

[13] above, wherein when the first dose is 1092 mg of paliperidone palmitate, the paliperidone plasma concentration in the patient reaches a peak of about 10 to about 125 ng / mL after administration of the second dose.

[15] The method according to

[13] above, wherein when the first dose is 1560 mg of paliperidone palmitate, the paliperidone plasma concentration in the patient reaches a peak of about 35 to about 145 ng / mL after administration of the second dose.

[16] The paliperidone palmitate extended release injectable suspension comprises: about 280 mg / mL to about 350 mg / mL of the paliperidone palmitate; about 8 mg / mL to about 12 mg / mL of a wetting agent; one or more buffering agents; about 65 mg / mL to about 85 mg / mL of a suspending agent; The method according to any one of the above [1] to

[15] , further comprising an appropriate amount of water to bring the total to 100%.

[17] The method according to

[16] above, wherein the suspension has a pH of about 6.0 to about 8.0.

[18] The method according to

[16] or

[17] above, wherein the one or more buffering agents comprise citric acid monohydrate, sodium dihydrogen phosphate monohydrate, disodium hydrogen phosphate anhydrous, or sodium hydroxide.

[19] The paliperidone palmitate extended release injectable suspension comprises: Paliperidone palmitate at approximately 312 mg / mL; Approximately 10 mg / mL of polysorbate 20; and about 75 mg / mL of polyethylene glycol 4000.

Claims

1. A composition comprising paliperidone palmitate for use in a method for administering paliperidone palmitate to a patient in need thereof who has been administered a first dose of paliperidone palmitate sustained-release injectable suspension having a six-month dosing interval (PP6M), comprising: the method comprises administering a second dose of the paliperidone palmitate extended release injectable suspension into the patient's deltoid or gluteal muscle, having a six-month dosing interval (PP6M), within a dosing window between up to two weeks before the time point that is six months after administration of the first dose and up to three weeks after the time point that is six months after administration of the first dose; wherein no paliperidone palmitate is administered between said first dose and said second dose; The paliperidone palmitate extended-release injectable suspension comprises about 312 mg / mL of paliperidone palmitate; The paliperidone palmitate sustained-release injectable suspension is an aqueous composition further comprising a suspending agent and a buffer; the first dose comprises about 1092 mg of paliperidone palmitate or about 1560 mg of paliperidone palmitate; A composition wherein the second dose comprises about 1092 mg of paliperidone palmitate or about 1560 mg of paliperidone palmitate.

2. The composition of claim 1 , wherein the second dose is administered to the gluteal muscle.

3. 3. The composition of claim 1 or 2, wherein the patient has a steady-state plasma concentration of paliperidone upon administration of the first dose.

4. The composition of any one of claims 1 to 3, wherein the patient is in need of treatment for psychosis, schizophrenia, schizoaffective disorder, schizophreniform disorder, or bipolar disorder.

5. The composition of claim 4 , wherein the patient is in need of treatment for schizophrenia.

6. 6. The composition of any one of claims 1 to 5, wherein the first dose and the second dose each comprise about 1092 mg of paliperidone palmitate.

7. 6. The composition of any one of claims 1 to 5, wherein the first dose and the second dose each comprise about 1560 mg of paliperidone palmitate.

8. 8. The composition of any one of claims 1 to 7, wherein the patient has a plasma concentration of paliperidone of about 5 to about 50 ng / mL upon administration of the second dose.

9. 9. The composition of claim 8, wherein when the first dose comprises 1092 mg of paliperidone palmitate, the paliperidone plasma concentration in the patient is from about 5 to about 30 ng / mL upon administration of the second dose.

10. 9. The composition of claim 8, wherein when the first dose comprises 1560 mg of paliperidone palmitate, the paliperidone plasma concentration in the patient is from about 9 to about 40 ng / mL upon administration of the second dose.

11. 11. The composition of any one of claims 1 to 10, wherein the paliperidone plasma concentration reaches a peak of about 10 to about 150 ng / mL after administration of the second dose.

12. 12. The composition of claim 11, wherein when the first dose is 1092 mg of paliperidone palmitate, the paliperidone plasma concentration in the patient reaches a peak of about 10 to about 125 ng / mL after administration of the second dose.

13. 12. The composition of claim 11, wherein when the first dose is 1560 mg of paliperidone palmitate, the paliperidone plasma concentration in the patient reaches a peak of about 35 to about 145 ng / mL after administration of the second dose.

14. A composition described in any one of claims 1 to 13, wherein the aqueous composition further comprises one or more of a preservative and an isotonicity agent.

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